Ministry Of Health, Labour And Welfare Research Articles

Bayesian network analysis of risk classification strategies in the regulation of cellular products

Cell therapy, a burgeoning therapeutic strategy, necessitates a scientific regulatory framework but faces challenges in risk-based regulation due to the lack of a global consensus on risk classification. This study applies Bayesian network analysis to compare and evaluate the risk classification strategies for cellular products proposed by the Food and Drug Administration (FDA), Ministry of Health, Labour and Welfare (MHLW), and World Health Organization (WHO), using real-world data to validate the models. The appropriateness of key risk factors is assessed within the three regulatory frameworks, along with their implications for clinical safety. The results indicate several directions for refining risk classification approaches. Additionally, a substudy focuses on a specific type of cell and gene therapy (CGT), chimeric antigen receptor (CAR) T cell therapy. It underscores the importance of considering CAR targets, tumor types, and costimulatory domains when assessing the safety risks of CAR T cell products. Overall, there is currently a lack of a regulatory framework based on real-world data for cellular products and a lack of risk-based classification review methods. This study aims to improve the regulatory system for cellular products, emphasizing risk-based classification. Furthermore, the study advocates for leveraging machine learning in regulatory science to enhance the assessment of cellular product safety, illustrating the role of Bayesian networks in aiding regulatory decision-making for the risk classification of cellular products.

Discrepancies of frequent symptoms in licorice‐induced pseudoaldosteronism: A comparison of a systematic case review and the Ministry of Health, Labour and Welfare's manual

AbstractBackgroundLicorice‐induced pseudoaldosteronism has been identified as a side effect of excessive licorice consumption. This condition is often characterized by hypertension, hypokalemia, and hyporeninemic hypoaldosteronism. If left untreated, this condition can lead to severe complications, such as arrhythmia and rhabdomyolysis, which can be life‐threatening. Thus, it is critical to recognize the early symptoms of pseudoaldosteronism to facilitate prompt intervention and effective management. Here, we investigated the frequency of various accompanying symptoms by systematically reviewing case reports of licorice‐induced pseudoaldosteronism not covered in similar studies and comparing findings with the manual on pseudoaldosteronism published by the Ministry of Health, Labour and Welfare (MHLW).MethodsA comprehensive search was conducted using MEDLINE/PubMed to gather relevant human studies published between 1960 and July 2023 and written in English; data focusing on accompanying symptoms were summarized.ResultsThirty‐seven pertinent articles, encompassing 48 case reports (26 females and 1 unreported sex, mean age 64.6 ± 14.6), were identified and scrutinized. The analysis revealed that hypertension was the most prevalent followed by weakness and edema. None of the researched cases reported instances of spasticity or rigidity.DiscussionThe study findings identified hypertension and weakness followed by edema as the predominant symptoms associated with pseudoaldosteronism which is in agreement with the MHLW manual. However, we doubt that spasticity, rigidity, and possibly numbness could be noticed by patients and their families as common initial symptoms outlined in the manual.

Pharmacological characteristics and clinical study results of ensitrelvir fumaric acid (XOCOVA® Tablets 125 ‍mg)

Ensitrelvir fumaric acid (Xocova® hereafter ensitrelvir) is a novel anti-SARS-CoV-2 drug for COVID-19. Hokkaido University and Shionogi & Co., Ltd. engaged in joint research targeting SARS-CoV-2 3C-like (3CL) protease at an early stage and started clinical trials in July 2021. In February 2022, an application was filed for manufacture and sales approval for the indication of "SARS-CoV-2 infection,". Ensitrelvir recieved the first emergency regulatory approval from the Ministry of Health, Labour and Welfare (MHLW) in Japan in November 2022, and has obtained standard approval in March 2024. This emergency approval was based on the confirmed safety in a Phase 2/3 study (T1221) conducted in Japan and other Asian countries (Korea and Vietnam) in patients with mild/moderate COVID-19 and the presumed efficacy in Phase 3 Part (SCORPIO-SR), and the standard approval is based on efficacy from the Phase 3 part. In the Phase 3 part, ensitrelvir administered orally 375/125 ‍mg once daily for five days, in patients with irrespective of risk factors for severe complications and vaccination status, demonstrating a significant reduction vs placebo in the time to resolution of five typical Omicron-related symptoms (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness), and also showed a significant reduction in viral RNA on day 4 relative to placebo (P < 0.001). In the Phase 2/3 study, there were no serious adverse events or deaths, indicating good tolerability and safety. We hope that ensitrelvir will contribute as a new treatment option for patients suffering from COVID-19 symptoms.

Regulatory Frameworks for Integrated Medicine Management in USA, Europe, Japan, and China

Integrated Medicine Management (IMM) is an all-encompassing healthcare approach that merges conventional Western medicine with complementary and alternative therapies. The primary objective of IMM is to address the underlying causes of illnesses and promote overall health and wellness of patients. As the utilization of complementary and alternative therapies becomes increasingly prevalent, the need for regulatory frameworks to ensure the safe and effective integration of these therapies into conventional healthcare systems is growing rapidly. Regulatory framework of IMM varies between countries, considering the facts that each country has its own unique approach to manage the integration of complementary and alternative therapies. In this article, we aim to explore the regulatory frameworks for IMM in four major markets, i.e. the United States (US), European Union (EU), Japan, and China. In the US, IMM regulation is centralized among different Federal agencies, however states have varying degrees of oversight. The US Food and Drug Administration (FDA) is responsible for regulating dietary supplements and herbal products, while state medical boards oversee the practice of alternative medicine. Additionally, the National Center for Complementary and Integrative Health (NCCIH) provides research and education on complementary and alternative therapies. Conversely, the regulation of IMM is more centralized in EU, where the European Medicines Agency (EMA) oversees the approval of herbal and homeopathic medicines, and the European Commission provides guidelines for the use of complementary and alternative therapies in healthcare. In Japan, the regulation of IMM is tightly controlled by the Ministry of Health, Labour and Welfare (MHLW), which approves traditional herbal medicines and acupuncture needles, and mandates practitioners to be licensed. China recognizes traditional medicine alongside with Western medicine. The State Administration of Traditional Chinese Medicine (SATCM) oversees the regulation of traditional medicine and promotes its integration with Western medicine.

Virological characteristics of a SARS-CoV-2-related bat coronavirus, BANAL-20-236

Although several SARS-CoV-2-related coronaviruses (SC2r-CoVs) were discovered in bats and pangolins, the differences in virological characteristics between SARS-CoV-2 and SC2r-CoVs remain poorly understood. Recently, BANAL-20-236 (B236) was isolated from a rectal swab of Malayan horseshoe bat and was found to lack a furin cleavage site (FCS) in the spike (S) protein. The comparison of its virological characteristics with FCS-deleted SARS-CoV-2 (SC2ΔFCS) has not been conducted yet. We prepared human induced pluripotent stem cell (iPSC)-derived airway and lung epithelial cells and colon organoids as human organ-relevant models. B236, SARS-CoV-2, and artificially generated SC2ΔFCS were used for viral experiments. To investigate the pathogenicity of B236 invivo, we conducted intranasal infection experiments in hamsters. In human iPSC-derived airway epithelial cells, the growth of B236 was significantly lower than that of the SC2ΔFCS. A fusion assay showed that the B236 and SC2ΔFCS S proteins were less fusogenic than the SARS-CoV-2 S protein. The infection experiment in hamsters showed that B236 was less pathogenic than SARS-CoV-2 and even SC2ΔFCS. Interestingly, in human colon organoids, the growth of B236 was significantly greater than that of SARS-CoV-2. Compared to SARS-CoV-2, we demonstrated that B236 exhibited a tropism toward intestinal cells rather than respiratory cells. Our results are consistent with a previous report showing that B236 is enterotropic in macaques. Altogether, our report strengthens the assumption that SC2r-CoVs in horseshoe bats replicate primarily in the intestinal tissues rather than respiratory tissues. This study was supported in part by AMED ASPIRE (JP23jf0126002, to Keita Matsuno, Kazuo Takayama, and Kei Sato); AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers "UTOPIA" (JP223fa627001, to Kei Sato), AMED SCARDA Program on R&D of new generation vaccine including new modality application (JP223fa727002, to Kei Sato); AMED SCARDA Hokkaido University Institute for Vaccine Research and Development (HU-IVReD) (JP223fa627005h0001, to Takasuke Fukuhara, and Keita Matsuno); AMED Research Program on Emerging and Re-emerging Infectious Diseases (JP21fk0108574, to Hesham Nasser; JP21fk0108493, to Takasuke Fukuhara; JP22fk0108617 to Takasuke Fukuhara; JP22fk0108146, to Kei Sato; JP21fk0108494 to G2P-Japan Consortium, Keita Matsuno, Shinya Tanaka, Terumasa Ikeda, Takasuke Fukuhara, and Kei Sato; JP21fk0108425, to Kazuo Takayama and Kei Sato; JP21fk0108432, to Kazuo Takayama, Takasuke Fukuhara and Kei Sato; JP22fk0108534, Terumasa Ikeda, and Kei Sato; JP22fk0108511, to Yuki Yamamoto, Terumasa Ikeda, Keita Matsuno, Shinya Tanaka, Kazuo Takayama, Takasuke Fukuhara, and Kei Sato; JP22fk0108506, to Kazuo Takayama and Kei Sato); AMED Research Program on HIV/AIDS (JP22fk0410055, to Terumasa Ikeda; and JP22fk0410039, to Kei Sato); AMED Japan Program for Infectious Diseases Research and Infrastructure (JP22wm0125008 to Keita Matsuno); AMED CREST (JP21gm1610005, to Kazuo Takayama; JP22gm1610008, to Takasuke Fukuhara; JST PRESTO (JPMJPR22R1, to Jumpei Ito); JST CREST (JPMJCR20H4, to Kei Sato); JSPS KAKENHI Fund for the Promotion of Joint International Research (International Leading Research) (JP23K20041, to G2P-Japan Consortium, Keita Matsuno, Takasuke Fukuhara and Kei Sato); JST SPRING (JPMJSP2108 to Shigeru Fujita); JSPS KAKENHI Grant-in-Aid for Scientific Research C (22K07103, to Terumasa Ikeda); JSPS KAKENHI Grant-in-Aid for Scientific Research B (21H02736, to Takasuke Fukuhara); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (22K16375, to Hesham Nasser; 20K15767, to Jumpei Ito); JSPS Core-to-Core Program (A. Advanced Research Networks) (JPJSCCA20190008, to Kei Sato); JSPS Research Fellow DC2 (22J11578, to Keiya Uriu); JSPS Research Fellow DC1 (23KJ0710, to Yusuke Kosugi); JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to Terumasa Ikeda); World-leading Innovative and Smart Education (WISE) Program 1801 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to Naganori Nao); Ministry of Health, Labour and Welfare (MHLW) under grant 23HA2010 (to Naganori Nao and Keita Matsuno); The Cooperative Research Program (Joint Usage/Research Center program) of Institute for Life and Medical Sciences, Kyoto University (to Kei Sato); International Joint Research Project of the Institute of Medical Science, the University of Tokyo (to Terumasa Ikeda and Takasuke Fukuhara); The Tokyo Biochemical Research Foundation (to Kei Sato); Takeda Science Foundation (to Terumasa Ikeda and Takasuke Fukuhara); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Terumasa Ikeda); The Naito Foundation (to Terumasa Ikeda); Hokuto Foundation for Bioscience (to Tomokazu Tamura); Hirose Foundation (to Tomokazu Tamura); and Mitsubishi Foundation (to Kei Sato).

Nationwide real-world usage of blood-based (liquid) biomarker testing in Japan.

e23311 Background: Despite the advances in precision oncology with biomarker testing including CGP (comprehensive genomic profiling), not all patients are able to benefit from tissue-guided treatment decisions, underscoring a significant demand for advancements in liquid-based biomarker testing for such patients. However, the treatment landscape based on the application and integration of liquid biopsy in clinical practice has yet to be fully characterized in Japan. Methods: Center for Cancer Genomics and Advanced Therapeutics (C-CAT), the national datacenter in Japan, was established by the Ministry of Health, Labour and Welfare (MHLW) with the start of cancer genome medicine since June 2019. The database collects the clinical and genomic data from 68,242 patients who underwent CGP by the end of 2023. This study included all patient records who underwent liquid CGP testing using FoundationOne Liquid test from the C-CAT database up to June 2023. Results: We analyzed data from 7,461 records, where the patients had an average age of 65.1 (±12.0) years; 58.8% were male. A majority (51.3%) exhibited an ECOG performance status of 0, and 66.5% reported a family history of carcinoma. Predominant cancer types included pancreatic (1,825; 24.5%), prostate (1,182; 15.8%) and biliary tract cancers (838; 11.2%). Following review by an MTB (molecular tumor board), new treatments were initiated in 5.8% (434) of cases, with targeted therapy (181; 41.7%) and chemotherapy (174; 40.9%) being the primary interventions. Separately, 9 (2.1%) of new treatments post-MTB occurred as part of clinical trials. Median (IQR) durations from specimen collection to MTB, MTB to treatment initiation, and specimen collection to post-MTB treatment were 28 (24-34), 35 (13-64), and 63 (42-94) days, respectively. The largest proportion of biomarker testing occurred after the start of second line of therapy (1,720; 23.1%) Pancreatic and biliary tract cancer patients tend to have biomarker testing at the earlier line, whereas prostate and ovarian cancer patients tend to have at the later line. Conclusions: Although the positioning of liquid CGP testing may differ among cancer types, it is important for patients to select appropriate tissue- and liquid-based biomarker testing at the right timing. Understanding this descriptive landscape of biomarker tests utilized in real-world settings will aid decision-making for addressing unmet needs (e.g., low accessibility to treatment) in cancer genome medicine and its positioning in improving the standard of cancer care.

Guideline for evaluating the effects of psychotropic drugs on motor vehicle driving performance in Japan: A tiered approach for the assessment of clinically meaningful driving impairment.

In December 2022, the Ministry of Health, Labour and Welfare (MHLW) of Japan issued and implemented the guideline for evaluating the effects of psychotropic drugs on motor vehicle driving performance. This guideline recommends the use of a tiered approach to assess clinically meaningful driving impairment. It is noted that adverse events cannot be solely explained by pharmacokinetics, as the onset and duration of these events vary. Among these adverse events, those affecting alertness, such as drowsiness caused by psychotropic drugs on driving performance, are more frequently observed during initial treatment stages and dose escalation. Hence, when evaluating the effects of psychotropic drugs on driving performance, it becomes crucial to assess the persistence of clinically meaningful impairment. Therefore, the MHLW guideline, developed by the authors, emphasizes the need to assess the temporal profile of adverse events affecting driving in all clinical trials. Additionally, the guideline states that when conducting driving studies, the timing of multiple dosing should consider not only the pharmacokinetics of the investigational drug but also its tolerance.

Postmarket safety communications on drugs approved in Japan: A 25-year analysis.

Drug safety communications (DSCs) are essential tools for communicating important postmarket serious drug safety information to healthcare professionals and patients. Previous studies characterized DSCs issued by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, knowledge about the activities of the Pharmaceuticals and Medical Devices Agency (PMDA)/the Ministry of Health, Labor and Welfare (MHLW) is limited. This study characterized DSCs by the PMDA/MHLW in comparison with previously reported DSCs by the FDA and the EMA. We retrospectively analyzed 37 DSCs of 41 adverse drug reactions (ADRs) for 33 drugs in Japan from 1997 to 2022. Most DSCs were related to non-oncology drugs (30/37, 81.1%), and the median (interquartile range) time from approval to DSC issuance was 19 (10-51) months. Notably, the regulatory review reports and the latest labels before DSC issuance did not describe 16/28 (57.1%) and 12/37 (32.4%) of the ADRs related to DSCs, respectively. Most DSCs resulted in label revisions (36/37, 97.3%) and seven drugs were eventually withdrawn. Some DSC characteristics are similar among the PMDA/MHLW, the FDA, and the EMA; however, the number, contents, and range of new safety issues addressed by DSCs differ among the three jurisdictions. Our study emphasized the importance of continuous efforts to gather postmarket drug safety information because substantial ADRs that led to DSCs were recognized after approval and were associated with critical label revisions and withdrawals. Future studies are required to address global challenges for regulatory harmonization of safety-related regulatory actions.

Fragility Fracture Network-Japan: The challenge of establishment of a national hip fracture database and successful achievement of nationwide health system change for hip fracture care in Japan

BackgroundIn April 2022, a new reimbursement scheme for hip fracture was implemented by the Japanese health ministry. Japan is one of the world's most aged societies, facing a significant, rapidly growing burden of osteoporosis and fragility fractures. The incidence of hip fractures is projected to increase from 240,000 in 2020 to 320,000 by 2040. In 2015, Fragility Fracture Network-Japan (FFN-Japan) was formally established as a nonprofit organization in order to create the optimal fragility fracture care system in Japan. MethodsFFN-Japan launched the Japan National Hip Fracture Database (JNHFD) in 2017, initially with only eight participating hospitals across Japan. The number of patients enrolled from May 2017 to the end of 2020 in the JNHFD from the 16 hospitals registered the patients during this period with amounting to 4271 patients in total. FFN-Japan invited officials from the Ministry of Health, Labor and Welfare (MHLW) to participate in round table meetings to discuss the data collected in the JNHFD and to consider opportunities for nationwide improvement in hip fracture care. ResultsThe proportion of patients who underwent surgery within 36 h of arrival at hospital was 48.1% in 2018, 58.6% in 2019, and 44.9% in 2020 indicating the delay of surgery. Regarding secondary fracture prevention, initiation of osteoporosis treatment during the in-patients was 60.2% in 2018, 54.0% in 2019, and 64.5% in 2020 indicating the inadequate post fracture care. In April 2022, the Central Social Insurance Medical Council of the Japanese MHLW announced a new reimbursement scheme for hip fracture care including two key components: Early surgery (within 48 h from injury) and Secondary fracture prevention immediately after fracture. DiscussionThe new reimbursement scheme of hip fracture care in Japan will catalyze and underpin major improvements on acute multidisciplinary care and post-fracture care with secondary fracture prevention. FFN-Japan played a key role on these policy changes to the health system by means the close collaboration and ongoing communication with the government. ConclusionWithin five years of establishment of the JNHFD, FFN-Japan in collaboration with visionary leaders from the Japanese government have successfully achieved a major reform of the Japanese health system's reimbursement of hip fracture care. This reform has laid the foundation for transformation of management of this debilitating and life-threatening injury that currently afflicts almost a quarter of a million older Japanese citizens each year.

Effectiveness of catch-up and routine program of the 9-valent vaccine on cervical cancer risk reduction in Japan.

In 2013, the national human papillomavirus (HPV) immunization program began. However, in June 2013, Japan's Ministry of Health, Labor and Welfare (MHLW) announced a "temporary" suspension of its recommendation for the human papillomavirus vaccine. Finally, in November 2021, the MHLW ended its suspension of the recommendation of the HPV vaccine. To address the 9-year gap in HPV vaccinations the suspension had caused, the MHLW conducted a program of catch-up vaccinations from April 2022 to March 2025. Finally, in April 2023, the 9-valent HPV vaccine was approved for both the routine and catch-up vaccination programs in Japan. In this study, we investigated the potential effects of the introduction of the 9-valent vaccine on the increased risk of cervical cancer in females born after fiscal year (FY) 2000. We estimated the lifetime relative risk of cervical cancer incidence and death using the improved routine and catch-up vaccination rates after the recent resumption of the governmental recommendation for women and girls to have the HPV vaccination. These relative risks were calculated using a lifetime risk of 1.000 for cervical cancer incidence and death for females born in FY 1993. We predicted that even if a 90% vaccination rate were to be achieved by FY 2024 with the 9-valent vaccine among women born between FY 2000 and FY 2005, the risk would remain higher than for the vaccination generation. Therefore, for women born between FY 2000 and FY 2005, it will be necessary to significantly improve the cervical cancer screening rate to compensate for this increased risk.

Review of a Series of Surveys on Adverse Reactions to the COVID-19 mRNA-1273 Vaccine at Okayama University.

This paper presents the results of a series of surveys conducted from July 2021 to March 2023 to investigate the post-vaccination adverse reactions to the mRNA-1273 (Moderna) vaccine among faculty, staff, and students at Okayama University. These studies complement the official surveys conducted by the Ministry of Health, Labour and Welfare (MHLW) and provide a more representative picture of adverse reactions in the general population including large numbers of healthy young people. Pain, swelling, redness at the injection site, fever, headache, and malaise were the main adverse reactions reported. The proportion of adverse reactions was generally higher after the second vaccination and decreased with each additional vaccination. No statistically significant differences in the adverse reactions were found for males and females and those with/without a history of allergy, but a lower proportion of fever was observed in older participants and those with underlying medical conditions. We also evaluated the association between adverse reactions and antibody titers after the third vaccination and found no significant differences in antibody levels one month after vaccination. This series of studies highlights the importance of conducting surveys in diverse populations to provide a more representative picture of post-vaccination adverse reactions during a pandemic.

Causes of Countermeasures Against Serious Accidents Caused by Health Hazards of Chemical Substances, Based on Cases of Occupational Accidents in Japan

The purpose of this study was to summarize the typical and specific causes and risk reduction measures of serious accidents in Japan caused by chemical substances in terms of the 10 types of human health hazards in the UN GHS (Globally Harmonized System of Classification and Labelling of Chemicals) classification. The list of "Cases of Major Accidents Caused by Chemical Substances" published on the "Safety in the Workplace Website" of the Ministry of Health, Labor and Welfare (MHLW) was linked to the "Results of GHS Classification by the Government" of the National Institute of Technology and Evaluation (NITE). Analysis was conducted by health hazards in order to obtain reference examples of measures taken against health hazards in response to the revision of the law on autonomous chemical substance management in 2022. Using the text mining tool KH Coder ver. Three using cluster analysis, we grouped causes and measures among serious disasters by health hazard, illustrated co-occurrence networks, and extracted typical examples of each in a co-occurrence network. Representative causes of and measures against occupational accidents caused by health hazardous properties were summarized from the extracted typical cases. Although few occupational accidents were caused by the health hazards of chemicals, when all health hazards were classified into acute toxicity, acute health hazard, and chronic health hazard, contact was a clear cause for many of the acute toxicity and acute health hazards, such as corrosiveness and sensitization. However, many occupational accidents were caused by the physical hazardous aspects of the chemical substances or by the safety aspects of the workplace. Causes of occupational accidents due to health hazards included unsafe behavior and unsafe conditions, or lack of understanding of the physicochemical properties of a substance and specific reactions such as mixing or hydrolysis of the substance. Typical risk reduction measures for health hazards included equipment to prevent human contact with health hazardous substances, systems to control unsafe behavior, promoting understanding of chemical reactions, and providing information about chemicals to all persons involved in testing, research, and subcontract work. The data of occupational accident cases of "death or more than 4 days lost from work" were used. Most of the cases were related to acute health hazards, but relatively few to chronic health hazards, and few occupational accidents were caused by health hazards. Most of the occupational accidents were caused by health hazards due to the physical hazards of chemical substances and inadequate workplace safety. In light of the above, it is necessary in autonomous chemical substance management to first take risk reduction measures for workplace safety and chemical physical hazards, then to prevent contact with acute toxicity and acute health hazards such as corrosiveness and sensitization, and, lastly, to take risk reduction measures for chronic health hazards, using allowable concentrations and controlled concentrations as indices.

A questionnaire survey on the prevention of HPV infection among females and males who came of age in Japan under various scenarios of HPV vaccine recommendation

ABSTRACT The Japanese Ministry of Health, Labor and Welfare (MHLW) temporarily suspended recommendation for HPV vaccinations for girls in June 2013. It resumed its recommendation in November 2021. To compensate for eight years of lost overage, a ‘catch-up HPV vaccination’ program began in April 2022. To determine intervention needs in regards to HPV vaccine hesitancy, from October 13 2021 to April 31 2022, we surveyed 12–28 year-old vaccine-eligible males and females (281 males, 583 females). We investigated the gender and ‘vaccine generational’ differences in attitudes, perceptions, and future intentions regarding HPV vaccination. Two generations were defined by the vaccine recommendation environment they grew up in. The ‘vaccine generation’ was born in FY 1994–1999; the ‘vaccine-suspension generation’ born in FY 2000–2009. Knowledge regarding the HPV vaccine correlated significantly with being female, of the vaccination generation, a medical student, and having received the COVID-19 vaccine. There was a significant ‘generational’ difference in terms of approval of the MHLW’s recommendation resumption. The attitudes, perceptions, and future intentions of Japan’s two generation groups are unique and should be dealt with accordingly. HPV vaccination promotion should consider the strong gender differences we identified. As an extension of the anti-cervical cancer program, HPV vaccinations for boys should begin immediately. Our study of their unique outlooks will contribute to the discussion surrounding that implementation.

Influenza vaccine viruses and the development of seasonal vaccines: A Japanese perspective

In Japan, the Ministry of Health, Labour and Welfare (MHLW) designates one specific virus strain for each component of the quadrivalent seasonal influenza vaccine, and four domestic manufacturers produce egg-based influenza vaccines with the same formulation (inactivated, split-virus) using uniform vaccine strains. Thus, discussions of the development of effective seasonal influenza vaccines so far has focused solely on the antigenic match between the vaccine strains and epidemic viruses. However, in 2017, the Japanese selection system of vaccine viruses demonstrated that even a candidate vaccine virus that is antigenically similar to the predicted circulating viruses is not necessarily suitable for vaccine production, given lower productivity of the vaccine. Taking this experience into account, the MHLW reformed the scheme of vaccine strain selection in 2018, and instructed the Vaccine Epidemiology Research Group created by the MHLW to probe how the virus strains for the seasonal influenza vaccine should be selected in Japan. In this context, a symposium, entitled “Issues of the Present Seasonal Influenza Vaccines and Future Prospects”, was held as part of the 22nd Annual Meeting of the Japanese Society for Vaccinology in 2018, and subjects related to the influenza vaccine viruses were discussed among relevant administrators, manufacturers, and researchers. This report summarizes the presentations given at that symposium in order to convey the present scheme of vaccine virus selection, the evaluation of the resulting vaccines, and the efforts at new vaccine formulation in Japan. Notably, from March 2022, the MHLW has launched a discussion of the merits of the seasonal influenza vaccines produced by foreign manufacturers.

Increased number of live births by migrant mothers shows areal inequality in Japan: A descriptive study

Japan has not implemented policy of accepting many migrants, and the proportion of migrants in the total population is much smaller than that in other economically developed countries. Therefore, issues regarding the health status of migrants, especially migrant mothers and their children, have not been discussed enthusiastically in Japan. In the present study, we aimed to describe the epidemiology (time trend of the number, areal distribution, and frequency of maternal nationality of newborn births) of live births by migrant mothers in Japan, which contributes to the administration of medical policies on the perinatal care of migrant mothers. This study used data from the vital statistics reported by the Ministry of Health, Labour and Welfare (MHLW) of Japan and from foreign resident statistics reported by Immigration Services Agency (ISA) of Japan. To show areal inequality in the number of live births by migrant mothers, we applied the Gini coefficient. This study demonstrated that the number of live births by migrant mothers increased from 16,154 (1.31% of the total) in 1990 to 26,517 (3.08%) in 2020. It also showed stronger areal inequality at prefecture level by Japanese mothers (Gini coefficient; 0.64 vs 0.46 in 2020), and this areal inequality has increased during the last decade. This study also illustrated that the frequency of maternal nationality of newborns from migrant mothers has been altered in the last decade, especially in the composition of Asian countries. In conclusion, the number of live births by migrant mothers in Japan has been progressively increasing; however, this trend is excessively concentrated in specific areas in Japan. These tendencies are expected to become more prominent in the future, and their possible impacts on medical institutions and administrative agencies in specific areas that treat migrant mothers should be investigated and discussed.

Evaluation ofMinistry ofHealth, Labour andWelfare diagnostic criteria forantineutrophil cytoplasmic antibody-associated vasculitis compared to ACR/EULAR 2022 classification criteria.

This study aimed to evaluate the Ministry of Health, Labour and Welfare (MHLW) diagnostic criteria for antineutrophil cytoplasmic antibody-associated vasculitis compared to the new American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 criteria. Two nationwide cohort studies were used, and participants were categorised as having eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA) according to the American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 and MHLW criteria. Of the entire patient population, only 10 (2.1%) were unclassifiable according to the MHLW probable criteria, while a significant number of patients (71.3%) met at least two criteria. The MHLW probable criteria for MPA had some challenges in differentiating between MPA and eosinophilic granulomatosis with polyangiitis, and the same was true for MHLW probable criteria for GPA in differentiating MPA from GPA. Nevertheless, improved classification results were obtained when the MHLW probable criteria were applied in the order of eosinophilic granulomatosis with polyangiitis, MPA, and GPA. The application of MHLW criteria could categorise a substantial number of patients with antineutrophil cytoplasmic antibody-associated vasculitis into one of the three antineutrophil cytoplasmic antibody-associated vasculitis diseases. The classification was in accordance with the American College of Rheumatology/European Alliance of Associations for Rheumatology 2022 criteria when considering the order of application.

Progress report of a cross-organ and biomarker-based platform study: BELIEVE trial NCCH1901.

TPS1611 Background: Cancer Genomic Medicine (CGM) has been developing and more patients have received the comprehensive genomic profiling (GCP) test under national healthcare system in Japan. However, the number of patients who could receive the genomically matched therapy based on the results of CGP tests was limited. To improve the drug accessibility, we initiated a cross-organ, biomarker-based clinical trial (NCCH1901, the BELIEVE trial). It was a platform trial and could be considered as the Japanese counterpart to the National Cancer Institute's Molecular Analysis for Therapy Choice (NCI-MATCH) study in the United States. Methods: It was a multi-institutional joint research nationwide led by NCCH with a master’s protocol. Several drug cohorts were pre-established, allowing patients to participate in molecularly targeted treatments recommended as a result of CGP test. All drugs were provided for free from the pharmaceutical companies. The objective of this trial was to administer off-label drugs for the respective genomic abnormalities and collect efficacy and safety data for patients of the drugs. The primary endpoint was the response rate based on the best overall response for up to 16 weeks. This trial has been conducted under both of the Japanese Clinical Trial Act and the patient-proposed healthcare services which enable patients to receive unapproved, off-label drugs partially covered by National Health Insurance. The protocol and the informed consent forms were approved by the National Cancer Center Hospital (NCCH) certified review board and the Ministry of Health, Labour and Welfare (MHLW). The trial was registered in the Japan Registry of Clinical Trials (jRCTs031190104). As of January 31, 2023, we have 20 drug cohorts and the planned number of enrollments for each cohort was 50 with the target lesions and 30 without the target lesions. There were more than 500 patients so far. The most common cancer was brain tumours, followed by carcinoma of endocrine organs and the colorectal cancer. BRAF mutation and ERBB2 amplification were the frequent genomic abnormalities registered in this trial. Five drug cohorts have already finished recruiting and 2 drug cohorts assessed their efficacies. We are still continuing to discuss several pharmaceutical companies to increase the drugs cohorts in this platform. This trial is now recruiting the patients and is contributing significantly to increase the treatment opportunity for the cancer patients. Clinical trial information: jRCTs031190104 .

Addressing practical issues in the smooth implementation of revised guidelines for non-clinical studies of vaccines for infectious disease prevention

Herein, we investigated possible practical issues for the smooth implementation of the revised Japanese Guidelines for Non-clinical Studies of Vaccines for the Prevention of Infectious Diseases, which were raised in response to public comments on the proposed guideline revision and a gap analysis of the World Health Organization and European Medicines Agency guidelines. We identified main issues such as the non-clinical safety studies of adjuvants and evaluation of local cumulative tolerance in toxicity studies. The revised Japanese Pharmaceuticals and Medical Devices Agency (PMDA)/Ministry of Health, Labour and Welfare (MHLW) guidelines require non-clinical safety studies for vaccines containing new adjuvants, but additional safety pharmacology studies or safety studies in two animal species may be required if non-clinical safety studies raise any concerns (i.e., systemic distribution). Adjuvant biodistribution studies may aid in understanding vaccine characteristics. The evaluation of local cumulative tolerance in non-clinical studies, which was the focus of the Japanese review, can be omitted by including a warning in the package insert to avoid injection to the same site. The study's findings will be reflected in a Q&A to be released by the Japanese MHLW. We hope that this study will contribute to the global and harmonized development of vaccines.

Conditional early approval for new drug applications in Japan: Current and emerging issues.

Conditional early approval for new drug applications in Japan: Current and emerging issues.

Current Status of the Disaster Health, Medical, and Welfare Coordination in Japan

Introduction:Non-coordinated support during disasters has negative effects on affected communities and people. From the 2004 Indian Ocean Tsunami, the United Nations introduced a cluster approach to avoid gaps and duplication of aid. Japan's disaster coordination of support for health and medical care was organized after the 2017 Kumamoto earthquake. The Ministry of Health, Labour and Welfare (MHLW) announced and issued the notice that the prefectures need to establish a system related to health and medical activities in the event of a large-scale disaster. In July 2022, welfare content was added. This study investigated the current status of health sector organizational coordination among health, medical, and welfare responders during 2022 the Large-Scale Earthquake National Exercise (LSENE).Method:The 2022 LSENE was conducted on October 1, 2022 with participation from the Disaster Medical Assistant Team (DMAT) and responders from each prefecture's health and welfare divisions and organizations. Each responder's exercise log sheet and the exercise controller's evaluation were reviewed.Results:Even though there was a notice from the MHLW, organized coordination was conducted only by several medical and health teams. DMAT is the only team with a system to dispatch teams from non-affected prefectures and coordinate well to allocate teams. Some other health and welfare organizations did not have a dispatching system. They had difficulty sending teams to affected areas, especially due to a lack of a systematic response system, training, coordination headquarters, and information sharing. It was suggested that information sharing and coordination among responders is necessary, although information gathering and request judgments related to dispatch coordination are different for each organization.Conclusion:In order to smoothly coordinate support teams for health, medical, and welfare in the event of a disaster, it is necessary not only to improve the coordination headquarters for health, medical, and welfare but also to verify its operation through training.