New Visualization Models of Designation Pathway and Group Categorization of Cell-Device and Protein-Device Combination Products in the United States.

PURPOSE: The developer and sponsor of new cell-device and protein-device combination products in the United States needs to forecast which classification and designation to the regulatory scheme of biological products or devices 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 cell-device and protein-device 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. METHODS: We searched the website of the FDA and the Alliance for Regenerative Medicine (ARM) on May 3, 2021 to identify the regulatory scheme of the FDA's capsular decision cases of cell-device and protein-device combination products, and of the tissue-engineered products approved by the FDA. RESULTS: By introducing a new definition of the primary intended use (PIU) of developers and sponsors extracted from the classification factors of primary mode of action (PMOA), as well as drug-device and biologic-device combination products, we developed new visualization models of the designation pathway and the two-dimensional model of group categorization, and proposed a new group categorization of cell-device and protein-device combination products, focusing on the device component function. DISCUSSION: The new visualization models and the group categorization proposed in this study may increase the predictability and acceptability of the classification of newly developed cell-device and protein-device combination products to regulatory schemes in the US for innovators, developers, and sponsors.

New Visualization Models of Designation Pathway and Group Categorization of Device-Drug and Device-Biologic Combination Products Classification in the United States: Analysis of FDA Capsular Decisions.

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.

Body Mass Index and Sudden Cardiac Death in Japanese Patients After Acute Myocardial Infarction: Data From the JCAD Study and HIJAMI-II Registry.

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 <18.5 kg/m2 (n=335), 18.5 to 23 kg/m2 (n=2371), 23 to 27.5 kg/m2 (n=2823), and ≥27.5 kg/m2 (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 <18.5 kg/m2 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/m2) was not associated with mortality compared with patients in the group with BMI ≥18.5 and <23 kg/m2. However, the long-term risk of SCD was increased in the group with BMI ≥27.5 kg/m2 (adjusted hazard ratio, 2.97; 95% confidence interval, 1.24-7.15). Multivariate analysis revealed that BMI ≥27.5 kg/m2 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/m2) was associated with the risk of SCD in Japanese patients after myocardial infarction, although an obesity paradox was found for all-cause mortality.

Application of Seizon and Life Sciences to Global Public Health Challenges: An International Symposium.

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.

Gender Differences in Anemia and Survival in Patients Hospitalized for Acute Decompensated Heart Failure With Preserved or Reduced Ejection Fraction.

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 <13.0 g/dl for men and <12.0 g/dl for women) at discharge, and a preserved or reduced EF with all-cause death or cardiac death after discharge. Men or women were divided into 4 groups based on left ventricular EF (preserved or reduced EF) and anemia status at discharge. The median follow-up period after discharge was 524 days (384 to 791). After adjustment for multiple co-morbidities, there was no adverse influence of anemia in men with a preserved EF, whereas anemia was an independent predictor of all-cause death in men with a reduced EF. Conversely, anemia was an independent predictor of all-cause death in women with a preserved EF but not in women with a reduced EF. With respect to cardiac death, multivariable analyses revealed highly similar trends as those for all-cause death in patients of both genders. In conclusion, in acute decompensated patients with HF with a preserved or reduced EF, there were marked differences between men and women with respect to the association of anemia and left ventricular EF with survival.

Gender Differences in Left Ventricular Ejection Fraction and Outcomes Among Patients Hospitalized for Acute Decompensated Heart Failure.

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% to <40%, 40% to <50%, 50% to <60%, 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 LVEF <30%, 30% to <40%, 40% to <50%, or 50% to <60% 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.

Etiology of Heart Failure and Outcomes in Patients Hospitalized for Acute Decompensated Heart Failure With Preserved or Reduced Ejection Fraction.

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.

Regulatory approval for autologous human cells and tissue products in the United States, the European Union, and Japan.

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.

Impact of clustered depression and anxiety on mortality and rehospitalization in patients with heart failure.

BACKGROUND: Anxiety is often present in patients with depression. The aim of this study was to evaluate the impact of clustered depression and anxiety on mortality and rehospitalization in hospitalized patients with heart failure (HF). METHODS: A total of 221 hospitalized patients with HF, who completed the questionnaires, were analyzed in this prospective study (mean age 62±13 years; 28% female). One-third patients had implanted cardiac devices. Depression was defined as a Zung Self-Rating Depression Scale index score of ≥60 and anxiety was defined as a State-Trait Anxiety Inventory score of ≥40 (male) or ≥42 (female). The primary outcome was the composite of death from any cause or rehospitalization due to worsened HF and refractory arrhythmia. RESULTS: Of the 221 HF patients, 29 (13%) had depression alone, 80 (36%) had anxiety alone, and 46 patients (21%) had both depression and anxiety. During an average follow-up of 41±21 months, patients with depression alone and those with clustered depression and anxiety were at an increased risk of the primary outcome [hazard ratio (HR) 2.24, 95% confidence interval (CI): 1.17-4.28, p=0.01 and HR 2.75, 95% CI: 1.51-4.99, p=0.01, respectively] compared to patients with no symptoms. Multivariate analysis after adjusting for age, gender, New York Heart Association functional class, B-type natriuretic peptide, device implantation, renal dysfunction, and left ventricular dysfunction showed clustered depression and anxiety, but not depression alone or anxiety alone, was an independent predictor of the primary outcome (HR 1.96, 95% CI: 1.00-3.27, p=0.04). CONCLUSIONS: Our results showed that clustered depression and anxiety were associated with worse outcomes in patients with HF.

Utility of ECG-gated MDCT to differentiate patients with ARVC/D from patients with ventricular tachyarrhythmias.

BACKGROUND: The accuracy of electrocardiogram-gated CT for diagnosing arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is uncertain. OBJECTIVE: We propose a comprehensive system for scoring characteristic CT findings to diagnose ARVC/D and discuss its utility. METHODS: Seventy-seven patients (mean age, 43.1 years; 48 male) diagnosed with ARVC/D or with suspected ARVC/D on the basis of ventricular tachyarrhythmias underwent CT with and without contrast enhancement. We retrospectively graded characteristic CT findings (fatty tissue, bulging appearance, and dilatation of the right ventricle) as minor (1 point) or major (2 points) and then validated our scoring system's utility for diagnosing ARVC/D with the use of the modified 2010 Task Force criteria as the reference standard. RESULTS: We diagnosed 27 of 77 patients with ARVC/D (23 definite, 4 borderline), observing each CT finding more often in patients with ARVC/D than in patients without ARVC/D: fatty tissue, 74.1% versus 12.0%; bulging appearance, 74.1% versus 34.0%; and RV dilatation, 92.6% versus 44.0%. However, observation of each finding in both groups could cause false positive diagnosis. Recursive partitioning analysis showed the superiority of our CT scoring system over methods that used each CT finding and CT findings without fatty tissue for distinguishing ARVC/D and non-ARVC/D. For overall (definite and borderline) and definite ARVC/D diagnosis, sensitivities were 77.8% and 87.0%, specificities were 96.0% and 94.4%, positive predictive values were 91.3% and 87.0%, negative predictive values were 88.9% and 94.4%, and accuracies were 89.6% and 92.2%, respectively. CONCLUSIONS: Our CT scoring system showed excellent diagnostic ability and might aid differentiation of ARVC/D from ventricular tachyarrhythmias.

The regulation of allogeneic human cells and tissue products as biomaterials.

The current definition of biomaterials differs vastly from it of just a decade ago. According to advancing technologies, it encompasses unpredictable materials such as engineered human cells and tissue. These biomaterials also have to be approved to use in health care business by regulatory authority, which are defined as drug, medical device, or biologics in the regulation. This Leading Opinion Paper addresses the regulatory issues of engineered human cells and tissue products using allogeneic cells that should have a great possibility to develop therapeutics for life-threating diseases or orphan diseases. Six allogeneic human cells and tissue products derived from neonatal or infant fibroblasts and/or keratinocytes were approved as medical devices or biologics in the United States as well as a hematopoietic cell product. For five of the seven products, well-controlled comparative clinical trials were conducted as pre-approval evaluation followed by post-approval evaluation. Although these products avoid a sterilization process usually used for medical devices, no serious malfunction that would lead to class 1 recall was reported. This article would provide insight for development of the engineered human cells and tissue.

Preliminary study on the development of a system dynamics model: the case of EVAHEART.

The Japanese medical device industry's stagnation over the years can be attributed to the uncertainty related to device development. The purpose of this study is to identify the major factors that impact development. We studied the ventricular assist device EVAHEART through interviews with the persons involved and created a development model using system dynamics. There are at least six stages in the device development process, including interactions with academia and the government. Through a simulation and comparison to Novacor, it was determined that the satisfaction of academia leads to government action in the subsequent measures. Our trial simulation of EVAHEART suggests that it has the potential to clarify unclear relationships in the development of devices.

Heterogeneity of hemodynamic parameters in untreated primary hypertension, and individualization of antihypertensive therapy based on noninvasive hemodynamic measurements.

Noninvasive measurement of hemodynamic parameter was undertaken in 240 patients with untreated primary hypertension using impedance cardiography (ICG) in outpatient clinics. High output was defined as a cardiac index (CI) >3.6 L/minute/m(2) and high resistance was defined as the total peripheral resistance index (TPRI) >2700 dyne·s·m(2)/cm(5). Of all patients, 67% had high-resistance hypertension (high TPRI with normal or low CI), and 16% had high-output hypertension (high CI with normal TPRI). Treatment with ß-blockers for high-output hypertension and with calcium channel blockers for high-resistance hypertension reduced blood pressure equally, and restored normal hemodynamic balance, as reported in studies using invasive monitoring methods. These findings suggest that it is appropriate to use noninvasive ICG measurements to guide antihypertensive therapy. Multivariate analysis showed that female gender, tachycardia, and low body mass index (BMI) were associated with high-output hypertension, but age was not. Heterogeneity of hemodynamic parameters is thought to be one of the reasons why the efficacies of antihypertensive agents differ between patients. It may be feasible to predict which antihypertensive agent would be the most effective for a particular patient based on hemodynamic measurements or combination of gender, heart rate, and BMI.

Optimal initial diagnostic strategies for the evaluation of stable angina patients: a multicenter, prospective study on myocardial perfusion imaging, computed tomographic angiography, and coronary angiography.

BACKGROUND: For stable patients suspected of having coronary artery disease (CAD), myocardial perfusion imaging (MPI) or computed tomographic angiography (CT) is used for initial evaluation, while coronary angiography (CAG) is used for confirming the diagnosis. The choice of the initial diagnostic test might influence the treatment strategy. METHODS AND RESULTS: Patients scheduled for MPI, CT, or CAG as the initial diagnostic test were enrolled. The primary and secondary end-points were a major adverse cardiac event (MACE) and revascularization, respectively. Of the 2,878 patients enrolled, 2,825 underwent initial diagnostic tests, and 2,780 were followed up for 1.42±0.49 years. After adjustment for CAD severity, Cox proportional hazard regression analysis showed that the risk of MACE in the MPI and CT groups were similar and significantly less than that in the CAG group (hazard ratio, 0.82 vs. 2.19; 95% confidence interval [CI], 0.43-1.58 vs. 1.40-3.44). Furthermore, the rate of revascularization in the MPI group was less than that of the CT (odds ratio, 1.62; 95% CI, 1.20-2.18) and CAG (odds ratio, 5.36; 95% CI, 4.07-7.05) groups. CONCLUSIONS: These data indicate that for stable patients with suspected CAD, the use of MPI or CT as the initial diagnostic test was associated with better prognosis than the use of CAG, and that initial evaluation with MPI was associated with a lower requirement of coronary intervention.

Landiolol, an ultra-short-acting ß1-blocker, more effectively terminates atrial fibrillation than diltiazem after open heart surgery: prospective, multicenter, randomized, open-label study (JL-KNIGHT study).

BACKGROUND: Recent studies have suggested that esmolol is the first choice for rate control in patients with postoperative atrial fibrillation (AF) after coronary artery bypass surgery, but side-effects of esmolol such as hypotension are problematic. To overcome this problem, landiolol, an ultra-short-acting ß(1)-blocker with a less negative inotropic effect than esmolol, has been developed. The aim of the present study was to investigate whether landiolol was effective for both rate control and conversion to normal sinus rhythm (NSR). METHODS AND RESULTS: A prospective, randomized, open-label comparison between i.v. landiolol and diltiazem in patients with postoperative AF was undertaken between January 2008 and June 2009 in Japan. Of 335 patients included in the analysis, 71 patients went into AF. Among these 71 patients, conversion to NSR within 8h after onset of AF occurred in 19 of 35 patients (54.3%) in the landiolol group vs. 11 of 36 patients (30.6%) in the diltiazem group (P<0.05). The incidence of hypotension was lower in the landiolol group (4/35, 11.4%) compared with the diltiazem group (11/36, 30.6%; P<0.05). The incidence of bradycardia was also lower in the landiolol group (0%) compared with the diltiazem group (4/36, 11.1%; P<0.05). CONCLUSIONS: Landiolol is more effective and safer than diltiazem for patients with postoperative AF after open heart surgery.

Estrogen-like activity and dual roles in cell signaling of an Agaricus blazei Murrill mycelia-dikaryon extract.

Agaricus blazei (A. blazei) Murrill mycelia-dikaryon has attracted the attention of scientists and clinicians worldwide owing to its potential for the treatment of cancer. However, little is known about its effect on other pathologies. This study sought to extend the potential medical usefulness of A. blazei for preventing vascular damage and to unravel its mechanism of action. The A. blazei extract showed estrogen-like activity in both gene expression profiling and a luciferase assay. Indeed, the extract inhibited oxidized low-density lipoprotein-stimulated activation of Erk1/2, Akt and p38 in HUVECs and macrophage-derived TIB-67 cells. Moreover, the extract enhanced transcription of the glutathione peroxidase 3 (GPX3), α-synuclein (SNCA) and endothelial nitrogen-oxide synthase (eNOS) genes. Furthermore, atherosclerotic lesions in rabbits were reduced by intake of A. blazei powder. Therefore, A. blazei may be useful for preventing atherosclerosis via dual roles in cell signaling, suppression of macrophage development and the recovery of endothelial cells from vascular damage.

Depression and outcomes in hospitalized Japanese patients with cardiovascular disease. - Prospective single-center observational study-.

BACKGROUND: Several studies have suggested that depression poses a risk in cardiovascular patients. The aim of the present study was to evaluate the prevalence of depression and its effect on cardiovascular events and mortality in Japanese inpatients with cardiovascular disease. METHODS AND RESULTS: A total of 505 patients hospitalized with cardiovascular disease (28% female; mean age, 61 ± 14 years; 31% ischemic heart disease; 47% New York Heart Association [NYHA] class II-IV; 25% implantation of pacing devices) were enrolled in the present prospective observational study. The Zung Self-Rating Depression Scale (SDS) was used to screen for depression. The primary outcome was the time to death or cardiovascular event, and the secondary outcome was death. In total, 109 patients (22%) were diagnosed with depression (Zung SDS index score ≥ 60). NYHA class III/IV, defibrillator implantation, and being unmarried were independently associated with depression. During an average follow-up period of 38 ± 15 months, 92 patients (18%) reached the primary outcome. There was a higher incidence of the primary outcome in patients with depression than in those who were not depressed (P<0.01). Depressed patients had a significantly higher rate of mortality than non-depressed patients (P<0.01). Depression was an independent predictor of the primary outcome (hazard ratio, 2.25; 95% confidence interval: 1.30-3.92, P<0.01). CONCLUSIONS: Depression was not uncommon in Japanese inpatients with cardiovascular disease and was associated with cardiovascular outcomes.

Risk of sudden death in end-stage hypertrophic cardiomyopathy.

BACKGROUND: It remains unclear whether end-stage hypertrophic cardiomyopathy (HCM) is associated with as high a rate of sudden death as occurs among HCM patients with preserved left ventricular (LV) systolic function. The purpose of this study was to evaluate the incidence of sudden death among patients with end-stage HCM and to identify high-risk end-stage patients. METHODS AND RESULTS: A total of 490 consecutive patients with HCM, who were diagnosed and followed-up at our hospital, were analyzed retrospectively. End-stage HCM was defined by an LV ejection fraction <50% on echocardiography during follow-up. Among the 490 HCM patients, 43 patients (8.8%) were diagnosed as having end-stage HCM during a mean follow-up period of 12 ± 7 years after the initial diagnosis. During a mean follow-up period of 5 ± 3 years after progression to end-stage HCM, sudden death occurred in 21 of 43 patients (47%). Cox proportional hazards analysis identified syncope as an independent predictor of sudden death (hazard ratio = 6.15; 95% confidence interval, 2.40-15.75; P < .001). CONCLUSIONS: This study demonstrated that patients with end-stage HCM have a high incidence of sudden death. Therefore, it is suggested that an aggressive therapeutic strategy to counter sudden death should be considered for patients with end-stage HCM.