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Objective The developer and sponsor of new combination products in US needs to forecast which classification and designation to the regulatory scheme of drug, biological product, or device would be required for the new products by the Food and Drug Administration (FDA). To improve the predictability and acceptability of the designation of new combination products for innovators, developers, and sponsors, and to encourage the development and early access of new combination products, we proposed new visualization models of the designation pathway and group categorization. Method We searched the website of the FDA on 15 November, 2020 to identify the regulatory scheme of the FDA’s 129 capsular decision cases of device–drug and device–biologics combination products and other publicly available cases the FDA designated to the drug/biologic or device regulatory scheme. Results By introducing a new definition for primary intended use (PIU) by developers and sponsors extracted from the classification factors of primary mode of action (PMOA), we developed new visualization models of the designation pathway and two-dimensional group categorization. And applying these models to the cases the FDA designated, we proposed a new group categorization of combination products while focusing on the device component function. Conclusions The new visualization models with PIU and PMOA and the new group categorization focusing on the device component function proposed in this study may increase predictability and acceptability of the classification of newly developed combination products into the regulatory scheme of drug, biological product, and device, for innovators, developers, and sponsors.

The JMA HSPH Taro Takemi Memorial International Symposium "Community Health Systems and Innovations: Building the Foundation for Universal Health Coverage" was held on February 17, 2018. The symposium was co-organized by the Japan Medical Association, Harvard T.H. Chan School of Public Health, the Tokyo Medical Association, and Takemi Memorial Trust for Research of Seizon and Life Sciences. The aim of this symposium was to offer a forum for medical associations, academia, health policy makers, and other stakeholders to discuss the way forward to expand universal health coverage (UHC) in a rapidly changing environment surrounding health and human well-being, a concept that can be traced to the philosophy of late Dr. Taro Takemi. The three keynote lectures provided wide social and ethical as well as historic and global perspectives on health. They were followed by three sessions that each addressed one central theme: lessons learnt from the Japanese experience of responding to unprecedented demographic challenges (Session 1), how innovations can link national and global health policies with people's well-being (Session 2), and how these efforts can be sustained (Session 3). Finally, a concluding lecture attempted to apply the philosophy of Dr. Taro Takemi, known as Seizon and Life Sciences, to UHC based on the discussions of the symposium. In our opinion, Dr. Taro Takemi's foresight and philosophy should be revisited when we attempt to address present and future challenges; therefore, this symposium will be remembered for opening new ways of thinking.

In patients with acute decompensated heart failure (HF), the association of gender and left ventricular ejection fraction (LVEF) with clinical outcomes has not been fully investigated. The aim of this study was to evaluate gender differences in LVEF and adverse outcomes across the full spectrum of LVEF in patients hospitalized for acute decompensated HF. Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes registry, 4,231 patients (2,461 men and 1,770 women) discharged alive after hospitalization for acute decompensated HF were investigated to assess the association of gender and LVEF with the primary end point (all-cause death and readmission for HF). Men or women were divided into 5 groups based on the LVEF at hospital discharge (30%, 30% to40%, 40% to50%, 50% to60%, and ≥60%). The median follow-up period after discharge was 523 (384 to 791) days. The frequency of the primary end point did not differ between men and women (36.5% vs 38.1%, p = 0.291). After adjustment for multiple comorbidities, male patients with an LVEF30%, 30% to40%, 40% to50%, or 50% to60% had a significantly higher risk of the primary end point than those with an LVEF ≥60%, indicating an inverse association between LVEF and adverse outcomes. In contrast, the adjusted risk of the primary end point was similar for all 5 LVEF groups of female patients. In conclusions, the association between LVEF and outcomes differs markedly between men and women hospitalized for acute decompensated HF, although event-free survival is similar for both genders.

Background Although an “obesity paradox” exists in patients after myocardial infarction, the association between obesity and the risk of sudden cardiac death (SCD) is limited. The aim of this study was to determine whether obesity is associated with an increased risk of SCD in Japanese survivors of acute myocardial infarction. Methods and Results Pooled data from 2 cohort studies in Japan, JCAD (Japanese Coronary Artery Disease) study and the Heart Institute of Japan Acute Myocardial Infarction‐II (HIJAMI‐II) registry, comprising of 6216 patients (mean age 65±11 years, 75.2% male) with acute myocardial infarction who were discharged alive, were studied. The patients were categorized into the following body mass index (BMI) groups at baseline according to the World Health Organization classification for Asian populations: BMI 2 (n=335), 18.5 to 23 kg/m 2 (n=2371), 23 to 27.5 kg/m 2 (n=2823), and ≥27.5 kg/m 2 (n=687). The main outcomes were all‐cause mortality and SCD. During an average follow‐up period of 3.6±1.4 years, all‐cause mortality was 10.1%, and SCD was 1.2%. Patients with BMI 2 had the highest rate of all‐cause mortality (adjusted hazard ratio, 1.61; 95% confidence interval, 1.20–2.16), but high BMI (≥27.5 kg/m 2 ) was not associated with mortality compared with patients in the group with BMI ≥18.5 and 2 . However, the long‐term risk of SCD was increased in the group with BMI ≥27.5 kg/m 2 (adjusted hazard ratio, 2.97; 95% confidence interval, 1.24–7.15). Multivariate analysis revealed that BMI ≥27.5 kg/m 2 was associated with an increased risk of SCD (hazard ratio, 2.78; 95% confidence interval, 1.35–5.74). Conclusions Obesity (BMI ≥27.5 kg/m 2 ) was associated with the risk of SCD in Japanese patients after myocardial infarction, although an obesity paradox was found for all‐cause mortality.

Rationale & Objective Epidemiologic and clinical studies have suggested that urate-lowering therapy may slow the progression of chronic kidney disease (CKD). However, definitive evidence is lacking. Study Design Randomized, double-blind, placebo-controlled trial. Setting & Participants 467 patients with stage 3 CKD and asymptomatic hyperuricemia at 55 medical institutions in Japan. Intervention Participants were randomly assigned in a 1:1 ratio to receive febuxostat or placebo for 108 weeks. Outcomes The primary end point was the slope (in mL/min/1.73 m2 per year) of estimated glomerular filtration rate (eGFR). Secondary end points included changes in eGFRs and serum uric acid levels at 24, 48, 72, and 108 weeks of follow-up and the event of doubling of serum creatinine level or initiation of dialysis therapy. Results Of 443 patients who were randomly assigned, 219 and 222 assigned to febuxostat and placebo, respectively, were included in the analysis. There was no significant difference in mean eGFR slope between the febuxostat (0.23 ± 5.26 mL/min/1.73 m2 per year) and placebo (−0.47 ± 4.48 mL/min/1.73 m2 per year) groups (difference, 0.70; 95% CI, −0.21 to 1.62; P = 0.1). Subgroup analysis demonstrated a significant benefit from febuxostat in patients without proteinuria (P = 0.005) and for whom serum creatinine concentration was lower than the median (P = 0.009). The incidence of gouty arthritis was significantly lower (P = 0.007) in the febuxostat group (0.91%) than in the placebo group (5.86%). Adverse events specific to febuxostat were not observed. Limitations GFR was estimated rather than measured, and patients with stages 4 and 5 CKD were excluded. Conclusions Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia. Funding Funded by Teijin Pharma Limited. Trial Registration Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343.

Human cells and tissue products belong to a relatively new class of medical products. Therefore, limited information is available on the classification and premarket evaluation of human cells and tissue products in the United States (US), the European Union (EU), and Japan. In this study, the definition, legislation, and approval system of these products were surveyed. A total of nine autologous human cells and tissue products approved until October 2013 were collected. The definitions of human cells and tissue products were compatible among the US, the EU and Japan. The products were classified as human cells, tissue, and cellular and tissue-based products (HCT/Ps) in the US, advanced therapy medicinal products (ATMPs) in the EU, and cell/tissue-engineered products in Japan. These products were categorized as biologics and medical device in the US and Japan, and drug in the EU. The issuance of new guidance induced regulatory impact for manufacturer, especially in the US. These products are subjected to the accelerated approval of biological product, the humanitarian device exemption approval, the premarket application approval, the biologics license application approval, and new drug application approval with specific targeting of postapproval registry or surveillance. Of nine autologous human cells and tissue products, four products had been evaluated using clinical experiences or open clinical trials with small subjects, although the rests of products had been evaluated using comparative clinical trials with control treatment. Our survey suggests that autologous human cells and tissue products would need postmarket-oriented evaluation rather than premarket-oriented evaluation for doctors and patients.

In patients with acute decompensated heart failure (HF), the influence of gender on anemia, left ventricular ejection fraction (EF), and outcomes is unclear. We evaluated the association of anemia and left ventricular EF with survival in men or women hospitalized for acute decompensated HF. Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes registry, 4,215 patients (2,450 men and 1,765 women) discharged alive after hospitalization for acute decompensated HF were enrolled to evaluate the association of gender, anemia (hemoglobin

In the setting of acute decompensated heart failure (HF), relations among the etiology of HF, left ventricular systolic function, and outcomes are unclear. The aim of this study was to investigate the association of HF etiology with outcomes in patients with acute decompensated HF with a preserved or reduced ejection fraction (EF). Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes registry, 3,810 patients (1,601 with a preserved EF and 2,209 with a reduced EF) who had a hypertensive, ischemic, valvular, or idiopathic dilated etiology of HF were investigated to assess the association of etiology with a composite end point (all-cause mortality and readmission for HF). The median follow-up period after admission was 502 (381 to 759) days. The composite end point was reached in 44.6% and 41.7% of the preserved and reduced EF groups, respectively. After adjustment for multiple co-morbidities, the risk of the composite end point was comparable among hypertensive, ischemic, and valvular etiologies in the preserved EF group. In contrast, in the reduced EF group, ischemic etiology was associated with a tendency toward greater risk of the composite end point than hypertensive etiology (but this difference was not significant), whereas valvular etiology was associated with a significantly greater risk of the composite end point relative to hypertensive or idiopathic dilated etiology. In conclusion, this study demonstrated that taking the etiology of HF into account may help to reduce the heterogeneity of acute decompensated HF and assist in identifying patients at risk of adverse outcomes, especially among patients with reduced EF.

Division of Medical Devices has been conducting the projects to accelerate the practical use of innovative medical devices to collaborate with TWIns, Center for Advanced Biomedical Sciences, Waseda University and School of Engineering, The University of Tokyo. The TWIns has been studying to aim at establishment of preclinical evaluation methods by "Engineering Based Medicine", and established Regulatory Science Institute for Medical Devices. School of Engineering, The University of Tokyo has been studying to aim at establishment of assessment methodology for innovative minimally invasive therapeutic devices, materials, and nanobio diagnostic devices. This report reviews the exchanges of personnel, the implement systems and the research progress of these projects.