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.

Long-Term Safety and Effectiveness of Tacrolimus in Patients With Lupus Nephritis in Japan: 10-Year Analysis of the Real-World TRUST Study.

OBJECTIVE: To assess the long-term safety and effectiveness of tacrolimus as maintenance therapy in patients with lupus nephritis (LN) receiving treatment in real-world clinical settings in Japan. METHODS: An open-label, noncomparative, observational, prospective postmarketing surveillance study was conducted in 1395 patients with LN receiving maintenance treatment with tacrolimus at 278 medical institutions across Japan over a period of 10 years. Tacrolimus continuation rate and cumulative incidence of adverse drug reactions (ADRs), relapse, progression to renal failure, and progression to dialysis were calculated using Kaplan-Meier analysis. RESULTS: Safety data were available for 1355 patients, almost half (49.3%) of whom remained on tacrolimus for the full 10 years of follow-up. A significant reduction in mean (SD) daily oral corticosteroid dose was observed from 16.0 (9.7) mg/day at 4 weeks after initiation of tacrolimus treatment to 7.2 (4.4) mg/day at year 10 (P < 0.001). The most frequently reported serious ADRs were infections (reported for 131 [9.7%] patients). Except for infections, no marked increase in the incidence of any other ADRs was seen over time, including renal impairment, malignant tumors, and cardiac dysfunction. Renal function was generally well maintained over the 10 years of follow-up. At year 10, cumulative rates of relapse, renal failure, and dialysis were 44.5%, 12.2%, and 4.5%, respectively. CONCLUSION: Tacrolimus was effective and generally well tolerated as maintenance therapy for LN in a large cohort of patients in Japan followed for 10 years, almost half of whom remained on therapy for the entire duration of follow-up. (ClinicalTrials.gov: NCT01410747).

Safety of recombinant activated factor VII for treatment of breakthrough bleeds in patients with congenital haemophilia A and inhibitors receiving emicizumab prophylaxis: Review of the real-world evidence.

BACKGROUND: Emicizumab is used as a subcutaneous prophylaxis for prevention of bleeding episodes in patients with haemophilia A (HA) with and without inhibitors. While low bleeding rates were observed in clinical trials, patients still experience breakthrough bleeds (BTBs) with emicizumab in the real-world. Current guidelines recommend use of recombinant activated factor VII (rFVIIa) for treatment of BTBs in patients with inhibitors. Due to thrombotic events observed in the HAVEN 1 study, activated prothrombin complex concentrate (aPCC) should be used with caution. OBJECTIVES: The objective of this review is to identify and discuss real-world data on the frequency of BTBs and the safety of concomitant rFVIIa use in patients with inhibitors on emicizumab prophylaxis. METHODS: A search of the following databases was conducted on 15 July 2022: BIOSIS Previews® , Current Contents Search® , Embase® , MEDLINE® . Search terms included 'real world', 'haemophilia A', and 'emicizumab'. RESULTS AND CONCLUSIONS: Eleven relevant publications were identified (seven original research articles and four congress abstracts). The frequency of BTBs specifically for HA patients with inhibitors was described in three publications with 5%-56% patients on emicizumab reporting ≥1 bleeding episode. Treatment of these BTBs appeared to be managed according to relevant guidelines. Importantly, no thrombotic complications occurred during concomitant rFVIIa use. Due to the nature of real-world studies, direct comparison of the results between studies is limited. However, real-world data show that BTBs in inhibitor patients during emicizumab prophylaxis can be safely treated with rFVIIa.

Improving Methods of Identifying Anaphylaxis for Medical Product Safety Surveillance Using Natural Language Processing and Machine Learning.

We sought to determine whether machine learning and natural language processing (NLP) applied to electronic medical records could improve performance of automated health-care claims-based algorithms to identify anaphylaxis events using data on 516 patients with outpatient, emergency department, or inpatient anaphylaxis diagnosis codes during 2015-2019 in 2 integrated health-care institutions in the Northwest United States. We used one site's manually reviewed gold-standard outcomes data for model development and the other's for external validation based on cross-validated area under the receiver operating characteristic curve (AUC), positive predictive value (PPV), and sensitivity. In the development site 154 (64%) of 239 potential events met adjudication criteria for anaphylaxis compared with 180 (65%) of 277 in the validation site. Logistic regression models using only structured claims data achieved a cross-validated AUC of 0.58 (95% CI: 0.54, 0.63). Machine learning improved cross-validated AUC to 0.62 (0.58, 0.66); incorporating NLP-derived covariates further increased cross-validated AUCs to 0.70 (0.66, 0.75) in development and 0.67 (0.63, 0.71) in external validation data. A classification threshold with cross-validated PPV of 79% and cross-validated sensitivity of 66% in development data had cross-validated PPV of 78% and cross-validated sensitivity of 56% in external data. Machine learning and NLP-derived data improved identification of validated anaphylaxis events.

Cases of less-than-expected FVIII activity in previously treated patients during post-marketing surveillance of N8-GP.

INTRODUCTION: Turoctocog alfa pegol (N8-GP) is a glycoPEGylated, extended half-life (EHL), human recombinant factor VIII (FVIII) approved for the treatment and prevention of bleeding episodes in patients with haemophilia A. Since its launch in August 2019, > 800 patients have been treated worldwide. AIM: To present data from identified post-marketing cases of less-than-expected FVIII activity in previously treated patients (PTPs) without inhibitors after switching to N8-GP. METHODS: The post-marketing safety database was searched using keywords such as 'coagulation FVIII level decreased'. Identified cases reported prior to 13 October 2021 were included in this report. Cases in which patients had FVIII inhibitors were excluded. RESULTS: Here we report 14 cases of less-than-expected FVIII activity. Details varied greatly amongst the cases. At presentation, FVIII activity ranged from 1% (15 min post-dose) to 51% (2 days post-dose). Seven patients experienced bleeding episodes after switching to N8-GP with heterogeneity in bleeding presentations. Six out of seven patients who were tested for anti-PEG IgG and/or IgM antibodies were positive. In all known cases, FVIII activity returned to the expected range when switched to an alternative FVIII replacement product. CONCLUSION: In conclusion, the 14 reported cases of less-than-expected FVIII activity, without presence of detectable FVIII inhibitors, presented with heterogenous characteristics, and wide variations in FVIII activity and anti-PEG antibody titre. FVIII activity returned to the expected range after switching to alternative FVIII products. In line with WFH guidelines, monitoring of FVIII activity can ensure FVIII activity in the expected range. The safety surveillance of N8-GP continues.

Preventive Pharmacovigilance: timely and precise prevention of adverse events through person-level patient screening and dose-level product surveillance.

The goal of pharmacovigilance (PV) is to prevent adverse events (AEs) associated with drugs and vaccines. Current PV programs are of a reactive nature and rest entirely on data science, i.e., detecting and analyzing AE data from provider/patient reports, health records and even social media. The ensuing preventive actions are too late for people who have experienced AEs and often overly broad, as responses include entire product withdrawals, batch recalls, or contraindications of subpopulations. To prevent AEs in a timely and precise manner, it is necessary to go beyond data science and incorporate measurement science into PV efforts through person-level patient screening and dose-level product surveillance. Measurement-based PV may be called 'preventive pharmacovigilance', the goal of which is to identify susceptible individuals and defective doses to prevent AEs. A comprehensive PV program should contain both reactive and preventive components by integrating data science and measurement science.

Safety and effectiveness of lusutrombopag in patients who have chronic liver disease with thrombocytopenia and undergoing invasive procedures: Real-world post-marketing surveillance in Japan.

AIM: Lustrombopag has been approved for the treatment of thrombocytopenia in patients with chronic liver diseases who are scheduled to undergo an invasive procedure. Here, we report the final results of a post-marketing surveillance assessing the safety and effectiveness of lusutrombopag in Japan. METHODS: This multicenter, prospective, real-world surveillance collected data from case report forms between October 2016 and May 2021. The observation period was 2 months after the first day of lusutrombopag treatment. Safety and effectiveness (proportion of patients avoiding preoperative platelet transfusion and responders who achieved platelet count increase from baseline) were assessed. RESULTS: The safety analysis set included 1033 (100.0%), 130 (12.6%), and 14 (1.4%) patients who received one or more, two or more, and three or more treatment cycle(s), and 482 (48.9%), 457 (46.3%), and 43 (4.4%) patients who were Child-Pugh class A, B, and C, respectively. The most common serious adverse drug reactions were portal vein thrombosis, pancytopenia, and white blood cell count decrease, reported in 14 (1.36%), three (0.29%), and two (0.19%) patients, respectively. The incidence of adverse drug reactions was not higher in patients with Child-Pugh class C or those undergoing retreatment cycles compared with other Child-Pugh classes or the first treatment cycle, respectively. During the observation period of the first treatment cycle, 94.7% (889/939) of patients avoided preoperative platelet transfusion and 82.8% (741/895) of the patients met the responder criteria. CONCLUSIONS: This surveillance study further supports the safety and effectiveness of lusutrombopag in a broad range of patients with chronic liver diseases undergoing planned invasive procedures. CLINICAL TRIAL REGISTRATION: JapicCTI-163432.

The safety profile of nivolumab plus ipilimumab combination therapy in Japanese patients with renal cell carcinoma: results from post-marketing surveillance.

BACKGROUND: Nivolumab and ipilimumab combination therapy is approved in Japan for unresectable or metastatic renal cell carcinoma. Because the clinical trials supporting the approval of nivolumab and ipilimumab combination therapy included relatively few Japanese patients, post-marketing surveillance was implemented to collate further safety data for nivolumab and ipilimumab combination therapy. METHODS: Patients with unresectable or metastatic renal cell carcinoma who started nivolumab and ipilimumab combination therapy between September 2018 and December 2019 were registered in this post-marketing surveillance. The observation period was 13 weeks. Safety data included treatment-related adverse events with a particular emphasis on the gastrointestinal-related (colitis, enteritis, diarrhoea and gastrointestinal perforation) and liver-related (hepatic failure, hepatic function abnormal, hepatitis and cholangitis sclerosing) treatment-related adverse events that are listed in the risk management plan for nivolumab and ipilimumab combination therapy. RESULTS: Of the 203 patients registered, safety data were available for 159 (119 males/40 females) with a median age of 67 years (range 22-88). Seventy-one patients received nivolumab and ipilimumab combination therapy four times per usual clinical therapy, and 33 continued nivolumab monotherapy thereafter. Any-grade treatment-related adverse events were reported in 102 (64.2%) patients and grade ≥ 3 in 63 (39.6%). Hepatic function abnormalities (13.2%), rash (8.8%) and interstitial lung disease (7.5%) were the most common treatment-related adverse events. Five patients died following treatment-related adverse events. Gastrointestinal-related and liver-related treatment-related adverse events occurred in 10 (6.3%; four with grade ≥ 3 treatment-related adverse events) and 27 (17.0%; 19 with grade ≥ 3 treatment-related adverse events) patients, respectively. CONCLUSIONS: This post-marketing surveillance in patients with unresectable or metastatic renal cell carcinoma revealed a safety profile for nivolumab and ipilimumab combination therapy consistent with CheckMate 214. Furthermore, no new safety concerns were identified including gastrointestinal-related and liver-related treatment-related adverse events.

Federated analyses of multiple data sources in drug safety studies.

PURPOSE: Studies of rare side effects of new drugs with limited exposure may require pooling of multiple data sources. Federated Analyses (FA) allow real-time, interactive, centralized statistical processing of individual-level data from different data sets without transfer of sensitive personal data. METHODS: We review IT-architecture, legal considerations, and statistical methods in FA, based on a Swedish Medical Products Agency methodological development project. RESULTS: In a review of all post-authorisation safety studies assessed by the EMA during 2019, 74% (20/27 studies) reported issues with lack of precision in spite of mean study periods of 9.3 years. FA could potentially improve precision in such studies. Depending on the statistical model, the federated approach can generate identical results to a standard analysis. FA may be particularly attractive for repeated collaborative projects where data is regularly updated. There are also important limitations. Detailed agreements between involved parties are strongly recommended to anticipate potential issues and conflicts, document a shared understanding of the project, and fully comply with legal obligations regarding ethics and data protection. FA do not remove the data harmonisation step, which remains essential and often cumbersome. Reliable support for technical integration with the local server architecture and security solutions is required. Common statistical methods are available, but adaptations may be required. CONCLUSIONS: Federated Analyses require competent and active involvement of all collaborating parties but have the potential to facilitate collaboration across institutional and national borders and improve the precision of postmarketing drug safety studies.

Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data.

Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.

A Pharmacovigilance Study of Adverse Drug Reactions Reported for Cardiovascular Disease Medications Approved Between 2012 and 2017 in the United States Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

PURPOSE: Between 2012 and 2017, the FDA approved 29 therapies for a cardiovascular disease (CVD) indication. Due to the limited literature on patient safety outcomes for recently approved CVD medications, this study investigated adverse drug reports (ADRs) reported in the FDA Adverse Event Reporting System (FAERS). METHODS: A disproportionality analysis of spontaneously reported ADR was conducted. Reports in FAERS from Quarter 1, 2012, through Quarter 1, 2019, were compiled, allowing a 2-year buffer following drug approval in 2017. Top 10 reported ADRs and reporting odds ratios (ROR; confidence interval (CI)), a measure of disproportionality, were analyzed and compared to drugs available prior to 2012 as appropriate. RESULTS: Of 7,952,147 ADR reports, 95,016 (1.19%) consisted of reports for newly approved CVD medications. For oral anticoagulants, apixaban had significantly lower reports for anemia and renal failure compared to dabigatran and rivaroxaban but greater reports for neurological signs/symptoms, and arrhythmias. Evaluating heart failure drugs, sacubitril/valsartan had greater reports for acute kidney injury, coughing, potassium imbalances, and renal impairment but notably, lower for angioedema compared to lisinopril. Assessing familial hypercholesterolemia drugs, alirocumab had greater reports for joint-related-signs/symptoms compared to other agents in this category. A newer pulmonary arterial hypertension treatment, selexipag, had greater reports of reporting for bone/joint-related-signs/symptoms but riociguat had greater reports for hemorrhages and vascular hypotension. CONCLUSION: Pharmacovigilance studies allow an essential opportunity to evaluate the safety profile of CVD medications in clinical practice. Additional research is needed to evaluate these reported safety concerns for recently approved CVD medications.

Real-world results with IgPro20 for hypo- or agammaglobulinemia in Japan.

BACKGROUND: Subcutaneous immunoglobulin is one of the standard treatments for hypogammaglobulinemia in primary immunodeficiencies (PID) worldwide. In Japan, IgPro20 (Hizentra® ; l-proline-stabilized 20% human subcutaneous immunoglobulin) is approved for agammaglobulinemia or hypogammaglobulinemia due to PID or secondary immunodeficiency (SID); however, its safety and effectiveness has not previously been assessed in a real-world setting. METHODS: This multicenter, open label post-marketing surveillance study was conducted between January 2014 and March 2019. Patients who received IgPro20 due to PID or SID were included after informed consent. Physicians completed a case report form for each patient. Safety was determined from reported adverse events (AEs), adverse drug reactions, and serious AEs (SAEs); effectiveness was assessed by infection rates after the first IgPro20 dose. RESULTS: Of 85 patients receiving IgPro20 in the safety analysis, 39 developed AEs (45.9%; PID n = 28, SID n = 11). At least one adverse drug reaction was observed in 27 patients (31.8%; PID n = 21, SID n = 6), and the most common were injection site reactions (n = 17, 20.0%). Four patients (PID n = 3, SID n = 1) reported SAEs but two were unrelated to IgPro20 administration. The infection rate decreased from 0.54 per patient during the 6 months before IgPro20 to 0.39 per patient during IgPro20 treatment. Serious bacterial infections occurred in six patients before IgPro20 (7.9%; PID n = 2; SID n = 4) but in only one patient with SID during IgPro20 treatment (1.2%). CONCLUSIONS: In Japan, IgPro20 was considered safe and effective among patients with agammaglobulinemia or hypogammaglobulinemia due to PID or SID.

[Market surveillance and control of substandard, falsified and unregistered medicines: integrative reviewVigilancia y control de medicamentos subestándar, falsificados y no registrados: una revisión integral]. / Vigilância e controle de medicamentos abaixo do padrão, falsificados e não registrados: revisão integrativa.

Objective: To identify the strategies employed by regulatory systems for the market surveillance and control of substandard, falsified, and unregistered medicines at the regional-global levels, especially regarding drug recall procedures. Method: An integrative literature review was performed. Searches were performed in MEDLINE via PubMed, Embase, and SciELO to select articles published from 2007 to 2019 in English, Portuguese, and Spanish, covering national regulatory system initiatives, with a focus on the recall of substandard, falsified, and unregistered medicines. Results: Of 483 articles initially identified, 21 global, regional, or national scope studies were selected. Prevention, detection, and response strategies, including drug recall, were grouped according to two broad market surveillance and control models (passive-reactive and proactive) used by regulatory systems. These models seem to combine passive and proactive, complementary or concurring actions that varied according to country development level and regulatory capacity. Although considered the most effective response for protection of populations, medicine recall was not implemented in a uniform manner in different regulatory systems as indicated by the studies. Conclusions: Addressing the complexity and magnitude of the problem of substandard, falsified, and unregistered medicines will demand effort, investment, and profound changes in the approaches, processes, and capacity of regulatory systems, with market surveillance and control strategies possibly converging toward a hybrid, multisectoral, multidisciplinary, global, and systemic model of human health protection.

Objetivo: Identificar las estrategias de actuación de los sistemas regulatorios en la vigilancia y control de los medicamentos subestándar, falsificados y no registrados a nivel regional-mundial, especialmente en lo que se refiere a los procesos de retirada de medicamentos del mercado (recall). Métodos: Se realizó una revisión bibliográfica integral en las bases de datos de MEDLINE a través de PubMed, Embase y SciELO. Se seleccionaron los estudios publicados entre 2007 y 2019, en inglés, portugués y español, en los que se abordaban las estrategias elaboradas por los sistemas regulatorios de los países, con énfasis en la retirada de los medicamentos subestándar, falsificados y no registrados. Resultados: De los 483 estudios identificados inicialmente, se incluyeron 21 publicaciones de ámbito nacional, regional o mundial. Las estrategias de prevención, detección y respuesta, incluida la retirada de medicamentos, se agruparon en dos modelos de actuación (pasivo-reactivo y proactivo) de los sistemas de regulación en la vigilancia y el control de los medicamentos. Estos modelos parecen combinar estrategias pasivas y proactivas, complementarias o concurrentes, que varían según el nivel de desarrollo de los países y su capacidad de regulación. Aunque la retirada de productos se considera la respuesta más eficaz para proteger a la población, según los estudios esta no se ha aplicado de manera uniforme en los sistemas de regulación. Conclusiones: La complejidad y la magnitud del problema de los medicamentos subestándar, falsificados y no registrados exigen esfuerzos, inversiones y cambios profundos en el enfoque, los procesos y las capacidades de los sistemas de regulación; y las estrategias de vigilancia y control del mercado pueden converger hacia un modelo híbrido, multisectorial, multidisciplinar, mundial y sistémico de protección de la salud humana.

Long-term safety and effectiveness of mycophenolate mofetil in adults with lupus nephritis: a real-world study in Japan.

OBJECTIVES: To assess the safety and effectiveness of mycophenolate mofetil (MMF) in Japanese adults with lupus nephritis (LN) in real-world clinical practice. METHODS: This multicentre, prospective, post-marketing surveillance study investigated the effectiveness and safety of MMF, as induction or maintenance therapy, in LN patients. Primary endpoints were adverse drug reactions (ADRs), changes in renal function from baseline, and relapse rate (RR) after 6 months in the maintenance group, estimated using the Kaplan-Meier method. Complete remission (CR) and partial remission (PR) were estimated by renal measurements. RESULTS: Overall, 112 patients were enrolled in the induction group and 340 in the maintenance group. Of these 452 patients, 418 were evaluable for safety and 396 for effectiveness. Eighty-three patients (19.85%) experienced ADRs, most commonly herpes zoster (3.34%) and diarrhoea (3.11%). Serious ADRs occurring in more than three patients were cytomegalovirus infections (1.43%), acute pyelonephritis (0.71%), and herpes zoster (0.71%). One patient died from herpes zoster disseminated. CR and PR were 19.54% and 44.82%, respectively, in the induction group, and 40.62% and 66.16%, respectively, in the maintenance group. RR in the maintenance group was 0.70%. CONCLUSIONS: The tolerability of MMF is in line with that reported in other studies. Since the average dose of MMF was <1.5 g/day, research into the optimal dose for achieving effectiveness is required.

Postmarketing observational study of pazopanib in patients with metastatic soft tissue sarcoma in Japan.

BACKGROUND: This study evaluated the safety and efficacy of pazopanib in patients with metastatic soft tissue sarcoma in routine clinical use in Japan. METHODS: It was a multicentre, centrally registered and uncontrolled observational study in patients who received pazopanib for metastatic soft tissue sarcoma, with an observation period of 1 year after the start of drug administration. The study was conducted at 378 investigational sites in Japan from September 2012 to September 2019. Progression-free survival (PFS) and overall survival (OS) were the efficacy endpoints of the study. RESULTS: A total of 1970 patients were enrolled. Of these, 680 with finalized study forms were included in the analysis. Overall, 649 patients were included in the safety analysis set, and 569 were included in the efficacy analysis set. Most of the patients (81.97%) experienced at least one adverse drug reaction (ADR); 22.34% of patients reported serious ADRs and 34.98% of patients experienced grade ≥ 3 ADRs in the safety set. Hypertension (40.37%) and hepatic dysfunction (26.50%) were the two most common ADRs. A total of 262 deaths were reported, of which 12 were due to ADRs. The median PFS was 3.09 months, whereas the median OS was not reached at the end of the 1-year observation period. CONCLUSIONS: The safety and efficacy profiles in this postmarketing observational study were consistent with prior data and registration clinical trials. No new safety signals were observed while treating patients with metastatic soft tissue sarcoma with pazopanib.

Prospective observational study of the efficacy of nivolumab in Japanese patients with advanced melanoma (CREATIVE study).

BACKGROUND: Nivolumab, the anti-programmed cell death protein 1 antibody, has been approved for advanced melanoma, mainly based on evidence from Western countries. The profile of melanoma differs between Caucasian and Asian patients. This study was performed to obtain post-marketing data of nivolumab in Japanese patients with advanced melanoma. METHODS: This prospective, observational study involved patients with unresectable or metastatic melanoma treated with nivolumab at dosages of 2 mg/kg every 3 weeks or 3 mg/kg every 2 weeks. The primary endpoints were objective response rate and overall survival. The secondary endpoints were progression-free survival and the objective response rate according to immune-related Response Evaluation Criteria in Solid Tumours. RESULT: Among 124 patients analysed, mucosal melanoma was the most common subtype, followed by acral lentiginous, nodular, superficial spreading and lentigo maligna melanoma. Response Evaluation Criteria in Solid Tumours evaluation showed an objective response rate of 17.7%. The median survival time was 15.93 months, and the 1-year overall survival rate was 66%. Outcomes were not significantly different among melanoma subtypes. Better overall survival and/or progression-free survival but not objective response rate were associated with performance status 0, lower levels of lactate dehydrogenase, C-reactive protein and neutrophil-to-lymphocyte ratio. Patients with immune-related adverse events showed a better objective response rate, 3-month landmark overall survival and progression-free survival than patients without immune-related adverse events. CONCLUSION: The objective response rate and median survival time in Japanese patients treated with nivolumab were lower in daily practice than the >30% and >30 months, respectively, seen in global phase III trials. The occurrence of immune-related adverse events may be a predictor for survival and response to treatment with nivolumab.

Monitoring real-life utilization of pembrolizumab in advanced melanoma using the Portuguese National Cancer Registry.

OBJECTIVES: To evaluate the effectiveness and safety of pembrolizumab use in advanced melanoma in a real-life context; and to explore the existence of an efficacy-effectiveness gap, comparing registry data with the reference clinical trial. METHODS: This study followed the guidelines for good pharmacoepidemology practice. An ambispective cohort was constituted, initiating the observation upon drug approval (17/07/2015) and following exposed patients until death or cut-off date (15/11/2019). The primary outcome was overall survival (OS); secondary outcomes comprised progression-free survival (PFS), overall response rate (ORR) and the occurrence of adverse events (AE). For all survival analyses, the Kaplan-Meier estimator was used, considering a 95% confidence interval (CI), aside with one-year survival rates. RESULTS: A total of 125 patients constituted the cohort, originating from 16 hospitals in Portugal. Median OS was estimated to be 16.9 months (CI95% 11.3-25.5) and the probability of survival after 1 year was 57.5% (CI95% 48.4%-65.6%). Median PFS was estimated to be 4.8 months (CI95% 3.9-6.7) and the probability of remaining progression-free after 1 year was 32.8% (CI95% 24.8-41.1). ORR was 30.4% (CI95% 22.5%-39.3%). AEs were experienced by 82% of patients, and 27% experienced AE≥ grade 3. CONCLUSIONS: Our data suggest lower effectiveness in a real-life context than the efficacy reported in the clinical trial. Safety data seems, however, quite comparable to KEYNOTE-006.

Machine Learning Approach for Active Vaccine Safety Monitoring.

BACKGROUND: Vaccine safety surveillance is important because it is related to vaccine hesitancy, which affects vaccination rate. To increase confidence in vaccination, the active monitoring of vaccine adverse events is important. For effective active surveillance, we developed and verified a machine learning-based active surveillance system using national claim data. METHODS: We used two databases, one from the Korea Disease Control and Prevention Agency, which contains flu vaccination records for the elderly, and another from the National Health Insurance Service, which contains the claim data of vaccinated people. We developed a case-crossover design based machine learning model to predict the health outcome of interest events (anaphylaxis and agranulocytosis) using a random forest. Feature importance values were evaluated to determine candidate associations with each outcome. We investigated the relationship of the features to each event via a literature review, comparison with the Side Effect Resource, and using the Local Interpretable Model-agnostic Explanation method. RESULTS: The trained model predicted each health outcome of interest with a high accuracy (approximately 70%). We found literature supporting our results, and most of the important drug-related features were listed in the Side Effect Resource database as inducing the health outcome of interest. For anaphylaxis, flu vaccination ranked high in our feature importance analysis and had a positive association in Local Interpretable Model-Agnostic Explanation analysis. Although the feature importance of vaccination was lower for agranulocytosis, it also had a positive relationship in the Local Interpretable Model-Agnostic Explanation analysis. CONCLUSION: We developed a machine learning-based active surveillance system for detecting possible factors that can induce adverse events using health claim and vaccination databases. The results of the study demonstrated a potentially useful application of two linked national health record databases. Our model can contribute to the establishment of a system for conducting active surveillance on vaccination.

Real-world use of temsirolimus in Japanese patients with unresectable or metastatic renal cell carcinoma: recent consideration based on the results of a post-marketing, all-case surveillance study.

OBJECTIVE: A prospective, observational, post-marketing surveillance was conducted to assess the safety and effectiveness of temsirolimus in patients with renal cell carcinoma in Japan. METHODS: Patients prescribed temsirolimus for advanced renal cell carcinoma were registered and received temsirolimus (25 mg weekly, intravenous infusion for 30-60 minutes) in routine clinical settings (observation period: 96 weeks). RESULTS: Among 1001 patients included in the safety analysis data set (median age, 65.0 years; men, 74.8%; Eastern Cooperative Oncology Group performance status 0 or 1, 69.6%), 778 (77.7%) reported adverse drug reactions. The most common (≥10%) all-grade adverse drug reactions were stomatitis (26.7%), interstitial lung disease (17.3%) and platelet count decreased (11.1%). The incidence rate of grade ≥3 interstitial lung disease was 4.5%. The onset of interstitial lung disease was more frequent after 4-8 weeks of treatment or in patients with lower Eastern Cooperative Oncology Group performance status (21.6% for score 0 vs 8.3% for score 4, P < 0.001). Among 654 patients in the effectiveness analysis data set, the response and clinical benefit rates were 6.7% (95% confidence interval 4.9-8.9) and 53.2% (95% confidence interval 49.3-57.1), respectively. The median progression-free survival was 18.3 weeks (95% confidence interval 16.9-21.1). CONCLUSIONS: The safety and effectiveness profile of temsirolimus observed in this study was similar to that observed in the multinational phase 3 study. The results are generalizable to the real-world scenario at the time of this research, and safety and effectiveness of temsirolimus as a subsequent anticancer therapy for renal cell carcinoma warrants further investigation. (ClinicalTrials.gov identifier NCT01210482, NCT01420601).

Safety and effectiveness of lusutrombopag in Japanese chronic liver disease patients with thrombocytopenia undergoing invasive procedures: Interim results of a postmarketing surveillance.

AIM: Lusutrombopag is approved for the treatment of thrombocytopenia in chronic liver disease patients undergoing invasive procedures. This real-world surveillance assesses the safety and effectiveness of lusutrombopag in Japan. METHODS: This ongoing, multicenter, prospective, real-world surveillance is collecting data from case report forms between October 2016 and May 2021. Interim data up to September 2018 were used to evaluate safety (adverse events and adverse drug reactions [ADRs]) and effectiveness (proportion of patients avoiding preoperative platelet transfusion and change in platelet count from baseline). RESULTS: The safety analysis set included 331 patients. The mean baseline platelet count was 46.2 ± 13.7 × 109 /L. Of 377 invasive procedures, radiofrequency ablation (110 procedures, 29.2%) was the most frequent. The mean time from starting lusutrombopag treatment to invasive procedure was 12.3 days. Incidences of serious adverse events and ADRs were 8.76% and 3.32%, respectively. Six cases (1.81%) of portal vein thrombosis were considered serious adverse events; of these, four cases (1.21%) were classified as serious ADRs. Of 300 patients who underwent an invasive procedure (excluding those with platelet transfusion refractoriness), 282 (94.0%) avoided preoperative platelet transfusion. In patients with platelet measurements before and after lusutrombopag administration who did not undergo platelet transfusion, the mean maximum change in platelet count from baseline was 41.7 ± 31.4 × 109 /L (range, -6 to 276; n = 286). All patients receiving second (n = 20) and third (n = 1) treatments avoided preoperative platelet transfusion without developing any ADRs. CONCLUSIONS: This real-world surveillance further supports the safety and effectiveness of lusutrombopag in patients with chronic liver disease undergoing invasive procedures.