Current situation and issues regarding termination of risk management plans in Japan.

Introduction: In Japan, drugs approved after the 2013 implementation of the risk management plan (RMP) have the opportunity to be evaluated for RMP termination. However, the guidelines for risk management following the termination of an RMP remain unclear. Drugs are evaluated for RMP termination at the timing of reexamination. Reexamination system is unique to Japan and initiated in 1979, verifies the approved efficacy and safety of a newly marketed drug based on the data from its actual use over a certain period. This study investigated drugs in Japan for which the RMP requirement was lifted upon reexamination and those for which it was not. We organized their characteristics and considered future issues. Methods: We identified drugs with RMPs and obtained information on RMP termination from the public website of the Pharmaceuticals and Medical Devices Agency (PMDA). The survey period spanned 10 years, from April 2013, when the RMP was implemented, to March 2023. Results: During the survey period, 72 drugs with RMPs completed reexamination in Japan. The RMP requirement was lifted for 69 drugs (95.8%) and remained for three drugs (4.2%). Upon RMP termination, 16 out of 69 drugs (23.2%) had important potential risks not listed in the package insert, with malignant neoplasm being the most common. Eleven drugs (15.9%) had important missing information not listed in the package insert, with the most common being the impact on cardiovascular risk. Two drugs (2.9%) had ongoing additional pharmacovigilance activities, and 43 drugs (62.3%) had additional risk minimization activities. Conclusion: Upon reexamination completion, the RMP requirement was lifted for many drugs and remained for a few. Should safety concerns require continued attention following reexamination, we advocate for the continuation of the RMP, guided by more explicit rules. In light of the harmonization of RMP rules with those of other countries, there is a desire for enhanced drug safety management.

Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary end points: A systematic review.

No systematic review of trial designs in patients with relapsing multiple sclerosis (RMS) was reported. This systematic review was conducted on the trial designs and primary end points (PEs) of phase II and III trials intended to modify the natural course of the disease in patients with RMS. The purpose of the study is to explore trends/topics and discussion points in clinical trial design and PE, comparing them to regulatory guidelines and expert recommendations. Three trial registration systems, ClinicalTrials.gov, the EU Clinical Trials Register, and the Japan Registry of Clinical Trials, were used and 60 trials were evaluated. The dominant clinical trial design was a randomized controlled parallel-arms trial and other details were as follows: in adult phase III confirmatory trials (n = 32), active-controlled double-blind trial (DBT) (53%) and active-controlled open-label assessor-masking trial (16%); in adult phase II dose-finding trials (n = 9), placebo- and active-controlled DBT (44%), placebo-controlled DBT (22%), and placebo-controlled add-on DBT (22%); and in pediatric phase III confirmatory trials (n = 8), active-controlled DBT (38%) and active-controlled open-label non-masking trial (25%). The most common PEs were as follows: in adult confirmatory trials, annual relapse rate (ARR) (56%) and no evidence of disease activity-3 (NEDA-3) (13%); in adult dose-finding trials, the cumulative number of T1 gadolinium-enhancing lesions (56%), combined unique active lesions (22%), and overall disability response score (22%); and in pediatric confirmatory trials, ARR (38%) and time to first relapse (25%). It was suggested that some parts of the regulatory guidelines and expert recommendations need to be revised.

Overall survival in Japanese patients with ER+/HER2- advanced breast cancer treated with first-line palbociclib plus letrozole.

BACKGROUND: An open-label, single-arm, Japanese phase 2 study (J-Ph2) investigated the efficacy and safety of first-line (1L) palbociclib (PAL) + letrozole (LET) in postmenopausal Japanese women with ER+/HER2- advanced breast cancer (ABC). In the final analysis, median progression-free survival was 35.7 months (95% CI 21.7-46.7); but overall survival (OS) data were immature. Here, we report the findings from a follow-up study of J-Ph2 (NCT04735367) evaluating OS and subsequent therapy in these Japanese women. METHODS: Patients (N = 42) who participated in J-Ph2 were enrolled in the OS follow-up study. The primary endpoint was OS and secondary endpoints included type and duration of subsequent therapy. RESULTS: Patients were a median age of 62.5 years; 48% had visceral metastases. At a median follow-up of 89.7 months, the median OS was 85.4 months (95% CI 64.3-not estimable). Median OS was longer in patients with nonvisceral versus visceral metastases (not reached vs 67.3 months), or with treatment-free interval > 12 months versus ≤ 12 months (85.4 vs 45.4 months), or with treatment duration ≥ 24 months versus < 24 months (not reached vs 47.5 months). Of patients who received a first subsequent therapy (81%), most (67%) continued endocrine-based therapy, while 7% received chemotherapy. The median duration of the first subsequent therapy was 8.3 months (95% CI 3.9-12.2), and the median chemotherapy-free survival was 69.1 months (95% CI 24.2-85.4). CONCLUSIONS: In this population of Japanese women with ER+/HER2- ABC, median OS was over 7 years with 1L PAL + LET, supporting the use of 1L PAL + endocrine therapy. TRIAL NUMBER: NCT04735367.

Risk Factors for Eribulin-induced Severe Neutropenia in Patients With Recurrent Breast Cancer.

BACKGROUND/AIM: Eribulin is an effective chemotherapeutic agent for advanced and metastatic breast cancer. However, severe neutropenia occurs in 30-40% of patients and interferes with the recommended treatment schedule. Neutropenia is a major cause of treatment interruptions, delays, or even relative dose reductions. This study aimed to examine the risk factors for severe neutropenia after eribulin treatment. PATIENTS AND METHODS: We retrospectively evaluated 263 patients with metastatic breast cancer who had received eribulin therapy. Risk factors for severe neutropenia in the first cycle were evaluated. RESULTS: Severe neutropenia in cycle 1 occurred in 50% of the patients. Multivariate analysis suggested six risk factors for severe neutropenia: low baseline neutrophil count and body mass index, high aspartate aminotransferase and bilirubin levels, creatinine clearance (CrCl) less than 50 ml/min, and eribulin dose of 1.4 mg/m2 Conclusion: This is one of the few studies to simultaneously examine both hepatic and renal functions in relation to severe neutropenia induced by eribulin. We have provided important information to support the close monitoring of patients with these risk factors and subsequent dosage adjustments, if necessary.

BRAF V600E-mutated Colorectal Neuroendocrine Carcinoma Effectively Treated with a Chemotherapy Protocol for BRAF-mutated Metastatic Colorectal Cancer: A Case Report.

Metastatic colorectal neuroendocrine carcinoma (NEC) is often treated using a chemotherapy protocol for small-cell lung cancer; however, the prognosis is extremely poor. A 55-year-old woman with BRAF V600E-mutated transverse colon NEC and liver metastases underwent colectomy followed by FOLFOXIRI plus bevacizumab. Consequently, the liver metastases markedly shrank. Owing to later worsening of the liver metastases, she received encorafenib and binimetinib plus cetuximab. Despite discontinuing binimetinib due to myalgia, she had a long-term response with a progression-free survival of 14 months and an overall survival of more than 27 months. A chemotherapy protocol for BRAF-mutated metastatic colorectal cancer may be a treatment option for BRAF V600E-mutated colorectal NEC.

Trends in oncology drug lags in Japan from 2001 to 2020: A cross-sectional study.

Anticancer drugs are essential in the treatment of serious diseases, but their applications are limited by drug lags. This study investigated the characteristics of anticancer drugs approved in Japan over the past 20 years and compared the drug lag trends between Japan and the US. We assessed the changes in drug lag between Japan and the US and the factors affecting the drug lags using publicly available data for anticancer drugs approved in Japan from January 2001 to December 2020. A total of 299 anticancer drugs were approved in Japan in the last 20 years. The approval lag median between the US and Japan was 498 days (16.6 months), peaking in 2002, and decreasing annually thereafter. The minimum approval lag was 173.5 days (5.7 months) in 2018. Multivariate regression analysis revealed that "global simultaneous strategy," "catch-up strategy," and "immunotherapy" are major factors shortening the drug lag. In the past decade, 226 anticancer drugs were approved in Japan. The drug lag for anticancer drugs between Japan and the US peaked in 2002, after which it declined sharply to less than a year. However, the lag was shortest in 2018.

Comparison of the Speed of Enrollment for Clinical Trials Conducted by Japanese and Global Pharmaceutical Companies.

Since the establishment of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), many countries in the world have rapidly improved their clinical trial performance, and the era has come to compare the clinical trial performance of each country. Japan's clinical trials are considered excellent quality, but costly and slow. In this study, we examined the speed of enrollment period in clinical trials. We surveyed clinical trials from January 1, 2010, to December 31, 2019, covering the top 10 pharmaceutical companies in each global sales ranking (Global 10) and the Japanese sales ranking (Japan 10). Clinical trial data were obtained from ClinicalTrials.gov, a clinical trial registration information database, and the speed of participant enrollment (cases/month) was compared for each phase of the trials. The number of clinical trials conducted during the 10 years was 8938 trials for Global 10 and 1439 trials for Japan 10. Comparing the speed of participant enrollment by phase, Japan 10 was significantly faster in phase 1 for both healthy subjects and oncology patients. [Japan 10: Global 10; 15.1 : 12.0 cases/month (healthy subjects) and 5.5 : 1.8 cases/month (oncology), respectively. p < 0.001]. Global 10 was also significantly faster in phase 3. [Japan 10: Global 10; 12.4: 36.9 cases/month, p < 0.001). No significant difference was observed in phase 2 and phase 4. There was a possibility that the speed of enrollment differed by phase between global companies and Japanese domestic companies.

Real-World Predictors of Severe Neutropenia Associated with Palbociclib and Endocrine Therapy for Metastatic Breast Cancer in Japanese Patients.

Therapy for patients of metastatic breast cancer based on palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has been approved in Japan. However, the risk factors for palbociclib-induced severe neutropenia in Japanese patients are rarely reported. Hence, the present study is aimed to identify the risk factors for adverse events requiring palbociclib dose reduction or discontinuation, and to identify the factors necessary to identify a more stable strategy for treatment continuation. This retrospective cohort analysis included patients with advanced breast cancer treated with 125 mg/d palbociclib. We demonstrated that severe neutropenia required significant dose reduction or therapy cessation. Most (77%) of the patients had severe neutropenia within the three courses. Risk factors for grade 3 or higher included low neutrophil counts (< 3250 /µL) before treatment [odds ratio (OR) = 9.10, 95% confidence interval (CI) (2.80-29.41), p < 0.001] and high age-adjusted Charlson comorbidity index (> 9) [OR = 1.64, 95% CI (1.09-2.48), p = 0.018]. Thus, low baseline neutrophil counts and high values for Age-adjusted Charlson comorbidity index are prospective predictive markers for palbociclib-induced severe neutropenia.

A Novel Method for Quantifying Plant Morphological Characteristics Using Normal Vectors and Local Curvature Data via 3D Modelling-A Case Study in Leaf Lettuce.

Three-dimensional measurement is a high-throughput method that can record a large amount of information. Three-dimensional modelling of plants has the possibility to not only automate dimensional measurement, but to also enable visual assessment to be quantified, eliminating ambiguity in human judgment. In this study, we have developed new methods that could be used for the morphological analysis of plants from the information contained in 3D data. Specifically, we investigated characteristics that can be measured by scale (dimension) and/or visual assessment by humans. The latter is particularly novel in this paper. The characteristics that can be measured on a scale-related dimension were tested based on the bounding box, convex hull, column solid, and voxel. Furthermore, for characteristics that can be evaluated by visual assessment, we propose a new method using normal vectors and local curvature (LC) data. For these examinations, we used our highly accurate all-around 3D plant modelling system. The coefficient of determination between manual measurements and the scale-related methods were all above 0.9. Furthermore, the differences in LC calculated from the normal vector data allowed us to visualise and quantify the concavity and convexity of leaves. This technique revealed that there were differences in the time point at which leaf blistering began to develop among the varieties. The precise 3D model made it possible to perform quantitative measurements of lettuce size and morphological characteristics. In addition, the newly proposed LC-based analysis method made it possible to quantify the characteristics that rely on visual assessment. This research paper was able to demonstrate the following possibilities as outcomes: (1) the automation of conventional manual measurements, and (2) the elimination of variability caused by human subjectivity, thereby rendering evaluations by skilled experts unnecessary.

Clinical Management of Potential Toxicity of Abemaciclib and Approaches to Ensure Treatment Continuation.

INTRODUCTION: The association between abemaciclib dose reduction and treatment adherence is not clear. In this study, we examined real-world data of Japanese patients with advanced breast cancer (ABC) to determine how abemaciclib dose reduction is related to treatment continuation. METHODS: This retrospective observational study involved 120 consecutive patients with ABC who received abemaciclib from December 2018 to March 2021. The time to treatment failure (TTF) was estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify factors associated with a TTF of >365 days (TTF365). RESULTS: According to the dose reduction during treatment, the patients were classified into 100, 200, and 300 mg/day abemaciclib groups. The 300 mg/day group had a TTF of 7.4 months, whereas the 100 and 200 mg/day groups had significantly longer TTFs (17.9 and 17.3 months, respectively; P = 0.0002). In this study, relative to the 300 mg/day arm, TTF was improved in 200mg/day arm and 100 mg/day arm (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.33-0.93) and [HR], 0.37; 95% CI, 0.19-0.74). For patients who received 300mg/day of abemaciclib dose arm, 200mg/day, and 100mg/day, the median TTF was 7.4 ,17.9 and 17.3 months. The frequently reported adverse effects (AEs) were anemia, increased blood creatinine levels, diarrhea, and neutropenia (90%, 83%, 83%, and 75% of the patients, respectively). Neutropenia, fatigue, and diarrhea were the top AEs causing dose reduction. A multivariate analysis that examined factors associated with achieving TTF 365 confirmed that dose down was an important factor (odds ratio: 3.95, 95% confidence interval: 1.68-9.36, P = 0.002). CONCLUSIONS: In this study, the 100 and 200 mg/day groups had a longer TTF than the 300 mg/day group, and dose reduction was identified as an important factor in achieving longer TTF.

Assessment of Surrogate End Point Trends in Clinical Trials to Approve Oncology Drugs From 2001 to 2020 in Japan.

Importance: A surrogate end point (SEP) is an end point used in clinical trials as an alternative for measuring the true clinical benefit. The use of SEPs in trials shortens their duration. Objectives: To investigate the use of SEPs in clinical trials to support the approval of anticancer drugs and to determine whether confirmatory studies that use overall survival (OS) as an end point are being conducted in Japan. Design, Setting, and Participants: In this cross-sectional study, drug approvals and background information were obtained from publicly available information, such as the Pharmaceuticals and Medical Devices Agency website, for anticancer drugs approved in Japan from January 2001 to December 2020. Data analysis was performed from September 2021 to March 2022. Main Outcomes and Measures: Characteristics of approved oncology drugs in Japan, end points for pivotal clinical trials, and outcomes of confirmatory trials using OS as an end point following drug approval. Results: There were 299 anticancer drugs approved in Japan during the study period. Of these, 142 (47.5%) were molecular-targeted drugs, the most common of which targeted non-small cell lung cancer. There were 111 (37.1%) anticancer drugs with orphan designation. From 2001 to 2005, OS was used as an end point in 1 approval (3.6%); however, from 2006 to 2020, OS was used in 86 approvals (31.7%). Of the 212 anticancer drugs approved on the basis of SEPs, confirmatory studies with OS as the end point were conducted for only 37 approvals (17.5%); for the remaining 175 approvals, studies are under way for 35 approvals (16.5%), were waivered for 75 approvals (35.4%), and were not conducted for 65 approvals (30.7%). Furthermore, in 20 drug approvals (9.4%), the conducted confirmatory studies were not effective in determining the OS, but the drugs were approved following re-examination. Conclusions and Relevance: The findings of this study suggest that starting from 2005, the use of OS as an end point has increased in studies supporting the approval of anticancer drugs in Japan. However, even after 2005, approximately two-thirds of these approvals were SEP based. Postmarketing surveillance studies of the true end points are necessary to validate the use of SEPs.

Programmed death ligand 1-positive immune cells in primary tumor or metastatic axillary lymph nodes can predict prognosis of triple-negative breast cancer even when present at < 1% in the tumor region.

BACKGROUND: The efficacy of pre-operative systemic treatment (PST) combined with immune checkpoint inhibition (ICI) for triple-negative breast cancer (TNBC) has been recognized recently as being independent of the degree of programmed death ligand-1 (PD-L1) positivity of infiltrating immune cells, especially for patients with axillary lymph node metastasis (ALNM). METHODS: TNBC patients with ALNM were treated surgically between 2002 and 2016 in our facility (n = 109), of whom 38 received PST before resection. The presence of tumor-infiltrating lymphocytes (TILs) expressing CD3, CD8, CD68, PD-L1 (detected by antibody SP142) and FOXP3 at primary and metastatic LN sites was quantified. RESULTS: The size of invasive tumor and the number of metastatic axillary LN were confirmed as prognostic markers. The numbers of both CD8+ and FOXP3+ TILs at primary sites were also recognized as prognostic markers, especially for overall survival (OS) (CD8, p = 0.026; FOXP3, p < 0.001). The presence of CD8+, FOXP3+ and PD-L1+ cells was better maintained in LN after PST and may contribute to improved antitumor immunity. Provided they were present as clusters of ≥ 70 positive cells, even < 1% of immune cells expressing PD-L1 at primary sites predicted a more favorable prognosis for both disease-free survival (DFS) (p = 0.004) and OS (p = 0.020). This was the case not only for 30 matched surgical patients, but also in all 71 surgical only patients (DFS: p < 0.001 and OS: p = 0.002). CONCLUSIONS: PD-L1+ , CD8+ or FOXP3+ immune cells in the tumor microenvironment (TME) at both primary and metastatic sites are significant on prognosis, which could be a clue to expect the potential for better responses to the combination of chemotherapy and ICI, especially for patients with ALNM.

Correlation of Anticancer Drug Prices with Outcomes of Overall Survival and Progression-Free Survival in Clinical Trials in Japan.

Drug pricing methods vary extensively across countries. Japan calculates drug prices using cost accounting and based on the efficacy of similar drugs. This study investigated the relationship between drug prices and their clinical efficacy and usefulness using public information on anticancer drugs reimbursed by the National Health Insurance price listing between January 2009 and March 2020. We investigated drug characteristics, prices, and clinical benefits based on overall survival (OS) and progression-free survival (PFS). Eighty anticancer drugs were approved in Japan during the study period. The largest number (28 drugs, 35.0%) was approved based on PFS, 18 (22.5%) were approved based on OS, and 13 (16.3%) based on the response rate. The mean (±SD) drug price was JPY 88,416.2 (±148,974.7), while the median drug price (with quartiles) was JPY 21,694 (JPY 4855.0-JPY 93,396.8). Drug prices were significantly higher for PFS than for OS, while cost index-the drug price to extend PFS or OS by one day-did not differ significantly between PFS and OS. The relationship between the 46 drugs approved based on OS or PFS and their prices was examined. A correlation was found between drug prices and their clinical usefulness in terms of OS but not PFS.

Postmarketing all-case surveillance trends and contribution to safety measures of drugs approved in Japan: a cross-sectional survey in 1999-2019.

BACKGROUND: Postmarketing all-case surveillance (PACS) is a safety monitoring activity predominantly conducted for drugs with few domestic clinical trials, orphan drugs, or anticancer drugs that potentially cause serious adverse events. AIM: This study comprehensively analyzed drugs in Japan requiring PACS as an approval condition and those implementing PACS-results-based safety measures. METHOD: We included drugs approved in Japan between 1999 and 2019. RESULTS: During the 20-year survey, 1871 drugs were approved in Japan, including 277 (14.8%) requiring PACS as an approval prerequisite. The drug number requiring PACS for approval and its ratio to the total approved-drug number is increasing annually. In 2018, the number and percentage of PACS-requiring drugs reached a 37-drug maximum (32.5%). Additionally, among the 277 PACS-requiring drugs, upon examining the results of 87 drugs for which reexamination results had already been obtained, all 87 drugs (31.4%) were found to be in Category 1 which means there is no need to revise drug-approval conditions, indicating that their usefulness is consistent with approval. Furthermore, measures such as revising the package insert and providing information to medical institutions were adopted for 53 drugs, 14 of which had PACS-results-based safety measures. CONCLUSION: PACS implementation for drug approval will potentially continue increasing. Normally, PACS is not conducted overseas, as it is a safety-monitoring activity exclusive to Japan, and the burden on institutions, such as medical sites and pharmaceutical companies, is heavy. Thus, ensuring a balance between the obtained effect and this burden is imperative.

YTHDC2 Promotes Malignant Phenotypes of Breast Cancer Cells.

YTH domain-containing 2 (YTHDC2) is known to be an important regulator for RNA metabolism. Here, we show that YTHDC2 is essential for breast cancer tumorigenesis and metastasis. We examined YTHDC2 expression levels by immunohistochemistry in human breast tumor tissues from 99 patients and found a significantly positive correlation between the YTHDC2 expression level and the tumor stage. We established YTHDC2-knocked-down cell lines using four breast cancer cell lines with different subtypes. Knockdown of YTHDC2 attenuated the sphere-forming and the metastatic ability of breast cancer cells. Although stemness and EMT markers, such as SOX2, c-MYC, and NANOG, were downregulated in several YTHDC2-knocked-down breast cancer cells, a common target gene of YTHDC2 in breast cancer cells was not identified. These findings suggest that while YTHDC2 is involved in malignant progression of breast cancers, the mechanism by which YTHDC2 regulates those phenotypes is different between subtypes of breast cancers.

Characteristics of the Compassionate Use Program in Japan: An Analysis of Expanded Access Clinical Trials from 2016 to 2021.

Compassionate use is a system that provides patients with exceptional access to investigational new drugs to treat life-threatening diseases that have no effective conventional treatments. The purpose of this study was to characterize and assess the current status of the compassionate use program's application in Japan by evaluating expanded access clinical trials (EACTs) conducted between 2016 and 2021. In this study, a data set containing all EACTs, and pivotal clinical trials (PCTs) conducted in Japan between February 2016 and April 2021 was obtained from the Pharmaceutical and Medical Devices Agency, systemically reviewed, and analyzed. During the 5 years since EACTs began in Japan, out of 2,031 PCTs, 31 EACTs were conducted in Japan. Twenty-four trials (77.4%) of the 31 EACTs used anticancer drugs and 5 of those trials (16.1%) were conducted in children. Furthermore, we conducted an EACT survey for drugs with a high degree of social and patient demands as recommended in the EACT notification. Among the 2,031 PCTs, we found 152 trials with high degree of social and patient demands. Of these, EACT was implemented in 17 trials (11.2%). Days from the start of the EACT to the submission of new drug applications and the approval were 9.0 (67.0-56.5) and 208.0 (172.8-308.8) days, respectively. Of the 31 EACTs conducted, 24 (77.4%) drugs have been approved as of August 2021. This first comprehensive study on EACTs clarified the current status and issues of Japan's compassionate use system and the 5 years since the program initiated.

Significance of prostate/pancreatic/skin cancer family history for detecting BRCA2 pathogenic variant careers among patients with breast cancer.

BACKGROUND: When considering BRCA1/2 genetic testing for diagnosis of hereditary breast and ovarian cancer (HBOC), family history (FH) of breast and ovarian cancer is commonly considered. However, FH of other HBOC-related cancers, such as prostate, pancreatic, and skin cancer (malignant melanoma), is often overlooked. METHODS: Among 945 patients who received genetic testing of BRCA1/2 at our hospital between October 2010 and September 2021, we compared the FH of 123 patients diagnosed with HBOC and 669 other patients who had breast cancer and had a documented FH. This study focused on the FH of HBOC-related cancers such as breast, ovarian, prostate, pancreatic, and skin cancer, as well as colorectal, gastric, liver, lung, and uterine cancers, which are common among Japanese, and other cancers. RESULTS: FH of prostate, pancreatic, and skin cancer was significantly higher in the BRCA2 pathogenic variant (PV) cases than in the wild-type (WT) cases. The mean number of family members are as follows: BRCA1 PV/ BRCA2 PV/ WT; prostate cancer: 0.05/ 0.34/ 0.09 (P < 0.0001, Kruskal-Wallis multiple comparisons test), pancreatic cancer: 0.13/ 0.21/ 0.10 (P = 0.01637), and skin cancer: 0.03/ 0.07/ 0.01 (P = 0.00129), respectively. CONCLUSIONS: When considering BRCA1/2 genetic testing, FH of prostate, pancreatic, and skin cancers may also be examined as HBOC-related cancers to provide testing for patients who would benefit from it. However, further studies for the association between skin cancer and HBOC will be required because it has not been reported in Japan.

Regulatory Approval With Real-World Data From Regulatory Science Perspective in Japan.

Recently, there has been a growing trend in clinical development to utilize real-world data (RWD) to improve the efficiency of drug/medical device development. Especially, the use of RWD to generate real-world evidence (RWE) in regulatory approval is currently undergoing a period of great change with an increasing degree of active discussion. In Japan, RWE has been used in the control arms of clinical trials, observational studies, post-marketing surveillance, and public knowledge-based applications for regulatory approval. However, the exclusive use of RWE applications has still not been applied. In this paper, we summarize the history and the current situation of RWE and focus on the utilization for the purpose of regulatory approval. In addition, we will discuss the issues and perspectives for registry research in the utilization for regulatory approval in Japan.