International Comparison of Qualification Process for Medical Product Development Tools.

INTRODUCTION: Qualification of medical product evaluation tools is underway in the United States, Europe, and Japan to reflect the advancements in the basic science of medical products. In Europe and the U.S., Guidance of Guidances (GoG) policies that clarify regulators'processes, tasks, and methods of sponsor involvement are adopted to issue tool guidance. However, in Japan, a non-GoG type policy focusing on supporting the research and development for tools without defining a tool guidance-making process has been adopted. METHODS: In this study, an analytical framework for the lifecycle of development tools was constructed, including pre- and post-tool qualification processes, to compare the two above-mentioned approaches. For this study, Japanese cases were selected as experimental cases, whereas Western cases served as controls. The progress of tool qualification and composition of deliverables were analyzed. RESULTS AND CONCLUSIONS: It was indicated that in the GoG type policy, in which processes are defined, and involvement methods are clarified, tool qualification can progress more smoothly than in a non-GoG type policy. This policy indicates that deliverables may have a consistent composition. Contrastingly, GoG-type policies alone present challenges in connecting upstream tools for R&D support.

Comparative analysis of rule elements for transportation of cell therapy products among regulations and standards.

Aim: This study aimed to identify the elements involved in the transportation of cell therapy products by conducting a comparative analysis of four related international standards for temperature-controlled delivery and good distribution practice (GDP). Methods: An analytical framework was constructed to cover the entire transportation process. The descriptions of each element in the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) GDP, International Organization for Standardization (ISO) 21973, Foundation for the Accreditation of Cellular Therapy Common Standards for Cellular Therapies and ISO 23412 were compared. Results: The study identified some elements that were present in the PIC/S GDP and other standards but were absent in ISO 21973, and vice versa. These elements are crucial in view of the increasing opportunities to transport allogeneic cells in the future. Conclusion: The study identified the necessary elements that should be included in the development of transport regulations for cell therapy products.

The quality of cell therapy products needs to be ensured during transportation to the hospital, just like during their manufacture. However, cell therapy products are living cells, and ensuring their quality during transportation is challenging. The International Organization for Standardization (ISO) has published ISO 21973 to address this issue, but transport regulations for cell therapy products have not been modified yet. To create draft guidance for the transportation of cell therapy products, it is necessary to analyze the relationship between ISO 21973, good distribution practice, Foundation for the Accreditation of Cellular Therapy Common Standards and ISO 23412. We compared these regulations and standards and identified some elements that are necessary for transporting cell therapy products. These elements are crucial in view of the increasing opportunities to transport allogeneic cells in the future. This study proposed elements to be included in the development of transport regulations for cell therapy products.

Integrated Analytical Framework for the Development of Artificial Intelligence-Based Medical Devices.

INTRODUCTION: A persistent fundamental problem in applying artificial intelligence (AI) to medical devices is achieving high performance while guaranteeing the safety and reliability of AI solutions. However, the regulation of medical devices and that of AI implementations both differ among countries, resulting in "double-layered" differences in the regulations for medical devices employing AI. METHODS: To overcome these differences and examine the universal requirements for AI-based medical devices, we clarify legal and ethical issues, regulatory requirements, and terms in representative guidances related to AI-based medical devices from different countries. Then, we propose an integrated framework for analyzing the requirements of AI-based medical devices for a comprehensive comparison. RESULTS: We demonstrate that no guidance completely covers all the evaluation requirements, and the differences in coverage per country may direct the international harmonization of these requirements. DISCUSSION: Consequently, we show two development strategies available to manufacturers, namely adherence to local regulations with tedious efforts or compliance with universal requirements using our integrated framework even under the low level of international harmonization; the latter is recommended for efficiency and convergence.

Technology Forecasting for Medical Devices Guidance Formulation: A Case Study in Japan.

In the advanced medical field, there is a constant need for efficient guidance formulation by regulators. Technology forecasting as a surveillance for regulation needs may be an effective solution by notifying regulatory authorities of the possible future changes in regulations. However, the lack of tangible frameworks has made the relationship between technology forecasting and regulation difficult to comprehend, and has led to an under-analyzed state of how technology forecasts are implemented into the guidance formulation process. In this study, we introduce a framework built specifically for facilitating the comprehension of the relationship between technologies enlisted in technology forecasting and guidances formulated after the forecasting, and applied the framework to a case of technology forecasting conducted by regulatory authorities in Japan. Four patterns of the relationships between a technology forecasting conducted by regulators and the guidances developed after the forecast are identified. The results and discussions provide suggestions of technology forecast design and application in the guidance formulation process by regulators in the field of medical devices.

Research and drug development activities in rare diseases: differences between Japan and Europe regarding influence of prevalence.

Orphan drug legislation has contributed enormously to promote drug development for rare diseases but further effective and sustainable approaches are required. This study focused on the difference of rare disease prevalence between Japan and Europe, classified the rare diseases comprehensively using cluster analysis and analyzed the influence of prevalence on research activity and drug development. Although overall strong correlative progress of research was found and absolute numbers of values were greater in Europe than in Japan, the regional higher prevalent diseases demonstrated more progress of research and development relatively in the region by examining clusters. Our findings suggest potential optimal drug development in consideration of regional differences. Moreover, an in-depth analysis of diseases that showed exceptional research achievements compared with prevalence speculated important determinants of progress.

Comparison of international guidelines for regenerative medicine: Knee cartilage repair and replacement using human-derived cells and tissues.

Regenerative medicine (RM) is an emerging field using human-derived cells and tissues (HCT). Due to the complexity and diversity of HCT products, each country has its own regulations for authorization and no common method has been applied to date. Individual regulations were previously clarified at the level of statutes but no direct comparison has been reported at the level of guidelines. Here, we generated a new analytical framework that allows comparison of guidelines independent from local definitions of RM, using 2 indicators, product type and information type. The guidelines for products for repair and replacement of knee cartilage in Japan, the United States of America, and Europe were compared and differences were detected in both product type and information type by the proposed analytical framework. Those findings will be critical not only for the product developers to determine the region to initiate the clinical trials but also for the regulators to assess and build their regulations. This analytical framework is potentially expandable to other RM guidelines to identify gaps, leading to trigger discussion of global harmonization in RM regulations.

Strategic balance of drug lifecycle management options differs between domestic and foreign companies in Japan.

INTRODUCTION: Drug approvals and patent protections are critical in drug lifecycle management (LCM) in order to maximize drug discovery investment returns. AREA COVERED: We analyzed drug LCM activities implemented by 10 top companies in Japan, focusing on drug approvals and patent term extensions. EXPERT OPINION: Foreign companies acquired numerous drug approvals primarily for new molecular entities (NMEs), while Japanese companies mainly obtained approvals for improved drugs including new indications, and intensively extended patent terms. Furthermore, we discovered three factors likely responsible for differences in drug LCM strategies of Japanese and foreign companies: research and development capacities for drugs, drug lags of foreign-origin NMEs, and cooperation between Research and Development Departments and Intellectual Property Departments.

Mapping lifecycle management activities for blockbuster drugs in Japan based on drug approvals and patent term extensions.

Drug lifecycle management (LCM), which entails acquiring drug approvals and patent protections, contributes to maximizing drug discovery investment returns. In a previous survey, a comparative analysis between Japan and the USA indicated that a unique patent term extension system has an important role in Japanese drug LCM. Therefore, in this survey, we focused on drug approvals and patent term extensions, and found that the LCM for blockbuster drugs in Japan can be categorized into three types (drug approval-oriented LCM, patent term extension-oriented LCM, and inactive-type LCM), of which the first two have been implemented recently. Here, we suggest a strategy for selecting a suitable LCM approach among these three types based on the prospects for drug improvements.

Patent term extension systems differentiate Japanese and US drug lifecycle management.

Drug lifecycle management (LCM) contributes to maximizing drug discovery investment returns. After initial drug approval, additional approvals can be sought for novel indications and formulations to extend product marketability. Patents provide additional barriers to entry and patent term extension systems facilitate extension of these. Several aspects of the US and Japanese patent term extension systems differ. Therefore, we compared both systems using a drug LCM case study to highlight the differences. Our findings indicate that the extension of multiple drug patents on multiple occasions in Japan produces a more complicated range of extended patent protections, compared with the US system.

Effects of intraperitoneal chemotherapy with mitomycin C on the prevention of peritoneal recurrence in colorectal cancer patients with positive peritoneal lavage cytology findings.

BACKGROUND: The detection of intraperitoneal free cancer cells in colorectal cancer (CRC) patients is associated with a poorer prognosis. The aim of this study was to investigate the effects of intraperitoneal chemotherapy (IPC) with mitomycin C (MMC) on preventing peritoneal recurrence in CRC patients with positive peritoneal lavage cytology findings. METHODS: A total of 52 CRC patients who had no clinically confirmed peritoneal dissemination and whose status of peritoneal lavage cytology was positive were investigated. Conventional peritoneal lavage cytology was performed. Overall, 31 of the 52 patients (59.6%) were administered IPC with MMC. Before closure of the abdomen, 4 silicon catheters were inserted into peritoneal cavity. After closure, the perfusate (diluting 20 mg MMC with 500 ml saline) was instilled from the catheter, and all catheters were clumped. All catheters were opened 1 h later. RESULTS: The mean follow-up period was 83.1 months. According to univariate analyses of all 52 patients and the subgroup of 36 patients with stage II or III tumors, patients with IPC had a significantly better peritoneal recurrence-free survival and cancer-specific survival than patients who did not receive IPC (P < 0.005). In multivariate analysis, IPC remained an independent prognostic factor for peritoneal recurrence-free survival in all patients. CONCLUSIONS: It appears that IPC with MMC is an effective treatment to prevent peritoneal recurrence and prolong the cancer-specific survival in CRC patients without peritoneal dissemination, but who have positive peritoneal lavage cytology. It is necessary to verify the effectiveness of IPC with MMC in a prospective trial.

Impact of metastatic lymph node ratio in node-positive colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant diseases in the world. Presently, the most widely used staging system for CRC is the tumor nodes metastasis classification system, which classifies patients into prognostic groups according to the depth of the primary tumor, presence of regional lymph node (LN) metastases, and evidence of distant metastatic spread. The number of LNs with confirmed metastasis is related to the severity of the disease, but this number depends on the number of LNs retrieved, which varies depending on patient age, tumor grade, surgical extent, and tumor site. Numerous studies and a recent structured review have demonstrated associated improvements in the survival of CRC patients with increasing numbers of LNs retrieved for examination. Hence, the impact of lymph node ratio (LNR), defined as the number of metastatic LNs divided by the number of LNs retrieved, has been investigated in various malignancies, including CRC. In this editorial, we review the literature demonstrating the clinicopathological significance of LNR in CRC patients. Some reports have indicated the advantage of considering the LNR compared to the number of LNs retrieved and/or LN status. When the LNR is taken into consideration for survival analysis, the number of LNs retrieved and/or the LN status is not always found to be a prognostic factor. The cut-off points for LNRs were proposed in numerous studies. However, optimal thresholds for LNRs have not yet received consensus. It is still unclear whether the LNR has more prognostic validity than N stage. For all these reasons, the potential advantages of LNRs in the staging system should be investigated in large prospective data sets.

[A case of lung metastasis from colon cancer controlled effectively by the stereotactic radiotherapy].

A 73-year-old man underwent a sigmoid colon resection and an insertion of a hepatic arterial infusion catheter for multiple liver metastases from sigmoid colon cancer. After the hepatectomy, the patient was detected a lung metastasis and was scheduled to undergo mFOLFOX6 chemotherapy. The tumor lesion was reduced once in size, but it has grown again after the chemotherapy. So, we underwent a stereotactic radiotherapy (60 Gy/10 Fr). The tumor lesion became a scar and the patient was doing well without any recurrence at 21 months after undergoing stereotactic radiotherapy. Lung resection has a better result than other treatments for a lung metastasis caused from colon cancer, but there are some cases with no indication of the operation due to a complication. Stereotactic radiotherapy can be an effective treatment for lung metastasis from colon cancer with no indication of the operation.

[A long-term disease-free survival case of advanced rectal cancer with massive metastasis to the lateral pelvic and para-aortic lymph nodes].

A 42-year-old man with advanced rectal cancer underwent a low anterior resection with TME and pelvic lateral lymph-node and paraaortic lymph-node dissections. Pathological examination revealed as Type 2, 84 × 70 mm, tub 2 > por, A-SE, int, INF b, ly3, v1, pN3 (35/68), M1 (No. 216: 24/37), Stage IV (Cur B) by Japanese Classification of Colorectal Carcinoma. Three kinds of chemotherapy, 3 courses of irinotecan and bolus fluorouracil plus Leucovorin (IFL), 4 courses of irinotecan and S-1 (IRIS), and one-year of S-1 were administered sequentially. After 5 years from the operation, the patient survived and showed no sign of recurrence. Aggressive lymph-node dissection for rectal cancer patients with massive lymph-node metastasis followed by intensive chemotherapy may result in long-term survival.