Nippon Medical School's Ethical Review Processes for Studies Involving Human Subjects.

All life science and medical research involving human subjects must be conducted in compliance with the Declaration of Helsinki and the relevant laws and guidelines. Additionally, its scientific and ethical suitability must be reviewed by a committee well versed in the nature and content of the research. Failure to comply with these requirements when conducting research involving human subjects is a serious violation of Japanese laws, guidelines, and local regulations, so several ethics committees and institutional review boards have been established within the Nippon Medical School (NMS) Foundation and its affiliated institutions. It is essential for investigators to keep up to date with the latest developments in the ethical review process and to ensure that any projects they propose to embark on are subjected to an appropriate ethical review before the research is initiated. To help researchers and other staff affiliated with the NMS Foundation keep abreast of these developments, this report outlines NMS's current ethical review processes for research involving human subjects.

Declaration of Helsinki: ethical norm in pursuit of common global goals.

The World Medical Association's Declaration of Helsinki is in the process of being revised. The following amendments are recommended to be incorporated in pursuit of the common goal of promoting health for all. 1. Data-driven research that facilitates broad informed consent and dynamic consent, assuring participant's rights, and the sharing of individual participant data (IPD) and research results to promote open science and generate social value. 2. Risk minimisation in a placebo-controlled study and post-trial access to the best-proven interventions for all who need them. 3. A future-oriented research framework for co-creation with all the relevant stakeholders.

Clinical development of a blood biomarker using apolipoprotein-A2 isoforms for early detection of pancreatic cancer.

BACKGROUND: We have previously reported apolipoprotein A2-isoforms (apoA2-is) as candidate plasma biomarkers for early-stage pancreatic cancer. The aim of this study was the clinical development of apoA2-is. METHODS: We established a new enzyme-linked immunosorbent sandwich assay for apoA2-is under the Japanese medical device Quality Management System requirements and performed in vitro diagnostic tests with prespecified end points using 2732 plasma samples. The clinical equivalence and significance of apoA2-is were compared with CA19-9. RESULTS: The point estimate of the area under the curve to distinguish between pancreatic cancer (n = 106) and healthy controls (n = 106) was higher for apoA2-ATQ/AT [0.879, 95% confidence interval (CI): 0.832-0.925] than for CA19-9 (0.849, 95% CI 0.793-0.905) and achieved the primary end point. The cutoff apoA2-ATQ/AT of 59.5 µg/mL was defined based on a specificity of 95% in 2000 healthy samples, and the reliability of specificities was confirmed in two independent healthy cohorts as 95.3% (n = 106, 95% CI 89.4-98.0%) and 95.8% (n = 400, 95% CI 93.3-97.3%). The sensitivities of apoA2-ATQ/AT for detecting both stage I (47.4%) and I/II (50%) pancreatic cancers were higher than those of CA19-9 (36.8% and 46.7%, respectively). The combination of apoA2-ATQ/AT (cutoff, 59.5 µg/mL) and CA19-9 (37 U/mL) increased the sensitivity for pancreatic cancer to 87.7% compared with 69.8% for CA19-9 alone. The clinical performance of apoA2-is was blindly confirmed by the National Cancer Institute Early Detection Research Network. CONCLUSIONS: The clinical performance of ApoA2-ATQ/AT as a blood biomarker is equivalent to or better than that of CA19-9.

A Phase â ¡ Study of Ubenimex Combined With Pembrolizumab, Nab-Paclitaxel, and Carboplatin for Previously Untreated Advanced Squamous Non-Small-Cell Lung Cancer: TORG2241 (UBE-Q).

BACKGROUND: According to the results of the KEYNOTE-407 trial, pembrolizumab plus platinum-based chemotherapy is the standard of care for patients with previously untreated advanced squamous non-small-cell lung cancer (NSCLC). Ubenimex, a potent aminopeptidase inhibitor, is an oral drug with immunostimulatory and antitumor activities. We aim to assess the safety and efficacy of ubenimex in combination with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. PATIENTS AND METHODS: This prospective, single-arm, multicenter, phase II clinical trial is conducted to confirm the tolerability and efficacy of the tested drugs. Patients with previously untreated advanced squamous NSCLC will receive a predetermined daily dose of ubenimex orally plus 4 cycles of pembrolizumab, nab-paclitaxel, and carboplatin, followed by continuous administration of ubenimex and pembrolizumab for a maximum of 2 years. To confirm tolerability, the daily dose of ubenimex will begin at level 1 (30 mg), which will be increased to levels 2 (60 mg) and 3 (120 mg) according to the escalation criteria, with a standard 3 + 3 design for achieving the target dose-limiting toxicity rate of 33%. The efficacy, safety, and tolerability of ubenimex at the determined dose level will be analyzed. The primary endpoint of the efficacy evaluation will be the objective response rate assessed by an independent review committee. CONCLUSIONS: This is the first study to evaluate the efficacy and safety of ubenimex combined with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. The results will help devise future treatment strategies.

Utilization of genetic information for medicines development and equitable benefit sharing.

Advances in genomic research have significantly enhanced modern drug development. However, equitable benefit sharing of the results of scientific advancement has not always been achieved. This paper shows how molecular biology has modified medicines development while also leaving open significant challenges for benefit sharing. Presented here is a conceptual modeling describing the processes in genetic-related medicines development and how these are related to specific ethical considerations. The focus is on three important areas: 1) population genetics and the need for discrimination prevention; 2) pharmacogenomics and the need for inclusive governance; and 3) global health to be achieved in open science frameworks. Benefit sharing is taken as the ethical value that underlies all these aspects. The implementation of benefit sharing requires a value shift in which the outcomes of health science are not viewed simply as trade commodities but also as a "global public good". This approach should lead to genetic science to contribute to promoting the fundamental human right to health to all members of the global community.

A Phase I/II Study of Necitumumab Plus Pembrolizumab, Nab-Paclitaxel, and Carboplatin for Previously Untreated Advanced Squamous Non-Small Cell Lung Cancer Study: (NEJ048A/NEXUS).

BACKGROUND: Platinum-based combination therapy plus a programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitor is a standard treatment for patients with stage IV non-small cell lung cancer. However, necitumumab is used with gemcitabine and cisplatin as a first-line treatment option for squamous cell lung cancer (SqCLC). Furthermore, the combination of necitumumab with immune checkpoint inhibitors has the potential to enhance tumor immunity and improve the therapeutic effect. Thus, we planned and initiated this phase I/II study to evaluate the safety and efficacy of necitumumab plus pembrolizumab, nanoparticle albumin-bound (nab)-paclitaxel), and carboplatin therapy for patients with previously untreated SqCLC. PATIENTS AND METHODS: In phase I, the primary endpoint is the tolerability and recommended dose of necitumumab combined with pembrolizumab plus nab-paclitaxel and carboplatin. In phase II, the primary endpoint is the overall response rate. Secondary endpoints are disease control rate, progression-free survival, overall survival, and safety. Forty-two patients will be enrolled in phase II. CONCLUSION: This is the first study to investigate the efficacy and safety of necitumumab plus pembrolizumab combined with platinum-based chemotherapy in patients with previously untreated SqCLC.

A cross-sectional survey on principal investigators' clinical research knowledge in Japan.

Principal investigators (PIs) play a key role in clinical research, and must thus understand the role of clinical research support staff to conduct successful and appropriate clinical research. This study evaluates clinical research capabilities by examining the clinical research knowledge of PIs and clinical research support staff. The participants of this cross-sectional study were academic researchers and clinical research support staff from Japanese universities and research institutions. The participants comprised of 54 respondents, among whom 36 were PIs (physicians) and 18 were clinical research support staff. A self-administered electronic survey was created and evaluated by experts, with 50 knowledge items. Mann-Whitney U tests were used to determine the significance of the differences in knowledge between clinical research support staff and PIs. We compared the correct answer rate of clinical research support staff and PIs for each knowledge category and observed that the clinical research support staff scored significantly higher than the PIs in all aspects of clinical research knowledge sections, including total score. Our findings showed that PIs did not have the same amount of clinical research knowledge as the clinical research support staff. Clinical research knowledge is essential for investigators, especially PIs, to protect patients and promote medical breakthroughs. Thus, more accessible clinical research education and mandatory knowledge testing will allow PIs to lead successful clinical research and further the level of medical research in Japan.

The association between research funding status and clinical research papers' citation impact in Japan: A cross-sectional bibliometric study.

Introduction: Studies have not sufficiently clarified the differences in citation impact between funded and non-funded clinical research papers. Hence, this study seeks to evaluate the relation between research funding status and clinical research papers' citation impact in different research fields using multiple evaluation indices. Methods: In this cross-sectional bibliometric study, clinical research papers published by core clinical research hospitals in Japan were compared retrospectively in terms of times cited (TC), category normalized citation impact (CNCI), citation percentile (CP), journal impact factor (JIF), the Software to Identify, Manage, and Analyze Scientific Publications (SIGAPS) category, and whether they were the funded clinical research. The association between research funding status or the SIGAPS category and CNCI ≥ 2 was analyzed using logistic regression analysis. Results: 11 core clinical research hospitals published 553 clinical research papers, of which 120 were non-funded and 433 were funded (public institution-funded and industry-funded). The study found that funded clinical research papers (public institution-funded and industry-funded) had significantly higher TC, CNCI, CP, and JIF than non-funded ones [TC: 8 (3-17) vs. 14 (8-31), p < 0.001; CNCI: 0.53 (0.19-0.97) vs. 0.87 (0.45-1.85), p < 0.001; CP: 51.9 (24.48-70.42) vs. 66.7 (40.53-88.01), p < 0.001; JIF: 2.59 (1.90-3.84) vs. 2.93 (2.09-4.20) p = 0.008], while the proportion of A or B rank clinical research papers of the SIGAPS category was not significantly different between the two groups (30.0 vs. 34.9%, p = 0.318). In the logistic regression analysis, having a CNCI ≥ 2 was significantly associated with research funding (public institution-funded and industry-funded) and publication in A or B rank journals of the SIGAPS category [research funding: Estimate 2.169, 95% confidence interval (CI) 1.153-4.083, p = 0.016; SIGAPS category A/B: Estimate 6.126, 95% CI 3.889-9.651, p < 0.001]. Conclusion: Analysis via multiple indicators including CNCI and the SIGAPS category, which allows for a comparison of the papers' citation impact in different research fields, found a positive relation between research funding status and the citation impact of clinical research papers.

The ethical responsibility to continue investigational treatments of research participants in situation of armed conflicts, economic sanctions or natural catastrophes.

This paper discusses the effects of armed conflict, economic sanctions, and natural catastrophes on ongoing clinical trials. We suggest that • stopping the accrual of new patients in clinical trials under such extreme conditions is acceptable. • research participants already receiving trial medication in such disruptive situations are to be considered highly vulnerable due to their medical dependency for ongoing treatment according to the approved clinical study protocol. • based on the present experience in Ukraine and Russia, we conclude that finishing ongoing trial treatments according to approved or amended protocols should be considered to be an ethical obligation of trial sponsors irrespective whether trial disruption is due to war, economic sanctions, or natural catastrophes. • it is important to devote more attention to the ethical challenges raised by such fundamentally disruptive situations to clinical trials generally in any region of the world.

Factors Associated With the Acceleration of Patient Enrollment in Clinical Studies: A Cross-Sectional Study.

Under-recruitment in clinical trials is an issue worldwide. If the number of patients enrolled is lower than expected, based on the required sample size, then the reliability of the study results and their validation tend to be impaired. The current study therefore evaluated factors associated with accelerating patient enrollment using data from an ongoing multicenter prospective cohort study. The researchers encouraged research institutions to accelerate patient enrollment via e-mail, newsletters, telephone calls, and site visits. We analyzed the relationship between several potential factors associated with acceleration of patient enrollment including site visits and patient enrollment in a real clinical study. Data were collected from 106 research institutions that participated in a multicenter prospective cohort study. Results showed that the following parameters differed in terms of patient enrollment and non-enrollment: urban area (47.2 vs. 67.6%, p = 0.04), clinical research coordinator (CRC) participation in data input to electronic data capture (EDC) (41.7 vs. 11.8%, p < 0.01), and site visit (38.9 vs. 11.8%, p < 0.01). A multivariate analysis revealed that patient enrollment was significantly associated with urban area (odds ratio [OR] 0.33, 95% confidence interval [CI] 0.12-0.86, p = 0.02), CRC participation in data input to EDC (OR 5.02; 95% CI 1.49-16.8; p < 0.01), and site visit (OR 4.54, 95% CI 1.31-15.7, p = 0.01). In conclusion, site visits and CRC participation in data input to EDC had a significant effect on patient enrollment promotion. Moreover, hospitals in rural areas were more effective in promoting patient enrollment than those in urban areas.

Performance Index for Types of Clinical Research Support Service Providers for Academic Research Organizations in Japan: A Cross-Sectional Survey.

The purpose of this study was to conduct a factual survey to evaluate the type of clinical research support offered by service providers (supporters) in Japanese academic research organizations (AROs). From September to October 2018, we conducted an online questionnaire targeting researchers and supporters of AROs, including individuals supporting research and development (R&D) planning, as well as those involved in study management, biostatistics, coordination, data management, monitoring, and auditing. The number of responses was tabulated for each survey item. For items with written descriptions, we compiled summaries using the inductive regression method of qualitative research. Responses were obtained from 124 researchers, 258 supporters, and 40 AROs. None of the institutions responded that they had a performance index for all types of service providers, whereas 47% of institutions had an index for 1-3 types of service providers, and 40% of institutions had no index. Many institutions responded that they had a performance index for coordinators and data management, but few responded that there was a performance index for individuals engaged in R&D and study management. Furthermore, for all evaluations of AROs and researchers, the level of supporter satisfaction was low at only 20%. There was a discrepancy between the levels of researcher expectations and the actual contribution of R&D in the process of research planning. Our survey revealed that there is currently no performance index for services supporting clinical research. In future studies, we need to examine a performance index that accurately reflects the researcher attitudes revealed in this study.

Linking the Declarations of Helsinki and of Taipei: Critical Challenges of Future-Oriented Research Ethics.

Expansion of data-driven research in the 21st century has posed challenges in the evolution of the international agreed framework of research ethics. The World Medical Association (WMA)'s Declaration of Helsinki (DoH) has provided ethical principles for medical research involving humans since 1964, with the last update in 2013. To complement the DoH, WMA issued the Declaration of Taipei (DoT) in 2016 to provide additional principles for health databases and biobanks. However, the ethical principles for secondary use of data or material obtained in research remain unclear. With such a perspective, the Working Group on Ethics (WGE) of the International Federation of Associations of Pharmaceutical Physicians and Pharmaceutical Medicine (IFAPP) suggests a closer scientific linkage in the DoH to the (Declaration of Taipei) DoT focusing specifically on areas that will facilitate data-driven research, and to further strengthen the protection of research participants.

Development and Use of Gene Therapy Orphan Drugs-Ethical Needs for a Broader Cooperation Between the Pharmaceutical Industry and Society.

Gene therapy orphan medicinal products constitute a unique group of new drugs which in case of hereditary diseases are usually administered only once at an early age, in the hope to provide sufficient gene product to last for the entire life of the patients. The combination of an exceptionally large single payment and the life-long clinical follow-up needed for understanding the long-term benefits and safety of gene therapy, represent new types of scientific, financial, social and ethical challenges for the pharmaceutical industry, regulators and society. With special consideration of the uniqueness and importance of gene therapy, the authors propose a three points plan for a close cooperation between the pharmaceutical industry and society to develop orphan gene therapy. (1) In fully transparent health technology negotiations a close and long-lasting, contractually fixed cooperation should be established between the manufacturers and local health-care stakeholders for sharing the medical and scientific benefits, the financial risks as well as the burdens of the post-authorization clinical and regulatory development. (2) The parties should agree on a fair, locally affordable drug price without the usually very high premium price calculated to compensate for the low number of patients. In case of high manufacturing costs, the companies should offer prolonged, 15-20 years long payment by installment with risk-sharing, especially considering that the late outcome of the treatment is unknown. Society should assist scientifically and financially organizing a specific patient registry, treatment in specialized hospitals and adequate long-term follow-up of patients, the coordinated management of financial transactions related to the risk sharing program. (3) The post-authorization treatment and prolonged observation of additional new cases coordinated by society should provide real world data needed for the modern complex regulatory evaluation of gene therapy products by the competent authorities. We assume that fair sharing of the benefits and risks as well as a well-organized cooperation of society with the industry in collecting real world evidence might result in better drug evaluation and improved accessibility due to lower prices. The outlined concept might support gene therapy more efficiently than the presently requested outstandingly high prices.

Corrigendum: Linking the Declarations of Helsinki and of Taipei: Critical Challenges of Future-Oriented Research Ethics.

[This corrects the article DOI: 10.3389/fphar.2020.579714.].

Importance of Quality Assessment in Clinical Research in Japan.

Background: The number of papers published by an institution is acknowledged as an easy-to-understand research outcome. However, the quantity as well as the quality of research papers needs to be assessed. Methods: To determine the relation between the number of published papers and paper quality, a survey was conducted to assess publications focusing on interventional clinical trials reported by 11 core clinical research hospitals. A score was calculated for each paper using Système d'interrogation, de gestionet d'analyse des publications scientifiques scoring system, allowing for a clinical paper quality assessment independent of the field. Paper quality was defined as the relative Journal impact factor (IF) total score/number of papers. Results: We surveyed 580 clinical trial papers. For each of the 11 medical institutions (a-k), respectively, the following was found: number of published papers: a:66, b:64, c:61, d:56, e:54, f:51, g:46, h:46, i:46, j:45, k:45 (median: 51, maximum: 66, minimum: 45); total Journal IF: a:204, b:252, c:207, d:225, e:257, f:164, g:216, h:190, i:156, j:179, k:219 (median: 207, maximum: 257, minimum: 156); relative Journal IF total score: a:244, b:272, c:260, d:299, e:268, f:215, g:225, h:208, i:189, j:223, k:218 (median: 225, maximum: 299, minimum: 189); and paper quality (relative Journal IF total score/number of papers): a:3.70, b:4.25, c:4.26, d:5.34, e:4.96, f:4.22, g:4.89, h:4.52, i:4.11, j:4.96, k:4.84 (median: 4.52, maximum: 5.34, minimum: 3.70). Additionally, no significant relation was found between the number of published papers and paper quality (correlation coefficient, -0.33, P = 0.32). Conclusions: The number of published papers does not correspond to paper quality. When assessing an institution's ability to perform clinical research, an assessment of paper quality should be included along with the number of published papers.

Cultivated oral mucosal epithelial transplantation for persistent epithelial defect in severe ocular surface diseases with acute inflammatory activity.

PURPOSE: To assess the clinical efficacy of cultivated oral mucosal epithelial transplantation (COMET) for the treatment of persistent epithelial defect (PED). METHODS: We treated 10 eyes of nine patients with PED (Stevens-Johnson syndrome: three eyes; thermal/chemical injury: five eyes; ocular cicatricial pemphigoid: two eyes) with COMET at Kyoto Prefectural University of Medicine, Kyoto, Japan from 2002 to 2008. RESULTS: Preoperatively, PED existed on over more than 50% of the corneal surface in seven eyes. Severe ocular surface inflammation with fibrovascular tissue surrounded the PED in all 10 eyes. At 24-weeks postoperative, PED had improved in all cases except 1 in which the patient was unable to return to the hospital (95% CI, 55.5-99.7; Wilcoxon signed-rank test, p = 0.0078). The preoperative median of logarithmic minimum angle of resolution was 1.85 (range 0.15-2.70), and 1.85, 1.85, and 1.52 at the 4th, 12th, and 24th postoperative week, respectively. The mean total preoperative ocular surface grading score was 7.0 (range 4-17). At 4 and 12 weeks postoperative, the total ocular surface grading score had improved significantly (p = 0.0020, p = 0.0078), and at 24 weeks postoperative, it was 3.0 (range 2-12, p = 0.0234). During the follow-up period (median 23.3 months, range 5.6-39.7 months), no recurrence of PED was observed in any eye, and long-term ocular surface stability was obtained. CONCLUSION: COMET enabled complete epithelialization of PED and stabilization of the ocular surface in patients with severe ocular surface disease, thus preventing end-stage cicatrization and vision loss at a later stage.

Visual improvement after cultivated oral mucosal epithelial transplantation.

PURPOSE: To report the effectiveness, disease-specific outcomes, and safety of cultivated oral mucosal epithelial sheet transplantation (COMET), with the primary objective of visual improvement. DESIGN: Noncomparative, retrospective, interventional case series. PARTICIPANTS: This study involved 46 eyes in 40 patients with complete limbal stem cell deficiency (LSCD) who underwent COMET for visual improvement. These LSCD disorders fell into the following 4 categories: Stevens-Johnson syndrome (SJS; 21 eyes), ocular cicatricial pemphigoid (OCP; 10 eyes), thermal or chemical injury (7 eyes), or other diseases (8 eyes). METHODS: Best-corrected visual acuity (BCVA) and ocular surface grading score were examined before surgery; at the 4th, 12th, and 24th postoperative week; and at the last follow-up. Data on COMET-related adverse events and postoperative management were collected. The outcomes in each disease category were evaluated separately. MAIN OUTCOME MEASURES: The primary outcome was the change in median logarithm of the minimum angle of resolution (logMAR) BCVA at the 24th postoperative week. The secondary outcome was the ocular surface grading score. RESULTS: Median logMAR BCVA at baseline was 2.40 (range, 1.10 to 3.00). In SJS, logMAR BCVA improved significantly during the 24 weeks after surgery. In contrast, the BCVA in OCP was improved significantly only at the 4th postoperative week. In 6 of the 7 thermal or chemical injury cases, logMAR BCVA improved after planned penetrating keratoplasty or deep lamellar keratoplasty. Grading scores of ocular surface abnormalities improved in all categories. Of 31 patients with vision loss (logMAR BCVA, >2) at baseline, COMET produced improvement (logMAR BCVA, ≤2) in 15 patients (48%). Visual improvement was maintained with long-term follow-up (median, 28.7 months). Multivariate stepwise logistic regression analysis showed that corneal neovascularization and symblepharon were correlated significantly with logMAR BCVA improvement at the 24th postoperative week (P=0.0023 and P=0.0173, respectively). Although postoperative persistent epithelial defects and slight to moderate corneal infection occurred in the eyes of 16 and 2 patients, respectively, all were treated successfully with no eye perforation. CONCLUSIONS: Long-term visual improvement was achievable in cases of complete LSCD. Cultivated oral mucosal epithelial sheet transplantation offered substantial visual improvement even for patients with end-stage severe ocular surface disorders accompanying severe tear deficiency. Patients with corneal blindness such as SJS benefited from critical improvement of visual acuity. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in anymaterials discussed in this article.

Phase II study of capecitabine and trastuzumab combination chemotherapy in patients with HER2 overexpressing metastatic breast cancers resistant to both anthracyclines and taxanes.

PURPOSE: The purpose of this study was to investigate the activity of capecitabine and trastuzumab in patients with HER2-overexpressing metastatic breast cancer resistant to both anthracyclines and taxanes. METHOD: From June 2003 and May 2006, 40 female patients with measurable or assessable metastatic breast cancer were enrolled and data from 38 patients were reviewed extramurally and analyzed. Patients were treated with weekly trastuzumab given at a dose of 2 mg/kg/day over 90 min (4 mg/kg/day on the first infusion) and capecitabine given at a dose 1,657 mg/m(2)/day during 21 days with a subsequent pause of 7 days. This cycle was repeated every 28 days. The primary endpoint was overall survival and secondary endpoints were progression-free survival and response rate. RESULT: A median of 4.5 cycles (range 1-9 cycles) were delivered. The median age was 53 (range 30-69 years). Median overall survival and progression-free survival was 22.3 and 4.1 months, respectively. Survival rate at 1 and 2 year was 81.6 and 47.4%, respectively. Response rate was 18.4% (95% CI, 7.7-34.3%). All evaluable patients have responded with two CR (5.3%), 5 PR (13.2%), 20 SD (52.6%), 8 PD (21.1%) and 3 NE (7.9%). Regarding the hematological toxicities, grade 1/2/3 neutropenia, grade 1/2 anemia, grade 1 thrombocytopenia and grade 1/2 liver dysfunction were also common. No treatment-related death was reported. CONCLUSION: The combination of capecitabine and trastuzumab is active and well-tolerated in patients with HER2-overexpressing breast caner resistant to both anthracyclines and taxanes.

Suppressive effects of Perilla frutescens on IgA nephropathy in HIGA mice.

BACKGROUND: Perilla frutescens (perilla) is a herbal medicine used in Japanese traditional Kampo medicine. The present study was conducted to evaluate the anti-nephritic effects of perilla in HIGA mice that spontaneously develop high levels of serum immunoglobulin A (IgA) along with mesangial IgA deposition. METHODS: A perilla decoction and its major active constituent, rosmarinic acid (RsA), were orally administrated to 10-week-old HIGA mice for 16 weeks. At study completion, we measured proteinuria and serum IgA levels and generated histological scores from kidney specimens. In addition, we measured concentrations of IgA in culture media of intestinal Peyer's patch cells and spleen cells obtained from the HIGA mice. RESULTS: Perilla suppressed proteinuria, proliferation of glomerular cells, serum levels of IgA, glomerular IgA and IgG depositions in HIGA mice. Cultured Peyer's patch cells and spleen cells from perilla-treated mice produced significantly less IgA than controls. Rosmarinic acid, by itself, suppressed serum IgA levels and glomerular IgA deposition in HIGA mice. Cultured spleen cells from RsA-treated mice produced less IgA than controls. CONCLUSIONS: The perilla decoction may suppress IgA nephropathy, in part, through modulation of the intestinal mucosal immune system. These effects were caused by RsA acting synergistically with other constituents.