Issues with infectious disease vaccine introduction into routine vaccination in Japan, and considerations for accelerating the process.

Routine vaccinations help prevent the outbreak and spread of infectious diseases; however, it can take up to ten years from vaccine approval to introduction into routine vaccination schedules in Japan. Here, we investigate the information required to introduce an approved vaccine into routine vaccination schedules and the reasons why it takes so long. Based on the published data of the Immunization and Vaccine Committee of the Health Science Council, we set out to explore ways to facilitate discussion on this topic. The following issues were identified as discussion points: disease burden, efficacy and safety, and cost-effectiveness. Until now, epidemiological information has been used to evaluate the efficacy of vaccines, and also to evaluate the safety in the presence of notable adverse reactions. However, in some cases, it took a long time to obtain epidemiological information regarding the frequency of rare but serious adverse reactions and the need for a booster dose. Given the risk of spreading infectious diseases due to delays in decision-making, vaccines may have to be introduced into routine vaccination schedules based on the results of clinical trials that can be obtained in a relatively short period. In contrast, epidemiological information is necessary to evaluate the disease burden, frequency of adverse reactions, and the necessity of booster doses. Therefore, developing an epidemiological information collection system is urgently required.

Creating an Assessment Indicator of Quality Culture Development in the Generic Pharmaceutical Industry in Japan.

In the past few years, there have been several instances of illicit pharmaceutical manufacturing in Japan, and there is a growing awareness of the importance of corporate compliance and pharmaceutical manufacturing and quality controls. One cause of illicit manufacturing is the inadequate development of quality culture. This study focuses on the degree of quality culture development in Japanese pharmaceutical companies manufacturing generic drugs. Because no evaluation index for Japan can visualize the degree of quality culture development in each company, this study sought to establish this index to utilize it as a tool for evaluating the degree of quality culture development that would enable each company to continuously monitor and improve its own. We conducted a questionnaire survey among Japan Generic Medicines Association members to evaluate the degree of their quality culture development. The questionnaire contained 28 questions in five evaluation categories. Potential indicators of quality culture development included "Employee growth and satisfaction"; "Management commitment"; "Improvement activities"; "Communication"; and "Environment, health, and safety." We obtained 294 responses from 37 Marketing Authorization Holder (MAH) and 61 manufacturing sites. Respondents were classified by roles of management, manager, and nonmanager. The results confirmed the current status of quality culture development efforts, showing that important messages such as the corporate philosophy as communicated by the management is well known, awareness of quality culture development level differs by role, and appropriate resources are not adequately allocated to employees or facilities. Based on the results, use of the index of quality culture development helped to make relative comparisons and visualize the areas to be addressed for quality culture development. This study established and visualized the index for the degree of quality culture development in domestic generic drug manufacturing companies and we hope this indicator becomes a useful tool for evaluating a company's quality culture development level.

Incidence of interstitial lung disease in patients with breast cancer: a nationwide database study in Japan.

Aim: This study estimated the incidence of moderate-to-severe drug-induced interstitial lung disease (ILD) among patients with breast cancer in Japan. Methods: We analyzed a large nationwide database of patients with breast cancer treated with anticancer therapies between 2009 and 2022. ILD was identified using diagnostic codes and treatment records. Results: Of the 81,601 patients, 1042 developed ILD requiring corticosteroids, corresponding to an incidence rate of 1.41 per 100 person-years. The incidence varied across years and treatment regimens. Most ILD incidents occurred within the initial 90-day period post-anticancer therapy initiation. Conclusion: Increase in ILD cases and potential risk variations among treatments underline the importance of continued monitoring, especially during treatment onset, and ILD management in patients with breast cancer undergoing therapy.

This article investigates how often a lung condition known as interstitial lung disease (ILD) occurs in patients treated for breast cancer in Japan. ILD can cause inflammation and damage to the lungs and can be a side effect of some cancer treatments. The study looked at over 81,000 patients with breast cancer from 2009 to 2022. A total of 1042 patients developed ILD that required treatment with steroids to reduce inflammation. This number suggests that ILD occurred in 1.41 out of every 100 patients treated each year. The study noted that the chances of developing ILD varied over the years and depended on the type of cancer treatment. The findings showed that ILD is a risk factor for patients undergoing breast cancer treatment, and the risk can change depending on the treatment they receive. This highlights the importance of doctors keeping a close eye on their patients, especially early in the treatment process, to identify and manage any signs of ILD. Careful monitoring can help improve the health and treatment outcomes of patients with breast cancer. The study also points to the need for more research to understand why ILD occurs and how to prevent or treat it.

Implementation status and consideration for the globalisation of decentralised clinical trials: a cross-sectional analysis of clinical trial databases.

OBJECTIVE: To comprehensively elucidate the current landscape of decentralised clinical trials (DCTs) and identify notable aspects that can facilitate DCT implementation. DESIGN: Cross-sectional analysis. SETTING: Data were extracted using selected DCT-specific search terms on 4 June 2022, from the ClinicalTrials.gov database and on 2 September 2022, from the Japan Registry of Clinical Trials and Japic Clinical Trials Information. PRIMARY OUTCOME MEASURE: We characterised trials based on the four components of DCT: telemedicine, home healthcare, direct-to-patient and the Internet of Healthcare Things (IoHTs)/Internet of Medical Things. RESULTS: Data obtained from ClinicalTrials.gov indicated that the number of DCTs has increased annually and exponentially since 2020. DCTs for cardiovascular diseases are the most common, and the digital platform for patient monitoring is used the most in DCTs. The Japanese databases also showed that DCTs have increased in recent years, and the data on disease areas and IoHTs were similar to those obtained from the ClinicalTrials.gov database, except for the number of studies. Approximately 9.2% of DCTs were conducted across multiple regions, whereas over 80% were conducted within a single country. CONCLUSIONS: This study revealed the comprehensive trend of DCTs in the USA and Japan and helped identify widely implemented DCT components and the therapeutic areas in which they are implemented. International consensus guidelines for DCTs are necessary to promote multiregional clinical trials with DCT components.

Quality Culture and Knowledge Management in the Japanese Pharmaceutical Industry-A Cross-Sectional Study and Case Report.

In the past few years, there have been several instances of illicit pharmaceutical manufacturing in Japan. Insufficient good manufacturing practice compliance and lack of quality culture in some pharmaceutical companies have been suggested as the underlying reasons for such cases. We aimed to focus on knowledge management and fostering of quality culture in pharmaceutical companies in Japan to understand their current situation and find a strategy for the availability of high-quality reliable pharmaceutical products. A wide-ranging questionnaire survey was conducted to understand the issues related to knowledge management and fostering of quality culture across pharmaceutical companies in Japan. A published investigation report on an illicit manufacturing case was closely examined by organizing the available facts using the diagram. Based on 395 responses to the questionnaire survey, we found that although pharmaceutical companies understand the importance of knowledge management and quality culture, issues exist in their operational methods. A total of 94% of the respondents agreed that they mentioned "knowledge management" as an enabler of the Pharmaceutical Quality System of ICH Q10, and 98% of the respondents accepted that insufficient fostering of quality culture leads to corporate risk. However, the survey revealed that many companies are struggling with this approach. Based on a report on an illicit manufacturing case, we analyzed the direct causes of misconduct and prepared a systematic summary that can be easily comprehended. Comparison of the illicit manufacturing case report with our questionnaire results suggests that many pharmaceutical companies do not regard the misconduct case as a situation that could occur in their company. With the revision of the Pharmaceuticals and Medical Devices Act and good manufacturing practice Ministerial Ordinance, we advocate the need for all employees of pharmaceutical companies to reconsider the priorities of their companies from the patient perspective.

Horizon Scanning in Tissue Engineering Using Citation Network Analysis.

BACKGROUND: Establishing a horizon scanning method is critical for identifying technologies that require new guidelines or regulations. We studied the application of bibliographic citation network analysis to horizon scanning. OBJECTIVE: The possibility of applying the proposed method to interdisciplinary fields was investigated with the emphasis on tissue engineering and its example, three-dimensional bio-printing. METHODOLOGY AND RESULTS: In all, 233,968 articles on tissue engineering, regenerative medicine, biofabrication, and additive manufacturing published between January 1, 1900 and November 3, 2021 were obtained from the Web of Science Core Collection. The citation network of the articles was analyzed for confirmation that the evolution of 3D bio-printing is reflected by tracking the key articles in the field. However, the results revealed that the major articles on the clinical application of 3D bio-printed products are located in clusters other than that of 3D bio-printers. We investigated the research trends in this field by analyzing the articles published between 2019 and 2021 and detected various basic technologies constituting tissue engineering, including microfluidics and scaffolds such as electrospinning and conductive polymers. The results suggested that the research trend of technologies required for product development and future clinical applications of the product are sometimes detected independently by bibliographic citation network analysis, particularly for interdisciplinary fields. CONCLUSION: This method can be applied to the horizon scanning of an interdisciplinary field. However, identifying basic technologies of the targeted field and following the progress of research and the integration process of each component of technology are critical.

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.

Points to Consider in the Development and Information Provision of Vaccines for Vaccination during Pregnancy: A Survey.

This report surveyed vaccination decisions during pregnancy based on the package inserts of vaccines approved in Japan, the USA, and Europe. Furthermore, it evaluates vaccination decision-making factors based on the characteristics of the target infections and the modality of the vaccines. Live vaccines known to cause fetal abnormalities are contraindicated for pregnant women, whereas vaccines for life-threatening infectious diseases are authorized for administration during pregnancy when the need is recognized, even for live vaccines. We compared the World Health Organization and European Medicines Agency guidelines on the development of vaccines for pregnant women and surveyed the details of the studies to collect information on SARS-CoV-2 vaccination during pregnancy. In compliance with the guidelines, for all SARS-CoV-2 vaccines, non-clinical reproductive and developmental toxicity studies and clinical trials including non-pregnant women of childbearing age were conducted prior to the vaccination of pregnant women. For all vaccines, information from registries on vaccination during pregnancy are used for post-marketing surveillance. While it is desirable to vaccinate women before pregnancy through planned immunization, whenever possible, pandemics such as H1N1 influenza and COVID-19 may require vaccination even during pregnancy. Necessary and sufficient studies for the decision of vaccination during pregnancy should be carried out promptly.

Proposal for the revision of guidelines for clinical trials of vaccines to prevent infectious diseases in Japan.

The development of vaccines against infectious diseases requires a different approach from that of therapeutics, because vaccines are inoculated into healthy individuals and have a preventive effect by activating the immunity of the inoculated human. In Japan, "The Guideline for Clinical Trials of Vaccines for the Prevention of Infectious Diseases" was published in 2010 before changes occurred in the vaccine development environment in Japan, such as the introductions of foreign vaccines and simultaneous global development. This study aimed to identify current challenges in vaccine development through a questionnaire-based survey of pharmaceutical companies in Japan and by comparing the domestic and international guidelines and surveying review reports of 35 vaccines approved in Japan between April 2010 and December 2020. Identified challenges included the requirement for protective efficacy trials, efficacy evaluation of combination vaccines, development of multiregional and foreign clinical trials, and immunization of older adults and immunocompromised patients. We propose that new vaccines against infectious diseases should be evaluated for the protective efficacy, preferably through multiregional clinical trials. Additionally, differences in the incidence of infectious diseases or in epidemic virus strains between regions may affect the trials, when multiregional clinical trials are conducted, but immunogenicity-based studies can be conducted if a correlation between protective efficacy and immunogenicity has been established. We suggest that licensed combination vaccines can be used as comparators when an antigen is added to a licensed combination vaccine. We also proposed that the efficacy of a vaccine in non-major subjects, such as older adults or immunocompromised patients could be evaluated by comparing immunogenicity in major subjects with the confirmed protective effects of the vaccine. It is expected that these revisions will lead to the rapid advancement of vaccine development, which should contribute to the improvement of public health.

Impact of the Clinical Trials Act 2018 on clinical trial activity in Japan from 2018 to 2020: a retrospective database study using new and conventional Japanese registries.

OBJECTIVE: To clarify the impact of Japan's Clinical Trials Act (CTA), which was enacted in April 2018, on subsequent clinical trial activity through an analysis of Japanese registry data. DESIGN: Retrospective database study. SETTING: We extracted information on clinical intervention studies registered between 1 April 2018 and 30 September 2020 in the conventional University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) and the new Japan Registry of Clinical Trials (jRCT). We collected and analysed information on registration dates, intervention types, funding, secondary sponsors and use of designated staff in multidisciplinary roles (research planning support, research administration, data management, statistical analysis, monitoring and auditing). The temporal trends in clinical trial activity after CTA enactment were examined. RESULTS: A total of 577 CTA-compliant specified clinical trials (ie, studies funded by pharmaceutical companies or studies evaluating the efficacy and safety of off-label drugs or devices in humans) were registered in the jRCT. During the same period, 5068 clinical trials were registered in the UMIN-CTR. The number of specific clinical trials increased immediately after the implementation of the CTA and stabilised in late 2019, whereas the number of clinical trials registered in the UMIN-CTR generally declined over time. Specified clinical trials that received industry funding and public grants were more likely to use designated staff in multidisciplinary roles. CONCLUSIONS: The implementation of the CTA has not reduced the number of specified clinical trials, but has reduced the total number of intervention trials. The use of designated staff in multidisciplinary roles is associated with funding, secondary sponsors and multicentre studies. It was inferred that funding was needed to establish research infrastructure systems that support high-quality research.

Application of Internet of Medical/Health Things to Decentralized Clinical Trials: Development Status and Regulatory Considerations.

Background: The need for a new style of clinical trials, called decentralized clinical trials (DCTs), has been increasing as they do not depend on physical visits to clinical sites. DCTs are expected to provide a new opportunity to patients who cannot participate in a clinical trial due to geographical and time limitations. For the adoption of DCTs, it is essential that medical devices with Internet of Medical Things (IoMT) and Internet of Health Things (IoHT) based technologies are developed and commercially adopted. In this study, we aimed to identify the regulatory considerations when IoMT/IoHT-based technologies are used in DCTs or products developed using DCTs. Method: To understand the study and development field of IoMT/IoHT comprehensively and panoramically, relevant papers published in Web of Science were searched online. Subsequently, a citation network was obtained and characterized as a cluster using a text mining method to identify IoMT/IoHT-based technologies expected to be utilized in DCTs or products developed using DCTs. Result and Discussion: Upon analysis of the top 15 clusters and subsequent 51 sub-clusters, we identified the therapeutic areas (psychology, neurology) and IoMT/IoHT-based technologies (telemedicine, remote monitoring, and virtual reality) that are expected to be used in DCTs. We also identified several considerations based on the current regulatory guidance. Conclusion: IoMT/IoHT-based technologies that are expected to be used or products developed using DCTs and key considerations made when they are used in DCTs were identified. The considerations could encourage conducting DCTs using IoMT/IoHT-based technologies.

Proposal for the revision of the guidelines for Non-clinical studies of vaccines for the prevention of infectious diseases in Japan.

The efficacy and safety of vaccines for the prevention of infectious diseases are mostly evaluated based on the induction of an immune response against antigens, and do not necessarily depend on the dose administered. Therefore, there are some specific aspects that need to be considered in the development of vaccines and have been described in "The Guidelines for the non-clinical studies of vaccines for the prevention of infectious disease" in Japan. Recent changes in the vaccine development field, such as the introduction of vaccines developed overseas in Japan and vaccine development on a global scale have increased the need for revision of these guidelines. In this study, we identified the current challenges in the development of vaccines through comparison of Japanese and international guidelines. We conducted a questionnaire-based survey of pharmaceutical industries in Japan, and found issues related to non-clinical studies, such as the necessity of safety pharmacology studies and repeated-dose toxicity studies for each route of administration. We examined international guidelines on these issues as well as review reports by regulatory authorities, and determined that the results of repeated-dose toxicity studies can be used to decide whether safety pharmacology studies are required, and that studies to evaluate toxicity due to systemic effects may not be necessary for both intramuscular and subcutaneous administration. We propose revision of the guidelines for the non-clinical studies of vaccines in Japan taking international harmonizaion into account. We expected that the revised guidelines will promote smooth and rational vaccine development.

Study on Horizon Scanning by Citation Network Analysis and Text Mining: A Focus on Drug Development Related to T Cell Immune Response.

Certain innovative technologies applied to medical product development require novel evaluation approaches and/or regulations. Horizon scanning for such technologies will help regulators prepare, allowing earlier access to the product for patients and an improved benefit/risk ratio. This study investigates whether citation network analysis and text mining of scientific papers could be a tool for horizon scanning in the field of immunology, which has developed over a long period, and attempts to grasp the latest research trends. As the result of the analysis, the academic landscape of the immunology field was identified by classifying 90,450 papers (obtained from PubMED) containing the keyword "immune* and t lymph*" into 38 clusters. The clustering was indicative of the research landscape of the immunology field. To confirm this, immune checkpoint inhibitors were used as a retrospective test topic of therapeutics with new mechanisms of action. Retrospective clustering around immune checkpoint inhibitors was found, supporting this approach. The analysis of the research trends over the last 3 to 5 years in this field revealed several candidate topics, including ARID1A gene mutation, CD300e, and tissue resident memory T cells, which shows notable progress and should be monitored for future possible product development. Our results have demonstrated the possibility that citation network analysis and text mining of scientific papers can be a useful objective tool for horizon scanning of life science fields such as immunology.

Study on Horizon Scanning with a Focus on the Development of AI-Based Medical Products: Citation Network Analysis.

Horizon scanning for innovative technologies that might be applied to medical products and requires new assessment approaches to prepare regulators, allowing earlier access to the product for patients and an improved benefit/risk ratio. The purpose of this study is to confirm that citation network analysis and text mining for bibliographic information analysis can be used for horizon scanning of the rapidly developing field of AI-based medical technologies and extract the latest research trend information from the field. We classified 119,553 publications obtained from SCI constructed with the keywords "conventional," "machine-learning," or "deep-learning" and grouped them into 36 clusters, which demonstrated the academic landscape of AI applications. We also confirmed that one or two close clusters included the key articles on AI-based medical image analysis, suggesting that clusters specific to the technology were appropriately formed. Significant research progress could be detected as a quick increase in constituent papers and the number of citations of hub papers in the cluster. Then we tracked recent research trends by re-analyzing "young" clusters based on the average publication year of the constituent papers of each cluster. The latest topics in AI-based medical technologies include electrocardiograms and electroencephalograms (ECG/EEG), human activity recognition, natural language processing of clinical records, and drug discovery. We could detect rapid increase in research activity of AI-based ECG/EEG a few years prior to the issuance of the draft guidance by US-FDA. Our study showed that a citation network analysis and text mining of scientific papers can be a useful objective tool for horizon scanning of rapidly developing AI-based medical technologies.

Identification of Novel Modalities Through Bibliometric Analysis for Timely Development of Regulatory Guidance: A Case Study of T Cell Immunity.

Background: The mission of medicines regulatory agencies is to ensure the timely access of innovative products for patients to improve public health. Thus, regulators should foresee evolving technologies and build expertise prior to reviewing innovative products. Novel modalities and new classes of therapeutics in biological or cell-based products represent a regulatory challenge because of knowledge gaps, as exemplified by the unexpected cytokine release syndrome in the first-in-human clinical trial of the CD28 super-agonist. Meanwhile, recent treatments harnessing T cell co-signaling pathways provide an opportunity for investigation. Therefore, this study aimed to systematically identify and evaluate novel modalities for T cell immunity to assess the need for regulatory guidance. Methods: A PubMed search was carried out using the query, "immun* AND t lymph*" to select publications. Subsequently, a citation network was created, followed by clustering and text mining to identify the modalities and classes of therapeutics under development. Results and Discussion: Analysis of the top 20 clusters revealed research domains characterized by keywords such as immune checkpoint antibody, chimeric antigen receptor (CAR)-T cells, microbiota, exosome, regulatory T cells, unconventional T cells, and vaccines. After reviewing the pharmacological concepts, clinical trial information, and available guidance, we presented a perspective on the future development of guidance for these domains. Conclusion: Bibliometric analyses identified a set of innovative modalities targeted for drug development with which regulatory guidance is going to catch up. This strategy could help in the successful development of upcoming modalities to ensure readiness for clinical application as part of horizon scanning.

Dissolution Profiles of Generic Products in Dissolution Media Defined by Japanese Guidelines for Bioequivalence Studies.

The International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use M9 Guidelines for Biopharmaceutics Classification System Biowaivers reached harmonization in November 2019. However, guidelines for bioequivalence studies are not internationally harmonized, and water as a dissolution medium is only required in Japanese guidelines, regardless of drug solubility. This study investigated the dissolution profiles of generic products in Japan that differ from those of original drugs in dissolution media defined in guidelines. Dissolution profiles disclosed on websites of generic manufacturers were investigated for 262 active ingredients listed in the bluebook (4638 oral solid products listed in the National Health Insurance drug price list) issued by the Ministry of Health, Labour and Welfare. 5% of all generic products were different from the original products in dissolution media, of which 20% was observed in water only. Among the active pharmaceutical ingredients that showed different dissolution profiles only in water, the ratio of original products that showed slower dissolution profiles to the generics was 73%. The ratio of products showing different dissolution in water only was higher than in other media investigated in this study; however, these do not reflect disintegration and dissolution of drug products in the gastrointestinal tract, since bioequivalence has been confirmed in human studies and the generic products were approved by Japanese authorities. Therefore, a discussion about the required use of water as a dissolution medium in the Japanese guidelines is needed among industry, academia, and regulatory authorities.

Impact of Quality by Design Development on the Review Period of New Drug Approval and Product Quality in Japan.

BACKGROUND: For pharmaceutical products, an in-depth understanding of manufacturing processes and quality risks associated with quality by design (QbD) development enables the production of high-quality products. Product recall due to quality issues could be minimized for QbD-developed products. Furthermore, the review period instituted by regulatory authorities could be shortened by allowing reviewers to access technical documents with QbD elements. The aim of this study was to examine the impact of QbD development from the viewpoints of regulatory flexibility, product quality related to recall, and review period in Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. METHODS: QbD developments for new active ingredients, approved from 2009 to 2018, were surveyed in the PMDA review reports, and review periods were investigated on the PMDA website. Voluntary product recalls and their rationale were investigated using the website of the Japan Ministry of Health, Labour and Welfare. RESULTS: Although the developmental ratio with QbD elements was increased from 9% in 2009 to 71% in 2018, the development of design space for drug substances and products between 2009 and 2018 was only 2%, and real time release testing (RTRT) for drug products was limited to 3%. Voluntary recall and extension of the review period for QbD-developed products were not observed. CONCLUSION: The advantages of systematic QbD development were suggested for no voluntary recall of QbD-developed products. Conversely, applicants did not actively seek regulatory flexibility with design space or RTRT, and QbD development failed to impact the PMDA review period.

Considerations and Regulatory Challenges for Innovative Medicines in Expedited Approval Programs: Breakthrough Therapy and Sakigake Designation.

BACKGROUND: In the breakthrough therapy designation (BTD) and Sakigake designation programs, rolling submission and close communication between applicants and regulatory authorities enable the timely access of patients to innovative medicines. However, challenges in the quality development, including chemistry, manufacturing, and control (CMC), are expected during the accelerated timeline. This study focused on development with quality by design (QbD) concept, shelf life of drug product, and post marketing commitment (PMC) to clarify developmental strategies and regulatory challenges associated with expedited approval programs. METHODS: QbD developments, shelf life of drug products, and PMC were surveyed in the review reports of the US Food and Drug Administration (FDA) and Pharmaceuticals and Medical Devices Agency (PMDA) websites. RESULTS: Overall, 86% of BTD products and two out of three Sakigake products were developed using a QbD approach. Furthermore, 92% of BTD products and two out of three Sakigake products were granted a shelf life of at least 18 months. In the BTD pathway, 50% of PMCs concerned the reevaluation of specification and test method. CONCLUSION: For most BTD and Sakigake products, the control strategy was developed utilizing the QbD concept, and long shelf life was granted despite the accelerated timeline. No discount for specification setting was observed for assuring quality, based on the available data at the time of approval in the BTD and Sakigake programs, although PMCs were mainly required for reevaluation of the specification and test method in BTD programs. Further efforts should focus on creating/revising guidelines for CMC development.

Indolent primary effusion lymphoma-like lymphoma in the pericardium: A case report and review of the literature.

We report a rare case of a 75-year-old man with a history of mild-to-moderate pericardial effusion that was detected on echocardiography performed in October 2011 when the patient was 69 years old. Follow-up echocardiography was performed every 6 months thereafter, showing that the pericardial effusion gradually subsided. However, in April 2017 he started experiencing several episodes of dyspnea, which prompted him to visit our hospital's outpatient department on June 22, 2017. Echocardiography revealed a large amount of pericardial effusion; thus, he was immediately hospitalized. After undergoing pericardiocentesis and drainage, 1740-ml of bloody pericardial fluid was collected. Serum antibody tests for human immunodeficiency virus, hepatitis C virus, and human herpes virus 8 were negative, whereas that for Epstein-Barr virus (EBV) was positive, indicating a prior infection. Cytopathological examination, immunocytochemical staining, lymphocyte surface marker analysis, and cytogenetic assessment were performed. EBV-encoded small ribonucleic acid in situ hybridization was negative. He was diagnosed with primary effusion lymphoma (PEL)-like lymphoma (LL) and was treated with 8 doses of rituximab 375 mg/m2 over a 2-month period. He has remained in complete response for the past 12 months. Our case shows the possibility of long-term existence of indolent PEL-LL in patients with mild-to-moderate pericardial effusion. .