Unveiling, Analyzing the Mechanisms of, and Proposing Solutions for Bribery in Japan's Medical Device Sector.

Both public and academic scrutiny of the financial relationships between the medical device industry and the healthcare society occur less frequently than those involving the pharmaceutical industry, and Japan is no exception to these shortcomings. This paper examines the ethical and legal challenges inherent in Japan's medical device industry through the lens of bribery scandals, placing these issues within the broader context of global healthcare corruption. It aims to derive lessons and suggest universal strategies for ethical and legal enhancements. The discussion includes two notable cases: one involving inappropriate transactions between a cancer center and a biliary stent manufacturer, and another concerning a corrupt donation scheme between a medical device company and a university's anesthesiology department, which was found guilty. In our analysis, we also acknowledge the industry's efforts toward compliance and reform to maintain a balanced perspective. The analysis not only highlights the unique culture and structure of the Japanese medical device industry, such as the exploitation of flexible pricing and opaque financial practices but also contrasts these issues with the tightly regulated pharmaceutical industry. This approach reveals both sector-specific challenges and common corruption drivers, enhancing our understanding of why such scandals occur and persist. We propose ethical and compliance-focused business measures such as centralizing donation decisions, limiting the financial independence of marketing divisions, and increasing transparency, alongside adopting mandatory disclosure practices based on successful models from the United States and Europe. By emphasizing integrity and presenting diverse perspectives, this study aims to elevate ethical and legal standards in the medical device industry and improve patient health outcomes worldwide.

The CARMEN-France registry of adult patients with immune thrombocytopenia and autoimmune hemolytic anemia in France.

The CARMEN-France registry is a prospective, multicenter registry in France including adult patients with a new diagnosis of immune thrombocytopenia or of autoimmune immune hemolytic anemia (2402 patients included in December 31, 2023). The recording of clinical, biological and treatment data allows detailed epidemiological and pharmacoepidemiological real-world studies. This review summarizes the CARMEN-France registry protocol, gives examples of studies conducted in the registry, and indicates future directions such as inclusion of patient reported outcomes, linkage with the French national health insurance database and linkage with other registries in Europe.

Large-scale, prospective observational study of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors in a real-world clinical setting.

Background: Regorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after standard chemotherapy in phase III trials in the 3rd-line setting. This large-scale, prospective observational study evaluated the safety and effectiveness of regorafenib in Japanese patients with GIST in a real-world clinical setting. Methods: Patients with GIST received oral regorafenib at a maximum daily dose of 160 mg for weeks 1-3 of each 4-week cycle (dose could be modified at investigator's discretion). The primary objective was to assess safety, particularly significant adverse drug reactions (ADRs), as well as the frequency of occurrence of ADRs, hand and foot syndrome (HFS), discontinuation of treatment due to disease progression and adverse events. A Cox proportional hazards model was used to evaluate associations between OS or time to treatment failure (TTF) and baseline characteristics or HFS. Results: Between August 2013 and March 2021, 143 evaluable patients were enrolled. ADRs occurred in 90.2% of patients and led to treatment discontinuation in 28.3%. The most frequent ADRs were HFS, hypertension, and liver injury. The overall response rate was 11.3% and disease control rate 56.5% (RECIST) based on investigators' assessments. Median OS was 17.4 months (95% CI 14.24-23.68). Median TTF was 5.3 (95% CI 4.0-6.5) months. Improved OS and TTF responses occurred in patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. Conclusion: The outcomes in this real-world study were consistent with those seen in clinical trials. No new safety concerns were identified. Clinical trial registration: https://clinicaltrials.gov, identifier NCT01933958.

Mining of neurological adverse events associated with valbenazine: A post-marketing analysis based on FDA adverse event reporting system.

PURPOSE: Valbenazine is commonly used to treat tardive dyskinesia, and we conducted a pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate neurological safety signals associated with valbenazine. METHODS: Data was collected in FAERS from the second quarter of 2017 to the fourth quarter of 2023 for data cleaning. Neurological adverse event (AE) signals of valbenazine were mined by calculating reporting odds ratios (ROR), information component (IC) and empirical Bayesian geometric mean (EBGM). The serious and non-serious cases and signals were prioritized using a rating scale. RESULTS: The number of neurological AE reports where the primary suspect (PS) drug was 8981 for valbenazine. Significant AE signals were identified by the preferred term (PT) analysis for valbenazine, including somnolence (ROR 19.69), tremor (ROR 15.17), and tardive dyskinesia (ROR 236.91), among which 18 AEs were identified as new signals. Patient age (p < 0.009) and sex (p = 0.197) might be associated with an increased risk of neurological AE severity. Notably, the association between valbenazine and neurological disorders remained when stratified by sex, age, and reporter type. AE timing analysis was performed for the drug and four moderate clinical priority signals [i.e., somnolence, balance disorder, parkinsonism, and akathisia (priorities 7)], showing the same early failure type profiles. CONCLUSIONS: The increase in neurological safety signals is identified in the post-marketing research of valbenazine. Clinicians need to pay attention to not only common AEs but also be alert to new neurological AE signals when using valbenazine.

Real-world safety and effectiveness of intravenous fomepizole in patients with ethylene glycol and methanol poisoning in Japan: results of a 7-year post-marketing surveillance study.

BACKGROUND: Fomepizole is a competitive alcohol dehydrogenase inhibitor used for the treatment of ethylene glycol and methanol poisoning. We evaluated the safety and effectiveness of fomepizole in patients with ethylene glycol or methanol poisoning in Japan. RESEARCH DESIGN AND METHODS: This retrospective post-marketing surveillance study conducted in Japan registered patients who received fomepizole intravenous infusion per the package insert (January 2015-June 2022). Endpoints included adverse drug reactions/infections (ADRs), arterial blood pH, and treatment outcomes. RESULTS: Of 147 patients registered (91 institutions), 131 and 126 were included in the safety and effectiveness analysis set, respectively. Mean age was 43.6 years, and 66.4% were male. Mean time from poison ingestion to treatment was 15.1 hours; 66.4% received concomitant hemodialysis. No serious ADRs were reported. ADRs were reported in seven patients; the most-reported ADR was vomiting (2.3%). Seven patients died, 105 survived without sequelae, and 19 survived with sequelae. Most common sequelae were renal failure or renal dysfunction. Mean arterial blood pH increased to 7.4 by 4 hours of treatment, remaining stable for 24 hours post-treatment. CONCLUSIONS: Fomepizole is well tolerated and helps improve clinical outcomes in patients with ethylene glycol or methanol poisoning in Japan. TRIAL REGISTRATION: Japanese Pharmaceutical Information Center (JapicCTI-152817).

[Considering the Professionalism of Pharmacists from the Perspective of Pharmacists Working in Government and Industry].

Through many years' experience in pharmaceutical administration, we believe that when pharmacists active in various workplaces are involved in research and development (especially clinical development) and post-marketing (especially proper usage and safety measures), they can better meet patients' hopes and expectations based on actual conditions in clinical practice and other settings by means of mutual communication and collaboration. The International Pharmaceutical Federation believes that for the benefit of patients, pharmaceutical researchers and pharmacists should work together and that the three pillars of research, practice, and education are closely and inseparably integrated. In today's rapidly evolving society, it is necessary-and beneficial-for pharmacists working in both government and industry to be better connected toward achieving better health care.

Safety and effectiveness of mogamulizumab in relapsed or refractory CC chemokine receptor 4-positive peripheral T-cell lymphoma and relapsed or refractory cutaneous T-cell lymphoma: A post-marketing surveillance in Japan.

Mogamulizumab is a humanized antibody targeting CC chemokine receptor 4 (CCR4). This post-marketing surveillance was conducted in Japan as a regulatory requirement from 2014 to 2020 to ensure the safety and effectiveness of mogamulizumab in patients with relapsed or refractory (r/r) CCR4-positive peripheral T-cell lymphoma (PTCL) or r/r cutaneous T-cell lymphoma (CTCL). Safety and effectiveness data were collected for up to 31 weeks after treatment initiation. A total of 142 patients were registered; safety was evaluated in 136 patients. The median number of doses was 8.0 (range, 1-18). The main reasons for treatment termination were insufficient response (22.1%) and adverse events (13.2%). The frequency of any grade adverse drug reaction was 57.4%, including skin disorders (26.5%), infections and immune system disorders (16.2%), and infusion-related reactions (13.2%). Graft-versus-host disease, grade 2, developed in one of two patients who underwent allogeneic-hematopoietic stem cell transplantation after receiving mogamulizumab. Effectiveness was evaluated in 131 patients (103 with PTCL; 28 with CTCL). The best overall response rate was 45.8% (PTCL, 47.6%; CTCL, 39.3%). At week 31, the survival rate was 69.0% (95% confidence interval, 59.8%-76.5%) [PTCL, 64.4% (54.0%-73.0%); CTCL, 90.5% (67.0%-97.5%)]. Safety and effectiveness were comparable between patients <70 and ≥ 70 years old and between those with relapsed and refractory disease. The safety and effectiveness of mogamulizumab for PTCL and CTCL in the real world were comparable with the data reported in previous clinical trials. Clinical Trial Registration.

Safety profile of lasmiditan: a retrospective post-marketing pharmacovigilance study based on the real-world data of FAERS database.

BACKGROUND: Lasmiditan offers a promising option for the treatment of migraines, particularly for individuals with cardiovascular concerns. It is crucial to gather comprehensive safety information of lasmiditan through large-scale post market monitoring. RESEARCH DESIGN AND METHODS: This study assessed the safety profile of lasmiditan based on real-world data of FDA Adverse Event Reporting System (FAERS) database. Four disproportionality analysis methods were applied to mining the significant signals. The differences in adverse event signals among different subgroups were investigated concerning race, sex, age, weight, dose, and concomitant drug. RESULTS: A total of 820 reports and 1,661 adverse events with lasmiditan as the primary suspected drug were identified. Two new adverse event signals related to nervous system disorders emerged. Females and males were more likely to develop paresthesia and dizziness, respectively. Most common adverse events were more likely to occur in the elderly patients and at high doses. CONCLUSIONS: It is essential to be vigilant about the relation of potential nervous system disorders with lasmiditan. The importance of heightened clinical vigilance regarding paresthesia in females and dizziness in males was underscored. Additionally, it is advised to administer a lower initial dose for elderly patients.

Safety of nivolumab monotherapy in five cancer types: pooled analysis of post-marketing surveillance in Japan.

BACKGROUND: Nivolumab has been approved for treating ≥ 10 cancer types. However, there is limited information on the incidence of rare, but potentially serious, treatment-related adverse events (TRAEs), as well as notable TRAEs in patients with certain medical disorders or older patients in Japan. METHODS: We performed pooled analyses of data from published post-marketing surveillance in Japan of nivolumab monotherapy for patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and gastric cancer to determine the frequencies of 20 categories of TRAEs of special interest overall and in patient groups with higher perceived safety risks (history of autoimmune disease, interstitial lung disease, tuberculosis, or hepatitis B/C; patients vaccinated during nivolumab treatment; and older patients [≥ 75 years]). RESULTS: The overall population comprised 7421 patients treated with nivolumab. TRAEs were reported in 49.1% of patients, with grade ≥ 3 TRAEs in 16.7%. Endocrine disorders (14.4%), hepatobiliary disorders (10.9%), and interstitial lung disease (7.0%) were the three most common categories (any grade). The incidences of rare TRAEs with high risk of becoming serious, which occurred in < 1% of patients, were consistent with those in previous reports. The frequencies of TRAEs were not markedly increased in the specified patient groups relative to the overall population. CONCLUSION: To our knowledge, this is the largest study examining the safety of nivolumab-treated patients in real-world clinical practice including rare but potentially serious TRAEs. We found no new signals in the safety of nivolumab among the patient groups relative to the overall population, and no additional safety measures are required in these groups. Trial registration UMIN000048892 (overall analysis), JapicCTI-163272 (melanoma), Japic-163271 (non-small cell lung cancer), JapicCTI-184071 (head and neck cancer), JapicCTI-184070 (gastric cancer), and JapicCTI-184069 (renal cell cancer).

A Longitudinal Analysis of Black Box Warnings: Trends and Implications for Drug Safety.

A black box warning, signaling potential life-threatening adverse effects of medications or medical devices, is crucial for public and healthcare professional awareness. Comprehending and adhering to these warnings can prevent serious harm. This review aims to elucidate their significance. Data on drugs with black box warnings were collected from the Food and Drug Administration's (FDA's) official website using the search term 'Boxed warnings' from January 1, 2015, to January 31, 2024. A Microsoft Excel spreadsheet (Microsoft Corporation, Redmond, WA, USA) containing black box warnings for this period was downloaded from the FDA's website. Additional parameters, such as drug class and whether the warnings were new or existing, were added to the downloaded spreadsheet. The collected data were organized by year, categorizing new and existing warnings, along with details on the evidence source, system-wise classification, and black box warnings for commonly used drugs, including their clinical significance. Results show that in the past decade, 40% of black box warnings were issued in 2023, followed by 12% in 2022. Most warnings (67%) comprised existing ones with minor revisions while 29% were new. Nine existing warnings were removed during the period. Post-marketing studies predominantly provided evidence for these warnings. Neuropsychiatric concerns like addiction potential (31%), suicidal tendency (7%), and hypersensitivity reactions (12%) were the frequently encountered black box warnings. Black box warnings play a crucial role in highlighting the serious adverse effects of medications. Neuropsychiatric warnings have been frequent over the past decade. Awareness of these warnings is essential to prevent adverse effects and enhance patient care, especially concerning drugs like guaifenesin/hydrocodone bitartrate, zolpidem, and montelukast commonly encountered in clinical practice.

Applications of Blockchain-Based Technology for Healthcare Devices Post-market Surveillance.

The volume of data analysis for medical device post-market surveillance (PMS) has increased dramatically in recent years. It is the more stringent and intricate regulatory criteria of the health authorities that are meant to improve the medical device safety review. As regulators scrutinize device safety more closely, proactive approaches to PMS processes are becoming crucial. To solve some of the issues brought on by this shifting regulatory landscape, new technologies have been investigated. This study envisages the technical features of blockchain technology (BCT) and its role in enhancing the PMS for medical devices. To address the aforementioned challenges, our model involves the establishment of a secure, permissioned blockchain for PMS data management, utilizing a proof-of-authority consensus mechanism. This blockchain framework will exclusively permit a carefully vetted and designated set of participants to validate transactions and record them in the PMS data ledger. The utilization of BCT holds the potential to introduce enhanced efficiency and provide several advantages to the various stakeholders involved in the PMS procedure, including its potential to support emerging regulatory efforts.

Safety and effectiveness of apremilast in Japanese patients with psoriatic disease: Results of a post-marketing surveillance study.

The safety and efficacy of apremilast in psoriatic disease has been demonstrated in clinical trials, including in Japanese patients. This post-marketing surveillance study was conducted after approval of apremalast in Japan in 2016 to evaluate the safety and effectiveness of the drug in Japanese patients with plaque psoriasis (PsO) and psoriatic arthritis (PsA) in routine clinical practice. Patients (enrolled between September 1, 2017, and August 31, 2019), were observed for 12 months after apremilast treatment initiation or until discontinuation or withdrawal. Safety was assessed by evaluating adverse reactions (ARs) and serious ARs. Effectiveness measures in PsO included the proportion of patients who achieved global improvement and Physician's Global Assessment (PGA) scores of 0/1 and the change from baseline in the Dermatology Life Quality Index (DLQI) after 6 and 12 months treatment. The safety analysis set included 1063 patients (PsO, n = 992; PsA, n = 127). ARs and serious ARs were reported in 29.4% and 0.7% of patients, respectively; most occurred <1 month after apremilast initiation. There were no reports of fatal ARs, serious infections, hypersensitivity, or vasculitis. No new safety signals were identified. Among the key survey items, gastrointestinal disorders were the most common ARs (21.3%). In patients with PsO, after 6 and 12 months of treatment, effectiveness rates of achieving highly effective or effective global improvement of were 90.9% and 93.8%; PGA 0/1 was achieved by 42.7% and 58.1% of patients; mean decrease from baseline in total DLQI score was 4.2 (p < 0.0001) and 5.7 (p < 0.0001), respectively. Effectiveness was evaluated in a small number of patients with PsA for some measures; after 6 and 12 months of treatment, improvements were observed in global improvement effectiveness rates, Disease Activity Score in 28 Joints score, Visual Analog Scale score, and DLQI score. We conclude that orally administered apremilast was well tolerated and effective in Japanese patients with PsO and/or PsA enrolled in this post-marketing surveillance study.

Prolonged Diabetic Ketoacidosis Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Postmarketing Cases.

OBJECTIVE: To describe reported cases of prolonged or relapsed ketoacidosis (KA) in adults with type 2 diabetes receiving treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors. METHODS: We performed a search of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System and medical literature, to identify our case series and to characterize cases of prolonged KA, relapsed KA, or persistent ketonemia, persistent ketonuria and/or persistent glucosuria in adults receiving SGLT2 inhibitors. RESULTS: The FDA identified 29 unique cases of prolonged or relapsed KA, as well as related terms persistent ketonemia, persistent ketonuria, and persistent glucosuria, in patients receiving SGLT2 inhibitors through July 26, 2022. The patients ranged in age from 26 to 85 years. Treatment duration of KA ranged from 3 to 20 days. There were 7 cases of relapsed KA when insulin was reduced or transitioned to subcutaneous route. Arterial pH value was 7.0 or below in 4 patients, and the median pH was 7.1. Associated factors for prolonged or relapsed KA included surgery, decreased caloric intake, and ketogenic/carbohydrate restricted diet. A total of 62% of the patients were taking 3 or more glycemic control medications including the SGLT2 inhibitor. All patients with sufficient follow-up information recovered. CONCLUSION: Although KA is a well-known risk associated with SGLT2 inhibitors, this case series demonstrated the potential for prolonged or recurrent KA events with serious outcomes. These cases informed updates to FDA's prescribing information to inform prescribers of this risk.

Safety of cardiovascular disease drugs approved between 2014 and 2021 in the US: a pharmacovigilance analysis.

BACKGROUND: Recently FDA-approved drugs for cardiovascular disease (CVD) require robust post-marketing surveillance. The objective of this study was to assess their safety using a large pharmacovigilance database. RESEARCH DESIGN AND METHODS: We analyzed adverse event (AE) reports for 17 drugs approved from 2014 to 2021, utilizing the FDA Adverse Event Reporting System (FAERS). Descriptive and disproportionality analyses were conducted by estimating the reporting odds ratio (ROR) and its 95% confidence interval. RESULTS: Among the 43,664,773 AE reports 97,702 (0.22%) were related to newly approved CVD drugs. No AEs were reported for finerenone and evinacumab. The results from the disproportionality analyses revealed potential risks of acute kidney injury (ROR = 8.24, 95% CI: 6.05-11.22), cardiac failure (ROR = 4.80, 95% CI: 3.82-6.05), and hypotension (ROR = 3.98, 95% CI: 3.44-4.61) among sacubitril/valsartan users. Additionally, ivabradine was found to be associated with tachycardia (ROR = 11.94, 95% CI: 8.35-17.08), abnormal feeling (ROR = 4.40, 95% CI: 2.70-7.18), and dizziness (ROR = 2.56, 95% CI: 1.68-3.90). CONCLUSIONS: This study identified specific safety concerns related to recently approved CVD drugs. Further research is required to understand the underlying mechanisms and clinical implications of these findings.

Real-world safety and effectiveness of anamorelin for cancer cachexia: Interim analysis of post-marketing surveillance in Japan.

BACKGROUND: Anamorelin was approved in Japan in 2021 to treat cancer cachexia associated with non-small cell lung, gastric, pancreatic, or colorectal cancers. Post-marketing surveillance is being conducted to evaluate the real-world safety and effectiveness of anamorelin. METHODS: This prospective, observational surveillance registered all patients who started treatment with anamorelin after April 21, 2021. Hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were defined as main safety specifications. Body weight (BW) and appetite were assessed as effectiveness specifications. RESULTS: This analysis was based on data as of January 21, 2023. The safety and effectiveness analysis sets included 6016 and 4511 patients, respectively. Treatment-related adverse events in ≥1% of patients were hyperglycemia (3.9%) and nausea (2.6%). The incidences of hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were 4.8%, 1.2%, and 1.1%, respectively. The mean changes (standard error [SE]) in BW from baseline to weeks 3, 12, 24, and 52 were 0.64 (0.05) kg, 1.19 (0.12) kg, 1.40 (0.21) kg, and 1.42 (0.39) kg, respectively. The mean changes (SE) in Functional Assessment of Anorexia/Cachexia Treatment 5-item Anorexia Symptom Scale total scores from baseline to weeks 3, 12, 24, and 52 were 3.2 (0.09), 4.8 (0.18), 5.2 (0.30), and 5.3 (0.47), respectively, exceeding the clinically meaningful improvement score (2.0 points). CONCLUSION: The overall safety of anamorelin raised no new safety concerns, although continued caution may be required for hyperglycemia and nausea. Improvements in BW and appetite were also observed in real-world clinical settings.

Real-world outcomes of ponatinib treatment in 724 patients with CML and Ph+ ALL: a post-marketing surveillance study with a special interest in arterial occlusive events in Japan.

BACKGROUND: In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase inhibitors and patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. METHODS: We conducted a post-marketing all-case surveillance to study the safety and efficacy of ponatinib in clinical practice, focusing on arterial occlusive events. RESULTS: Data from 724 patients were collected for 2 years from the initiation of ponatinib. The arterial occlusive events were reported in 6.49% (47/724) with an exposure-adjusted incidence rate of 6.8/100 person-years. The risks associated with arterial occlusive events were age and comorbidities including hypertension and diabetes. At 104 weeks, the cumulative major molecular response rate in patients with chronic-phase chronic myeloid leukemia was 67.2% and the complete cytogenetic response in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was 80.0%. Furthermore, the estimated 1-year overall survival rate was 98.5% for chronic-phase chronic myeloid leukemia and 68.6% for Philadelphia chromosome-positive acute lymphoblastic leukemia. CONCLUSIONS: This surveillance demonstrated that ponatinib has a favorable safety and efficacy profile in Japanese patients and also showed the necessity of closely monitoring arterial occlusive events in older adults and patients with predisposing factors for atherosclerosis.

Thrombosis and meningococcal infection rates in pegcetacoplan-treated patients with paroxysmal nocturnal hemoglobinuria in the clinical trial and postmarketing settings.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated hemolysis and thrombosis. Complement component 5 (C5) inhibitors have decreased PNH-related thrombosis rates and reduced mortality compared with those of age-matched controls. A small but significantly increased risk of life-threatening Neisseria infections, especially N meningitidis, represents a long-term safety risk of complement inhibition. Objectives: To evaluate the rates of thrombosis and meningococcal infections in patients with PNH treated with the complement component 3-targeted therapy pegcetacoplan. Methods: Cumulative patient-year exposure to pegcetacoplan was calculated, and thrombotic events and meningococcal infections were reviewed in 7 clinical trials and in the postmarketing setting. The clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae, N meningitidis, and Haemophilus influenzae before pegcetacoplan use; the label allowed for prophylactic antibiotic use if pegcetacoplan must be administered before vaccination. Results: As of November 13, 2022, 464 patients with PNH had 619.4 patient-years of pegcetacoplan exposure in completed/ongoing clinical trials and the postmarketing setting. Seven thrombotic events were reported: 5 in clinical trials (2 in the same patient) and 2 in the postmarketing setting. The overall thrombosis rate was 1.13 events per 100 patient-years (clinical trials: 1.22 events/100 patient-years in 409.4 years; postmarketing: 0.95 events/100 patient-years in 210.0 years). No infections with meningococcal bacteria were reported. Conclusion: Event rates for thrombosis were comparable between pegcetacoplan and previously reported rates of C5 inhibitors in patients with PNH, and no cases of meningococcal infection were reported with pegcetacoplan. Continued follow-up is required.

Matching study design to prescribing intention: The prevalent new-user design for studying abuse-deterrent formulations of opioids.

PURPOSE: In drug studies, research designs requiring no prior exposure to certain drug classes may restrict important populations. Since abuse-deterrent formulations (ADF) of opioids are routinely prescribed after other opioids, choice of study design, identification of appropriate comparators, and addressing confounding by "indication" are important considerations in ADF post-marketing studies. METHODS: In a retrospective cohort study using claims data (2006-2018) from a North Carolina private insurer [NC claims] and Merative MarketScan [MarketScan], we identified patients (18-64 years old) initiating ADF or non-ADF extended-release/long-acting (ER/LA) opioids. We compared patient characteristics and described opioid treatment history between treatment groups, classifying patients as traditional (no opioid claims during prior six-month washout period) or prevalent new users. RESULTS: We identified 8415 (NC claims) and 147 978 (MarketScan) ADF, and 10 114 (NC claims) and 232 028 (MarketScan) non-ADF ER/LA opioid initiators. Most had prior opioid exposure (ranging 64%-74%), and key clinical differences included higher prevalence of recent acute or chronic pain and surgery among patients initiating ADFs compared to non-ADF ER/LA initiators. Concurrent immediate-release opioid prescriptions at initiation were more common in prevalent new users than traditional new users. CONCLUSIONS: Careful consideration of the study design, comparator choice, and confounding by "indication" is crucial when examining ADF opioid use-related outcomes.

Eculizumab for adult patients with atypical haemolytic-uraemic syndrome: full dataset analysis of Japanese post-marketing surveillance.

BACKGROUND: Eculizumab has been approved for atypical haemolytic-uraemic syndrome (aHUS) in Japan since 2013. Post-marketing surveillance enrolled patients with aHUS who received ≥ 1 dose of eculizumab to assess eculizumab safety and effectiveness. METHODS: We evaluated serious adverse events and effectiveness endpoints, i.e., haematologic normalization, a decrease of ≥ 25% in serum creatinine (sCr) levels, and complete thrombotic microangiopathy (TMA) response in adult patients with aHUS without other underlying diseases. In addition, the difference of baseline characteristics between patients who did and did not meet effectiveness endpoints was examined. RESULTS: In this safety and effectiveness analysis, 79 adult patients were included; median age was 54.0 years, median treatment duration was 30 weeks. Total exposure time of eculizumab was 75.51 patient-years, and 94 serious adverse events were reported in 39 patients. No unexpected safety signals were identified in this population. Mean platelet count, lactate dehydrogenase and estimated glomerular filtration rate significantly improved after 7 days of treatment. Complete TMA response, haematologic normalization and the improvement of sCr levels were met by 35.3%, 40.4% and 51.3% of patients, respectively. Median treatment duration was shorter in patients who did not achieve complete TMA response (6 weeks) than in patients who did (114 weeks). Multivariate analysis suggested that the time from the most recent TMA episode to start of eculizumab treatment was negatively associated with kidney function improvement. CONCLUSIONS: No unexpected safety signals of eculizumab were identified in Japanese patients with aHUS in a real-world setting. Renal outcomes were negatively associated with the time from the most recent TMA episode to the initiation of eculizumab treatment.

Safety of sarilumab in a Japanese population with rheumatoid arthritis by age group: Data from an interim analysis of a post-marketing surveillance study.

OBJECTIVES: Using data from a post-marketing surveillance, this interim subgroup analysis investigated the safety of sarilumab in younger (<65 years) and older patients (≥65 and ≥75 years) with rheumatoid arthritis. METHODS: During this interim analysis, patients who were treated with sarilumab in Japan were enrolled between June 2018-2021. Data collected by 12 January 2022 were analysed, with adverse drug events monitored over 52 weeks. RESULTS: Of 972 patients with available data, proportion of patients aged <65 years, ≥65 years and ≥75 years were 40.8%, 59.2% and 27.8%, respectively. Most patients (95.5%) received the standard 200 mg dose of sarilumab as the initial dose. Adverse drug reactions were reported in 24.6% of patients, with serious events accounting for 6.4% of cases. No malignancy and low incidences of adverse drug reactions of special interest were reported across all age groups (<65 years, 7.8%; ≥65 years, 8.2%; ≥75 years, 8.5%). When stratified by absolute neutrophil count above and below the lower limit of normal, there were no numerical differences in incidences of serious and non-serious infections between age groups. CONCLUSIONS: Regardless of age, sarilumab therapy was well tolerated by patients with rheumatoid arthritis, with no new safety signals reported in this study.