Evaluation of Drug Lag and Drug Loss in Japan: Participation in Global Phase III Oncology Trials

Evaluation of Drug Lag and Drug Loss in Japan: Participation in Global Phase III Oncology Trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluation of Drug Lag and Drug Loss in Japan: Participation in Global Phase III Oncology Trials Kaname Shiga, Taro Shibata, Toshio Miyata This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5456839/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Apr, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background: Despite efforts to mitigate drug lag, discrepancies in drug approval timelines persist between Japan and the US, and increase in unapproved drugs has become a significant challenge. This study aimed to evaluate potential drug lag and drug loss by assessing Japan's participation in global phase III multinational/multiregional clinical trials (MRCTs) targeted cancers. Methods: Phase III MRCTs of anticancer drugs initiated between 2008 and 2022 were collected. Information of participant countries, study sponsor, study design, and cancer type were collected and analyzed by. logistic regression analysis to identify factors affected Japan’s participation. Results: Of 999 phase III MRCTs, Japan's participation every 5 year increased over 15 years (2008-2012: 34.3%, 2013-2017: 51.6%, 2018-2022: 60.2%), while Japan’s non-participation numbers didn’t change (2008-2012: 157, 2013-2017: 167, 2018-2022: 165). In the multivariate logistic regression analysis, the absence of an operational base in Japan and minor cancers were negatively associated with Japan’s participation in phase III MRCTs. Japan’s participation was also associated with some cancer organs and drug modalities. Conclusion: Potential future drug lag and increases of unapproved drug were expected to increase. Since inclusion of Japan in MRCTs results in shorter or no approval lag, Japan should promote to make the circumstances where small overseas companies can include Japan in MRCTs. Drug lag drug loss anticancer drug development MRCT phase III Figures Figure 1 Figure 2 Introduction Cancer is a serious and fatal disease, accounting for approximately 25% of all deaths in Japan [ 1 ], and it is reported that 65.5% of Japanese men and 51.2% of women will be diagnosed with cancer during their lifetime [ 2 ]. As a result, there is a need for new and innovative drugs to improve the prognosis of cancer patients, and clinical development of anticancer drugs is active in Japan and overseas. However, there is a difference in the timing of anticancer drug approvals between Japan and other countries, particularly the US. This problem is known as "drug lag" and is a serious issue because it affects patient access to medicines, especially anticancer drugs [ 3 , 4 ]. From the late 2000s to the early 2010s, the Ministry of Health, Labour and Welfare (MHLW) issued several guidelines and notifications to promote the use of multinational/multiregional clinical trials (MRCTs) to support the marketing authorization of new drugs in Japan [ 5 – 7 ]. In recent years, the development of clinical trial systems and expansion of capabilities of the Pharmaceuticals and Medical Devices Agency (PMDA) system have narrowed the gap between Japan and the US in the development of anticancer drugs [ 8 , 9 ], but the issue of "drug loss", where drugs are not developed due to there are no companies to develop them in Japan and the number of unapproved drugs increases in the future, has become a major challenge [ 10 , 11 ]. Previous reports have shown that Japanese participation in MRCTs is associated with both drug submission and approval lags [ 12 , 13 ]. It has been reported that the approval lag is shorter when Japan is included in an MRCT than when a separate local trial is conducted in Japan [ 14 ]. Therefore, including Japan in MRCTs is advantageous for pharmaceutical companies as it makes it easier to obtain approval in the Japanese market. In addition, recent reports indicate that the potential for future approval lags and undeveloped drugs can be measured by the rate of Japanese participation in MRCTs. It has been reported that 80% of drugs not participating in MRCTs for anticancer, anti-infective, antipsychotic, and cardiovascular drugs were not developed in Japan (potential drug loss) [ 15 ] . Investigating the reasons why it is difficult to include Japan in MRCTs will also contribute to efficient drug development strategies for drugs of foreign origin. This study therefore aimed to investigate the situation of “potential drug lag/drug loss” based on Japan's participation rate in phase III MRCTs of anticancer drugs, explored associated factors. Materials & Methods Criteria for trial selection This study included phase III MRCTs that were funded by pharmaceutical companies, included the US as one of the participant countries, and targeted cancer (either solid tumors or hematological malignancies), started between 01/01/2008 and 12/31/2022. Trials that did not intend efficacy to cancers, conducted only in the US, and were not led by pharm, extension or rollover studies were excluded. Data sources and collected information Data were collected from ClinicalTrials.gov (https://clinicaltrials.gov/). The collected information includes study start year, participant country, sponsor, type of cancer, study drug, study design, sample size, and primary endpoint. Cancer Incidence To investigate the difference in Japan’s participation by cancer incidence, the cancer targeted by each clinical trial was categorized by incidence as either major (6 or more cases/100,000 individuals/year) or minor (<6/100,000 individuals/year) by utilizing the definition for rare cancer by International Rare Cancers Initiative (https://project.eortc.org/irci/) (RARECARE definition) [16–18]. Cancer organ Each cancer was classified to each organ (biliary tract, brain, breast, cervix, colorectum, esophagus, head and neck, kidney, liver, lung, mesothelium, neuroendocrine, ovary, pancreas, prostate, skin, soft tissue, stomach, thyroid, urothelium, and uterus). Hematologic malignancies were classified to leukemia, lymphoma, and myeloma [19]. Drug modality Each drug modality was classified according to the existing report as antibodies (including monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies), protein and peptides, cell therapies (including CAR-T), gene therapies, nucleic acids (DNA and RNA), other new modalities (including oncolytic viruses), small molecules (cytotoxic agents and molecular targeted drugs), and radiotherapies (including radio-drug conjugates) [20]. Company size definition To investigate the relevance of company size in Japan’s participation, each company was categorized as either “Large company” or “Non-large company” based on global sales ranking top 20 between 2018-2022. If the company was involved in top 20 for multiple times, the company was categorized as “Large company”. The Large companies are followings; Pfizer, Johnson&Johnson (Janssen), Roche/Genentech, Merck (MSD), AbbVie (Abbott), Novartis, Bristol Myers Squibb, Sanofi, AstraZeneca, Glaxosmithkline (GSK), Takeda, Eli Lilly, Bayer, Amgen, Glead Sciences, Boehringer Ingelheim. Subsidiaries of large companies were classified as “Large company”. Outcome measures and statistical analyses The participation rate of the target countries was calculated as the number of target countries included in the total number of phase III MRCTs. The US participation rate was assumed to be 100%. The five most populous European countries (Germany, UK, France, Italy, and Spain) were grouped together for analysis as the “EU5”. East Asia countries (Japan, Korea, China, Hong Kong, and Taiwan) were included in the “East Asia Total”. Also, the participation number and its difference between the US and Japan, and between East Asia total and Japan were calculated to investigate Japan’s non-inclusion to phase III MRCTs. Univariate and multivariate logistic regression analyses were performed using the extracted trial characteristics to explore factors affecting Japanese participation/non-participation in oncology phase III MRCTs. Odd ratios and 95% confidence intervals were calculated. For univariate analysis, the following factors were analyzed: company size (large/non-large), operational base in Japan, number of countries, sample size, study start year, study design (comparative/non-comparative), primary endpoint (overall survival/surrogate), cancer incidence (major/minor), and cancer type (solid tumors/hematological malignancies). For multivariate analysis, the following independent variables were used: operational base in Japan, number of countries, study start year, primary endpoint, and cancer incidence. Statistical analyses were performed using JMP®Pro and statistical significance was set at P < 0.05. Results Clinical trials selected There were 8364 phase III MRCTs initiated in the US between 1 January 2008 and 31 December 2022. Excluding trials that did not meet the inclusion criteria, there were 999 phase III MRCTs of anticancer agents included in this study (Fig. 1 ). There was no clear trend in the proportion of cancer trials in the total number of trials. Characteristics of the trials The characteristics of the 999 extracted studies are shown in Table 1 . The number of phase III MRCTs increased every 5 years (2008–2012: 239, 2013–2017: 345, and 2018–2022: 415). 35% of the total were minor cancers and 25% were hematological malignancies (all minor cancers). The median number of participating countries was 19 (range: 2–56) and the median sample size was 522. Japan's participation rate was 51% for the entire period. Table 1 Characteristics of Oncology Phase III MRCTs started from 2008 to 2022 N = 999 Cancer incidence – n (%) Major 649 (65) Minor 350 (35) Cancer type – n (%) Solid tumors 754 (75) Hematological malignancies 245 (25) Company size – n (%) Large 674 (67) Non-large 325 (33) Operational base in Japan – n (%) Yes 771 (77) No 228 (23) Number of countries – median (range) 19 (2–56) Sample size – median (range) 522 (0–6000) Start year 2008–2012 239 (24) 2013–2017 345 (35) 2018–2022 415 (42) Japan’s participation – n (%) Yes 510 (51) No 489 (49) Study design – n (%) Comparative 974 (97) Non-comparative 25 (3) Primary endpoint – n (%) Overall survival 280 (28) Other 719 (72) Japan's participation in the oncology phase III MRCTs The five-year trends of the participation rate and participation number in the oncology phase III MRCTs are shown in Fig. 2 . As shown in Fig. 2 a, the participation rates of the EU5 have remained around 80% over the 15 years, whereas Japan’s participation rates increased from 34–60% and East Asia's Total increased from 59–82%. However, Japan’s non-participation number has been almost constant (around 160 trials by each 5 years), which resulted in 489 oncology phase III MRCTs that Japan was not included (Fig. 2 b). Moreover, among MRCTs that did not include Japan, the number of MRCTs that included East Asian countries other than Japan increased every 5 years to 58, 80, and 91 trials (Fig. 2 c). Potential factors associated with the Japan’s participation in phase III MRCTs Table 2 shows the results of the logistic regression analyses for each of the characteristics. In the univariate analysis, non-large sponsor company, sponsor who doesn’t have an operational base in Japan, non-comparative study, major cancer, and hematological malignancies are negative factors for Japan’s participation in oncology phase III MRCTs whereas large trials (whose number of countries are more than 19, whose sample size are more than 522 patients), start year after 2013 (2013–2017 and 2018–2022), and surrogate endpoint are positive factors. In the multivariate logistic regression analysis using variables that were independent among those used in the univariate analysis, sponsor who doesn’t have an operational base in Japan (OR 0.07, 95% CI 0.04–0.11, p < 0.01) and minor cancer (OR 0.47, 95% CI 0.34–0.65, p < 0.01) were identified as negative factors, and the number of countries is more than 19 (OR 4.00, 95% CI 2.92–5.48, p < 0.01), the start year after 2013 (2013–2017: OR 2.49, 95% CI 1.66–3.74, p < 0.01; 2018–2022: OR 4.23, 95% CI 2.78–6.43, p < 0.01, respectively) were identified as positive factors. Table 2 Results of univariate and multivariate logistic regression analysis Factors, p < 0.05 Univariate logistic regression analysis Multivariate logistic regression analysis OR 95% CI p value OR 95% CI p value Sponsor company profile Company size Large Ref. Ref. Non-large 0.19 0.14–0.25 < 0.01** - - - Operational base in Japan Yes Ref. Ref. No 0.06 0.03–0.09 < 0.01** 0.07 0.04–0.11 < 0.01** Trial profile Number of countries ≤ 19 Ref. Ref. 19 < 5.82 4.43–7.65 < 0.01** 4.00 2.92–5.48 < 0.01** Sample size ≤ 522 Ref. Ref. 522 < 2.92 2.26–3.77 < 0.01** - - - Start year 2008–2012 Ref. Ref. 2013–2017 2.04 1.45–2.87 < 0.01** 2.49 1.66–3.74 < 0.01** 2018–2022 2.90 2.08–4.04 < 0.01** 4.23 2.78–6.43 < 0.01** Study design Comparative Ref. Ref. Non-comparative 0.18 0.06–0.52 < 0.01** Primary endpoint Overall survival Ref. Ref. Surrogate 1.35 1.02–1.78 0.036* 1.04 0.73–1.49 0.827 Cancer incidence Major Ref. Ref. Minor 0.43 0.33–0.57 < 0.01** 0.47 0.34–0.65 < 0.01** Cancer type Solid tumors Ref. Ref. Hematological malignancies 0.65 0.48–0.86 < 0.01** - - - OR: odds ratio, 95% CI: 95% confidence interval, * < 0.05, ** < 0.01 Japan's participation in the oncology phase III MRCTs by cancer organ To further investigate the trend of Japan’s participation in oncology phase III MRCTs, we next performed a subgroup analysis by cancer organ. In Table 3 , Japan tended to participate in oncology phase III MRCTs when the cancer organs were esophagus (OR 7.78, p = 0.039), head and neck (OR 3.29, p < 0.01), lung (R 1.73, p < 0.01), stomach (OR 2.71, p = 0.015), and urothelium (OR 2.05, p = 0.036). On the other hand, Japan was unlikely to participate in oncology phase III MRCTs for pancreas (OR 0.15, p < 0.01), skin (OR 0.23, p < 0.01), and soft tissue (OR 0.36, p = 0.013). Among hematological malignancies, Japan was unlikely to participate in leukemia trials (OR 0.40, p < 0.01), while there was no such trend in terms of lymphoma and myeloma. Table 3 Japan’s participation in Oncology Phase III MRCTs by cancer organ Cancer organ Cancer type Total With Japan, n(%) OR 95% CI p value Biliary Tract Solid tumors 4 4 (100) ∞ ∞ 0.125 Brain Solid tumors 12 4 (33) 0.48 0.14–1.59 0.255 Breast Solid tumors 116 67 (58) 1.36 0.92–2.01 0.139 Cervix Solid tumors 7 5 (71) 2.41 0.47–12.49 0.452 Colorectum Solid tumors 27 18 (67) 1.95 0.87–4.39 0.119 Esophagus Solid tumors 9 8 (89) 7.78 0.97–62.41 0.039* Head and Neck Solid tumors 26 20 (77) 3.29 1.31–8.25 < 0.01** Kidney Solid tumors 34 19 (56) 1.22 0.61–2.43 0.604 Leukemia Hematological malignancies 120 38 (32) 0.40 0.27–0.60 < 0.01** Liver Solid tumors 36 24 (67) 1.96 0.97–3.97 0.063 Lung Solid tumors 177 110 (62) 1.73 1.24–2.42 < 0.01** Lymphoma Hematological malignancies 68 32 (47) 0.84 0.51–1.38 0.531 Mesothelium Solid tumors 6 2 (33) 0.48 0.09–2.62 0.443 Myeloma Hematological malignancies 57 35 (61) 1.56 0.90–2.70 0.133 Neuroendocrine Solid tumors 7 1 (14) 0.16 0.02–1.32 0.064 Ovary Solid tumors 39 16 (41) 0.66 0.34–1.26 0.253 Pancreas Solid tumors 22 3 (14) 0.15 0.04–0.50 < 0.01** Prostate Solid tumors 69 29 (42) 0.68 0.41–1.11 0.135 Skin Solid tumors 45 9 (20) 0.23 0.11–0.47 < 0.01** Soft Tissue Solid tumors 29 8 (28) 0.36 0.16–0.81 0.013* Stomach Solid tumors 30 22 (73) 2.71 1.20–6.15 0.015* Thyroid Solid tumors 8 4 (50) 0.96 0.24–3.85 1.000 Urothelium Solid tumors 40 27 (68) 2.05 1.04–4.01 0.036* Uterus Solid tumors 9 4 (44) 0.77 0.20–2.87 0.748 OR: odds ratio, 95% CI: 95% confidence interval, * < 0.05, ** < 0.01 Table 4 Japan’s participation in Oncology Phase III MRCTs by drug modality Drug modality Total With Japan, n(%) OR 95% CI p value Antibodies 391 267 (68) 3.23 2.47–4.22 < 0.01** Monoclonal antibodies 3318 220 (69) 3.03 2.28–4.01 < 0.01** Antibody-drug conjugates 57 36 (63) 1.69 0.97–2.94 0.075 Bispecific antibodies 16 11 (69) 2.13 0.74–6.19 0.208 Proteins and Peptides 64 11 (17) 0.18 0.09–0.35 < 0.01** Cell Therapies 14 5 (36) 0.53 0.18–1.59 0.290 Gene Therapies 3 1 (33) 0.48 0.04–5.29 0.617 Nucleic Acids 5 0 (0) 0.00 0.00–0.00 0.028* Small Molecule 494 221 (45) 0.61 0.47–0.78 < 0.01** Cytotoxic agents 53 5 (9) 0.09 0.04–0.23 < 0.01** Molecular targeted drugs 441 216 (49) 0.86 0.67–1.10 0.252 Radiotherapies 16 2 (13) 0.13 0.03–0.59 < 0.01** Other New Modalities 12 3 (25) 0.32 0.08–1.17 0.085 OR: odds ratio, 95% CI: 95% confidence interval, * < 0.05, ** < 0.01 Japan's participation in the oncology phase III MRCTs by drug modality In terms of drug modalities, Japan is likely to participate in antibody trials (especially monoclonal antibodies: OR 3.03, p < 0.01) and unlikely to participate in trials of protein/peptide (OR 0.18, p < 0.01), nucleic acid (OR 0.00, p = 0.028), small molecule (especially cytotoxic agents: OR 0.09, p < 0.01), and radiotherapies (OR 0.13, p < 0.01). On contrast, there was no trend in new modalities such as cell therapies (e.g. CAR-T), gene therapies and other new modality trials. Discussion This study aimed to investigate the situation of “potential drug lag/drug loss” based on Japan's participation rate in phase III MRCTs of anticancer drugs to predict future drug lag and drug loss. The data from our study indicate that for anticancer drugs, Japan's participation rate in phase III MRCTs has increased over the past 15 years, while the number of non-participations has not decrease, which potentially indicates there might still be drug approval lag or even drug loss in the future. This suggests that the efforts taken by the Japanese government and regulatory authorities and industry were at least partially successful in terms of Japan’s participation rate to MRCTs. On the other hand, in terms of unapproved drugs, there could be space for making efforts to improve. Previous reports indicate that the drug lag in the field of rare diseases is increasing when unapproved drugs are taken into account, and that many unapproved drugs are being developed by non-Japanese companies without Japan's participation in global clinical trials [ 11 ]. Our study differs from the previous report in that the analysis was based on phase III MRCTs of anti-cancer drugs, but the results suggest that the presence or absence of an operating base in Japan affect the participation rate of Japan in oncology phase III MRCTs, which is consistent with the trend reported in the previous report [ 11 ]. In addition, a previous report, which analyzed US-approved cancer drugs by drawing a Kaplan-Meier curve with unapproved drugs treated as “censored” and Japanese approval as the event, reported a median approval lag of 961 days for 2011–2016 and 1555 days for 2017–2022, indicating that the approval lag is increasing, mainly due to an increase in unapproved drugs [ 21 ]. Our study demonstrated that the approval lag is expected to expand, and the number of unapproved drugs will continue to increase in the future as well because the number of non-participations of Japan in phase III MRCTs has not decrease. Interestingly, the number of cases in which Japan did not participate but other East Asian countries (Korea, China, Hong Kong, or Taiwan) have participated increased over the past 15 years. This suggests a trend of declining importance of Japan in oncology phase III MRCTs, which should be addressed in the future. Since non-large companies that do not have an operating base in Japan are less likely to participate in MRCTs in Japan (Fig. 3 b), it is necessary to promote drug development in Japan by these companies (many of which are overseas start-up companies). Reasons why small overseas companies do not develop drugs in Japan include: 1) the Japanese market is not attractive (due to the drug price system, which offer constantly decreasing drug price), 2) the cost performance of conducting clinical trials in Japan is poor, and 3) licensing and In-country Clinical Care-taker (ICCC) clinical trials’ implementation are time-consuming and labor intensive [ 22 ]. Resolution of these issues is needed. Recently, the MHLW has clarified the need for Japanese data in the regulatory review process, and in principle, additional Japan phase I studies are not required when participating in global clinical trials [ 23 ]. Although it is said for anticancer drugs that, from the viewpoint of safety, more careful judgment is needed to determine whether Japan phase I studies are required or not, the MRCT participation rate for anticancer agents in Japan is expected to also increase in the future. In this study, there were differences in Japan's participation/non-participation in MRCTs according to cancer incidence, and the likelihood of Japan's participation in MRCTs was low for minor cancers. The main reason for this could be the increasing number of applications and approvals based on early-stage clinical trials for minor cancers. The approval lag between Japan and the US for major cancers improved from 2006–2011 to 2012–2016, but there was no improvement for minor cancers, and a development strategy using MRCTs is reportedly needed to shorten the approval lag [ 18 ]. In terms of regulatory characteristics, Breakthrough Therapy Designation by FDA and/or Accelerated Approval is associated with a shorter approval lag in Japan [ 24 ], and in the US, Breakthrough Therapy Designation and/or Accelerated Approval is more common in minor cancers [ 25 ]. Pivotal trials for orphan anticancer drugs tend to be early-stage, non-randomized studies whose primary endpoint are response rates [ 26 ]. In order to decrease the drug lag in rare cancers, it is necessary to promote Japan’s participation not only in phase III MRCTs but also in early phase MRCTs. Since the trend of Japan’s participation in oncology phase I MRCTs has differed depending on the sponsor company as reported in a previous report [ 27 ], action to include Japan in phase I MRCTs may be necessary, especially for companies that have a low trend of Japan’s participation in phase I MRCTs. Interestingly, Japan’s participation in MRCTs varied by target cancer organ. Japan’s participation in MRCTs tended to be high for lung and stomach cancers, which are the most common site-specific cancers among Japanese, suggesting that drug development is driven by medical needs. On the other hand, Japan’s participation in MRCTs for pancreatic cancer, which is one of the main causes of cancer death among Japanese, tended to be low. And the number of MRCTs themselves was also low. This indicates the unmet medical need in pancreatic cancer and the need for further improvement in Japan. Also, differences in Japan’s participation rated in MRCT were observed by drug modality. The number of small molecule and monoclonal antibody trials for molecular targets has increased since the MHLW/PMDA measures to promote international joint clinical trials, and Japan’s participation rate in phase III MRCT has been considered high, while Japan’s participation in phase III MRCT is low when it comes to cytotoxic agents because many cytotoxic agents have been approved through bridging or public knowledge-based application in Japan [ 28 ]. In fact, in the MRCT analysis of all diseases, the odds ratio (OR) for Japan’s participation in MRCT was 2.19 (1.33–3.62, P = 0.002) for biological drugs, while the OR for chemical compounds was 0.63 (0.39–0.99), a trend similar to that of the present study [ 29 ]. There are limitations in our study. Including only phase III trials as a target is a limitation since the number of approvals based on early-stage trials such as phase I and II studies as pivotal trials has increased in Japan for mainly rare cancers in recent years. In the U.S., the FDA often grants accelerated approval based on early-stage trials and then grants full approval with the results of the phase III trial as a confirmation trial. In Japan, SAKIGAKE designation and conditional early approval for new drug applications are equivalent to the FDA's Breakthrough Therapy designation and Accelerated Approval [ 30 , 31 ], however, there are not yet many examples of use, and it is hoped that the early approval system will be expanded to the same level as that of the FDA. Many previous reports have analyzed the drug lag resulting from drug approval dates in the US and Japan [ 8 , 12 , 18 , 24 ]. On the other hand, this study is significant in that it can predict the possibility of a lag not only in past trends but also in drugs/indications scheduled for approval in the future, based on the inclusion rate of Japan in phase III MRCTs. The number of Japan’s non-participation in phase III MRCTs continues to increase, and future expansion of drug lag and drug loss was anticipated. Promotion of Japan's inclusion in the MRCTs and expansion of the early approval system are desirable. Declarations Acknowledgements We would like to thank TWIns (Joint Graduate School of Tokyo Women's Medical University and Waseda University) members for their valuable suggestions and assistance in data interpretation. Conflict of Interest Kaname Shiga is an employee of Janssen Pharmaceutical K.K., a subsidiary of Johnson & Johnson Innovative Medicine, Raritan, NJ, USA. Taro Shibata and Toshio Miyata have no conflict of interest. References Ministry of Health, Labour and Welfare (2022) Summary of Vital Statistics Monthly Report Annual Total Cancer and Disease Control Division, Ministry of Health, Labor and Welfare (2019) Cancer Incidence of Japan Tsuji K, Tsutani K (2008) Follow the leader. Nature 453:851–852. https://doi.org/10.1038/453851a Yonemori K, Hirakawa A, Ando M, Hirata T, Yunokawa M, Shimizu C, Katsumata N, Tamura K, Fujiwara Y (2011) The notorious drug lag for oncology drugs in Japan. 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Eur J Clin Pharmacol 75:1193–1200. https://doi.org/10.1007/s00228-019-02695-0 Nakayama H, Tsukamoto K (2018) Unique characteristics of regulatory approval and pivotal studies of orphan anticancer drugs in Japan. Invest New Drugs 36:702–708. https://doi.org/10.1007/s10637-018-0603-z Maki A, Narukawa M (2024) Factors Associated with Inclusion of Japan in Phase I Multiregional Clinical Trials in Oncology. Ther Innov Regul Sci 58:766–772. https://doi.org/10.1007/s43441-024-00655-0 Maeda H, Fukuda Y, Uchida M (2021) Assessment of Drugs Approved by Public Knowledge-Based Applications ( Kouchi‐shinsei ) During the Last Two Decades in Japan. Clin Pharmacol Ther 110:1127–1135. https://doi.org/10.1002/cpt.2332 Rokuda M, Matsumaru N, Tsukamoto K (2018) Identification of Drug Characteristics for Implementing Multiregional Clinical Trials Including Japan. Clin Ther 40:284–295. https://doi.org/10.1016/j.clinthera.2017.12.010 Lyerly HK, Ren J, Canetta R, Kim GH, Nagai S, Yamaguchi T, Hatogai K, Katayama H, Da Rocha Dias S, McManus D, Soltys K, Yang Z, Olopade O, Goodman N, Reaman G, Gross T (2018) Global Development of Anticancer Therapies for Rare Cancers, Pediatric Cancers, and Molecular Subtypes of Common Cancers. J Glob Oncol 4:1–11. https://doi.org/10.1200/JGO.18.00092 Tanaka M, Miyazawa H, Terashima R, Ikuma M (2023) Conditional early approval for new drug applications in Japan: Current and emerging issues. Clin Transl Sci 16:1289–1293. https://doi.org/10.1111/cts.13536 Supplementary Files ShigaetalIJCOMRCTsSupplemental.docx Cite Share Download PDF Status: Published Journal Publication published 11 Apr, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 01 Jan, 2025 Reviewers agreed at journal 23 Nov, 2024 Reviewers invited by journal 23 Nov, 2024 Editor assigned by journal 15 Nov, 2024 First submitted to journal 14 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5456839","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":381826125,"identity":"64c0d02e-bdda-4e1e-a2a2-1ad68f6c68a1","order_by":0,"name":"Kaname Shiga","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0002-3390-464X","institution":"Waseda University Faculty of Science and Engineering: Waseda Daigaku Riko Gakujutsuin","correspondingAuthor":true,"prefix":"","firstName":"Kaname","middleName":"","lastName":"Shiga","suffix":""},{"id":381826126,"identity":"6437e902-99d1-4d03-8e36-05d228cde0f6","order_by":1,"name":"Taro Shibata","email":"","orcid":"","institution":"National Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Taro","middleName":"","lastName":"Shibata","suffix":""},{"id":381826127,"identity":"ca6cb19e-ff78-41e3-8d12-72c975dcc41d","order_by":2,"name":"Toshio Miyata","email":"","orcid":"","institution":"Waseda University Faculty of Science and Engineering: Waseda Daigaku Riko Gakujutsuin","correspondingAuthor":false,"prefix":"","firstName":"Toshio","middleName":"","lastName":"Miyata","suffix":""}],"badges":[],"createdAt":"2024-11-15 01:39:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5456839/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5456839/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-025-02756-8","type":"published","date":"2025-04-11T16:05:39+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":72283253,"identity":"9c0d62ff-746d-4c68-8d1c-970548b98bb9","added_by":"auto","created_at":"2024-12-24 16:40:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":169610,"visible":true,"origin":"","legend":"\u003cp\u003ePhase III multi-regional clinical trials of anticancer drugs initiated between January 1, 2008, and December 31, 2022.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5456839/v1/e4e631b896d9c0b8aec8d9d3.png"},{"id":72281799,"identity":"1a25f139-b2cc-45e7-9ce6-8d2c507a82bf","added_by":"auto","created_at":"2024-12-24 16:32:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":572124,"visible":true,"origin":"","legend":"\u003cp\u003eTrends of participation in Oncology Phase III MRCTs started between 2008 to 2022. a) Participation rates in Oncology Phase III MRCTs. b) Participation numbers in Oncology Phase III MRCTs. c) Difference in participation numbers between the US and Japan, and between East Asia Total and Japan\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5456839/v1/655109d9358890740ffee0f4.png"},{"id":80558664,"identity":"4d5d5b40-489d-401d-a51f-2b8fb8a8e9c9","added_by":"auto","created_at":"2025-04-14 16:15:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1776100,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5456839/v1/289161c5-e599-4c12-ac33-1e855ea66ab9.pdf"},{"id":72281811,"identity":"fcd1eeff-3d62-4779-b21f-f2c243f22b1b","added_by":"auto","created_at":"2024-12-24 16:32:25","extension":"docx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":50425,"visible":true,"origin":"","legend":"","description":"","filename":"ShigaetalIJCOMRCTsSupplemental.docx","url":"https://assets-eu.researchsquare.com/files/rs-5456839/v1/bf7edaa4a11db2bb628cba2c.docx"}],"financialInterests":"","formattedTitle":"Evaluation of Drug Lag and Drug Loss in Japan: Participation in Global Phase III Oncology Trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCancer is a serious and fatal disease, accounting for approximately 25% of all deaths in Japan [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], and it is reported that 65.5% of Japanese men and 51.2% of women will be diagnosed with cancer during their lifetime [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. As a result, there is a need for new and innovative drugs to improve the prognosis of cancer patients, and clinical development of anticancer drugs is active in Japan and overseas.\u003c/p\u003e \u003cp\u003eHowever, there is a difference in the timing of anticancer drug approvals between Japan and other countries, particularly the US. This problem is known as \"drug lag\" and is a serious issue because it affects patient access to medicines, especially anticancer drugs [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFrom the late 2000s to the early 2010s, the Ministry of Health, Labour and Welfare (MHLW) issued several guidelines and notifications to promote the use of multinational/multiregional clinical trials (MRCTs) to support the marketing authorization of new drugs in Japan [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn recent years, the development of clinical trial systems and expansion of capabilities of the Pharmaceuticals and Medical Devices Agency (PMDA) system have narrowed the gap between Japan and the US in the development of anticancer drugs [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], but the issue of \"drug loss\", where drugs are not developed due to there are no companies to develop them in Japan and the number of unapproved drugs increases in the future, has become a major challenge [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious reports have shown that Japanese participation in MRCTs is associated with both drug submission and approval lags [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. It has been reported that the approval lag is shorter when Japan is included in an MRCT than when a separate local trial is conducted in Japan [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Therefore, including Japan in MRCTs is advantageous for pharmaceutical companies as it makes it easier to obtain approval in the Japanese market. In addition, recent reports indicate that the potential for future approval lags and undeveloped drugs can be measured by the rate of Japanese participation in MRCTs. It has been reported that 80% of drugs not participating in MRCTs for anticancer, anti-infective, antipsychotic, and cardiovascular drugs were not developed in Japan (potential drug loss) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e. Investigating the reasons why it is difficult to include Japan in MRCTs will also contribute to efficient drug development strategies for drugs of foreign origin.\u003c/p\u003e \u003cp\u003eThis study therefore aimed to investigate the situation of \u0026ldquo;potential drug lag/drug loss\u0026rdquo; based on Japan's participation rate in phase III MRCTs of anticancer drugs, explored associated factors.\u003c/p\u003e"},{"header":"Materials \u0026 Methods","content":"\u003cp\u003e\u003cstrong\u003eCriteria for trial selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study included phase III MRCTs that were funded by pharmaceutical companies, included the US as one of the participant countries, and targeted cancer (either solid tumors or hematological malignancies), started between 01/01/2008 and 12/31/2022. Trials that did not intend efficacy to cancers, conducted only in the US, and were not led by pharm, extension or rollover studies were excluded.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData sources and collected information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were collected from ClinicalTrials.gov (https://clinicaltrials.gov/). The collected information includes study start year, participant country, sponsor, type of cancer, study drug, study design, sample size, and primary endpoint.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCancer Incidence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo investigate the difference in Japan\u0026rsquo;s participation by cancer incidence, the cancer targeted by each clinical trial was categorized by incidence as either major (6 or more cases/100,000 individuals/year) or minor (\u0026lt;6/100,000 individuals/year) by utilizing the definition for rare cancer by International Rare Cancers Initiative (https://project.eortc.org/irci/) (RARECARE definition) [16\u0026ndash;18].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCancer organ\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach cancer was classified to each organ (biliary tract, brain, breast, cervix, colorectum, esophagus, head and neck, kidney, liver, lung, mesothelium, neuroendocrine, ovary, pancreas, prostate, skin, soft tissue, stomach, thyroid, urothelium, and uterus). Hematologic malignancies were classified to leukemia, lymphoma, and myeloma [19].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDrug modality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach drug modality was classified according to the existing report as antibodies (including monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies), protein and peptides, cell therapies (including CAR-T), gene therapies, nucleic acids (DNA and RNA), other new modalities (including oncolytic viruses), small molecules (cytotoxic agents and molecular targeted drugs), and radiotherapies (including radio-drug conjugates) [20].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompany size definition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo investigate the relevance of company size in Japan\u0026rsquo;s participation, each company was categorized as either \u0026ldquo;Large company\u0026rdquo; or \u0026ldquo;Non-large company\u0026rdquo; based on global sales ranking top 20 between 2018-2022. If the company was involved in top 20 for multiple times, the company was categorized as \u0026ldquo;Large company\u0026rdquo;. The Large companies are followings; Pfizer, Johnson\u0026amp;Johnson (Janssen), Roche/Genentech, Merck (MSD), AbbVie (Abbott), Novartis, Bristol Myers Squibb, Sanofi, AstraZeneca, Glaxosmithkline (GSK), Takeda, Eli Lilly, Bayer, Amgen, Glead Sciences, Boehringer Ingelheim. Subsidiaries of large companies were classified as \u0026ldquo;Large company\u0026rdquo;.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures and statistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe participation rate of the target countries was calculated as the number of target countries included in the total number of phase III MRCTs. The US participation rate was assumed to be 100%. The five most populous European countries (Germany, UK, France, Italy, and Spain) were grouped together for analysis as the \u0026ldquo;EU5\u0026rdquo;. East Asia countries (Japan, Korea, China, Hong Kong, and Taiwan) were included in the \u0026ldquo;East Asia Total\u0026rdquo;. Also, the participation number and its difference between the US and Japan, and between East Asia total and Japan were calculated to investigate Japan\u0026rsquo;s non-inclusion to phase III MRCTs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUnivariate and multivariate logistic regression analyses were performed using the extracted trial characteristics to explore factors affecting Japanese participation/non-participation in oncology phase III MRCTs. Odd ratios and 95% confidence intervals were calculated. For univariate analysis, the following factors were analyzed: company size (large/non-large), operational base in Japan, number of countries, sample size, study start year, study design (comparative/non-comparative), primary endpoint (overall survival/surrogate), cancer incidence (major/minor), and cancer type (solid tumors/hematological malignancies). For multivariate analysis, the following independent variables were used: operational base in Japan, number of countries, study start year, primary endpoint, and cancer incidence.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed using JMP\u0026reg;Pro and statistical significance was set at P \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eClinical trials selected\u003c/h2\u003e \u003cp\u003eThere were 8364 phase III MRCTs initiated in the US between 1 January 2008 and 31 December 2022. Excluding trials that did not meet the inclusion criteria, there were 999 phase III MRCTs of anticancer agents included in this study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There was no clear trend in the proportion of cancer trials in the total number of trials.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of the trials\u003c/h2\u003e \u003cp\u003eThe characteristics of the 999 extracted studies are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The number of phase III MRCTs increased every 5 years (2008\u0026ndash;2012: 239, 2013\u0026ndash;2017: 345, and 2018\u0026ndash;2022: 415). 35% of the total were minor cancers and 25% were hematological malignancies (all minor cancers). The median number of participating countries was 19 (range: 2\u0026ndash;56) and the median sample size was 522. Japan's participation rate was 51% for the entire period.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of Oncology Phase III MRCTs started from 2008 to 2022\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;999\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer incidence \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMajor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e649 (65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e350 (35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer type \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e754 (75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematological malignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e245 (25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompany size \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLarge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e674 (67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-large\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e325 (33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOperational base in Japan \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e771 (77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e228 (23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of countries \u0026ndash; median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (2\u0026ndash;56)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSample size \u0026ndash; median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e522 (0\u0026ndash;6000)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStart year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2008\u0026ndash;2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e239 (24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2013\u0026ndash;2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e345 (35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2018\u0026ndash;2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e415 (42)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJapan\u0026rsquo;s participation \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e510 (51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e489 (49)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy design \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComparative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e974 (97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-comparative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary endpoint \u0026ndash; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e280 (28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e719 (72)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eJapan's participation in the oncology phase III MRCTs\u003c/h2\u003e \u003cp\u003eThe five-year trends of the participation rate and participation number in the oncology phase III MRCTs are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, the participation rates of the EU5 have remained around 80% over the 15 years, whereas Japan\u0026rsquo;s participation rates increased from 34\u0026ndash;60% and East Asia's Total increased from 59\u0026ndash;82%. However, Japan\u0026rsquo;s non-participation number has been almost constant (around 160 trials by each 5 years), which resulted in 489 oncology phase III MRCTs that Japan was not included (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Moreover, among MRCTs that did not include Japan, the number of MRCTs that included East Asian countries other than Japan increased every 5 years to 58, 80, and 91 trials (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePotential factors associated with the Japan\u0026rsquo;s participation in phase III MRCTs\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the results of the logistic regression analyses for each of the characteristics. In the univariate analysis, non-large sponsor company, sponsor who doesn\u0026rsquo;t have an operational base in Japan, non-comparative study, major cancer, and hematological malignancies are negative factors for Japan\u0026rsquo;s participation in oncology phase III MRCTs whereas large trials (whose number of countries are more than 19, whose sample size are more than 522 patients), start year after 2013 (2013\u0026ndash;2017 and 2018\u0026ndash;2022), and surrogate endpoint are positive factors. In the multivariate logistic regression analysis using variables that were independent among those used in the univariate analysis, sponsor who doesn\u0026rsquo;t have an operational base in Japan (OR 0.07, 95% CI 0.04\u0026ndash;0.11, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and minor cancer (OR 0.47, 95% CI 0.34\u0026ndash;0.65, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) were identified as negative factors, and the number of countries is more than 19 (OR 4.00, 95% CI 2.92\u0026ndash;5.48, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), the start year after 2013 (2013\u0026ndash;2017: OR 2.49, 95% CI 1.66\u0026ndash;3.74, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; 2018\u0026ndash;2022: OR 4.23, 95% CI 2.78\u0026ndash;6.43, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, respectively) were identified as positive factors.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults of univariate and multivariate logistic regression analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactors, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnivariate logistic regression analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMultivariate logistic regression analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSponsor company profile\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompany size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLarge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-large\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.14\u0026ndash;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOperational base in Japan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.03\u0026ndash;0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.04\u0026ndash;0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTrial profile\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of countries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19 \u0026lt;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.43\u0026ndash;7.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.92\u0026ndash;5.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSample size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;522\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e522 \u0026lt;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.26\u0026ndash;3.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStart year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2008\u0026ndash;2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2013\u0026ndash;2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.45\u0026ndash;2.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.66\u0026ndash;3.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2018\u0026ndash;2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.08\u0026ndash;4.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.78\u0026ndash;6.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComparative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-comparative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.06\u0026ndash;0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary endpoint\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurrogate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.02\u0026ndash;1.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.036*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.73\u0026ndash;1.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.827\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCancer incidence\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMajor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.33\u0026ndash;0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.34\u0026ndash;0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCancer type\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematological malignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.48\u0026ndash;0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eOR: odds ratio, 95% CI: 95% confidence interval,\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e* \u0026lt; 0.05, ** \u0026lt; 0.01\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eJapan's participation in the oncology phase III MRCTs by cancer organ\u003c/h2\u003e \u003cp\u003eTo further investigate the trend of Japan\u0026rsquo;s participation in oncology phase III MRCTs, we next performed a subgroup analysis by cancer organ. In Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Japan tended to participate in oncology phase III MRCTs when the cancer organs were esophagus (OR 7.78, p\u0026thinsp;=\u0026thinsp;0.039), head and neck (OR 3.29, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), lung (R 1.73, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), stomach (OR 2.71, p\u0026thinsp;=\u0026thinsp;0.015), and urothelium (OR 2.05, p\u0026thinsp;=\u0026thinsp;0.036). On the other hand, Japan was unlikely to participate in oncology phase III MRCTs for pancreas (OR 0.15, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), skin (OR 0.23, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and soft tissue (OR 0.36, p\u0026thinsp;=\u0026thinsp;0.013). Among hematological malignancies, Japan was unlikely to participate in leukemia trials (OR 0.40, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), while there was no such trend in terms of lymphoma and myeloma.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eJapan\u0026rsquo;s participation in Oncology Phase III MRCTs by cancer organ\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer organ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCancer type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWith Japan, n(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiliary Tract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026infin;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026infin;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.14\u0026ndash;1.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.255\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.92\u0026ndash;2.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.139\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCervix\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.47\u0026ndash;12.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.452\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColorectum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.87\u0026ndash;4.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.119\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEsophagus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.97\u0026ndash;62.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.039*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHead and Neck\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.31\u0026ndash;8.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKidney\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.61\u0026ndash;2.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.604\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHematological malignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.27\u0026ndash;0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.97\u0026ndash;3.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.063\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e110 (62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.24\u0026ndash;2.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHematological malignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.51\u0026ndash;1.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.531\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMesothelium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.09\u0026ndash;2.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.443\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyeloma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHematological malignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.90\u0026ndash;2.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.133\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeuroendocrine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.02\u0026ndash;1.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.34\u0026ndash;1.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.253\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePancreas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.04\u0026ndash;0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProstate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.41\u0026ndash;1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.135\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.11\u0026ndash;0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSoft Tissue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.16\u0026ndash;0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.013*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStomach\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.20\u0026ndash;6.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.015*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.24\u0026ndash;3.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrothelium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.04\u0026ndash;4.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.036*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUterus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.20\u0026ndash;2.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.748\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eOR: odds ratio, 95% CI: 95% confidence interval,\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e* \u0026lt; 0.05, ** \u0026lt; 0.01\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eJapan\u0026rsquo;s participation in Oncology Phase III MRCTs by drug modality\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug modality\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWith Japan, n(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e391\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e267 (68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.47\u0026ndash;4.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonoclonal antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3318\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e220 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.28\u0026ndash;4.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibody-drug conjugates\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.97\u0026ndash;2.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBispecific antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.74\u0026ndash;6.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.208\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProteins and Peptides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.09\u0026ndash;0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCell Therapies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.18\u0026ndash;1.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.290\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene Therapies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.04\u0026ndash;5.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.617\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNucleic Acids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.00\u0026ndash;0.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.028*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmall Molecule\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e494\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e221 (45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.47\u0026ndash;0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytotoxic agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.04\u0026ndash;0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular targeted drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e216 (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.67\u0026ndash;1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.252\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.03\u0026ndash;0.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01**\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther New Modalities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.08\u0026ndash;1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.085\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eOR: odds ratio, 95% CI: 95% confidence interval,\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e* \u0026lt; 0.05, ** \u0026lt; 0.01\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eJapan's participation in the oncology phase III MRCTs by drug modality\u003c/h2\u003e \u003cp\u003eIn terms of drug modalities, Japan is likely to participate in antibody trials (especially monoclonal antibodies: OR 3.03, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and unlikely to participate in trials of protein/peptide (OR 0.18, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), nucleic acid (OR 0.00, p\u0026thinsp;=\u0026thinsp;0.028), small molecule (especially cytotoxic agents: OR 0.09, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and radiotherapies (OR 0.13, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). On contrast, there was no trend in new modalities such as cell therapies (e.g. CAR-T), gene therapies and other new modality trials.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aimed to investigate the situation of \u0026ldquo;potential drug lag/drug loss\u0026rdquo; based on Japan's participation rate in phase III MRCTs of anticancer drugs to predict future drug lag and drug loss.\u003c/p\u003e \u003cp\u003eThe data from our study indicate that for anticancer drugs, Japan's participation rate in phase III MRCTs has increased over the past 15 years, while the number of non-participations has not decrease, which potentially indicates there might still be drug approval lag or even drug loss in the future. This suggests that the efforts taken by the Japanese government and regulatory authorities and industry were at least partially successful in terms of Japan\u0026rsquo;s participation rate to MRCTs. On the other hand, in terms of unapproved drugs, there could be space for making efforts to improve. Previous reports indicate that the drug lag in the field of rare diseases is increasing when unapproved drugs are taken into account, and that many unapproved drugs are being developed by non-Japanese companies without Japan's participation in global clinical trials [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Our study differs from the previous report in that the analysis was based on phase III MRCTs of anti-cancer drugs, but the results suggest that the presence or absence of an operating base in Japan affect the participation rate of Japan in oncology phase III MRCTs, which is consistent with the trend reported in the previous report [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition, a previous report, which analyzed US-approved cancer drugs by drawing a Kaplan-Meier curve with unapproved drugs treated as \u0026ldquo;censored\u0026rdquo; and Japanese approval as the event, reported a median approval lag of 961 days for 2011\u0026ndash;2016 and 1555 days for 2017\u0026ndash;2022, indicating that the approval lag is increasing, mainly due to an increase in unapproved drugs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Our study demonstrated that the approval lag is expected to expand, and the number of unapproved drugs will continue to increase in the future as well because the number of non-participations of Japan in phase III MRCTs has not decrease. Interestingly, the number of cases in which Japan did not participate but other East Asian countries (Korea, China, Hong Kong, or Taiwan) have participated increased over the past 15 years. This suggests a trend of declining importance of Japan in oncology phase III MRCTs, which should be addressed in the future.\u003c/p\u003e \u003cp\u003eSince non-large companies that do not have an operating base in Japan are less likely to participate in MRCTs in Japan (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb), it is necessary to promote drug development in Japan by these companies (many of which are overseas start-up companies). Reasons why small overseas companies do not develop drugs in Japan include: 1) the Japanese market is not attractive (due to the drug price system, which offer constantly decreasing drug price), 2) the cost performance of conducting clinical trials in Japan is poor, and 3) licensing and In-country Clinical Care-taker (ICCC) clinical trials\u0026rsquo; implementation are time-consuming and labor intensive [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Resolution of these issues is needed. Recently, the MHLW has clarified the need for Japanese data in the regulatory review process, and in principle, additional Japan phase I studies are not required when participating in global clinical trials [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Although it is said for anticancer drugs that, from the viewpoint of safety, more careful judgment is needed to determine whether Japan phase I studies are required or not, the MRCT participation rate for anticancer agents in Japan is expected to also increase in the future. In this study, there were differences in Japan's participation/non-participation in MRCTs according to cancer incidence, and the likelihood of Japan's participation in MRCTs was low for minor cancers. The main reason for this could be the increasing number of applications and approvals based on early-stage clinical trials for minor cancers. The approval lag between Japan and the US for major cancers improved from 2006\u0026ndash;2011 to 2012\u0026ndash;2016, but there was no improvement for minor cancers, and a development strategy using MRCTs is reportedly needed to shorten the approval lag [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In terms of regulatory characteristics, Breakthrough Therapy Designation by FDA and/or Accelerated Approval is associated with a shorter approval lag in Japan [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], and in the US, Breakthrough Therapy Designation and/or Accelerated Approval is more common in minor cancers [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Pivotal trials for orphan anticancer drugs tend to be early-stage, non-randomized studies whose primary endpoint are response rates [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In order to decrease the drug lag in rare cancers, it is necessary to promote Japan\u0026rsquo;s participation not only in phase III MRCTs but also in early phase MRCTs. Since the trend of Japan\u0026rsquo;s participation in oncology phase I MRCTs has differed depending on the sponsor company as reported in a previous report [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], action to include Japan in phase I MRCTs may be necessary, especially for companies that have a low trend of Japan\u0026rsquo;s participation in phase I MRCTs.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eInterestingly, Japan\u0026rsquo;s participation in MRCTs varied by target cancer organ. Japan\u0026rsquo;s participation in MRCTs tended to be high for lung and stomach cancers, which are the most common site-specific cancers among Japanese, suggesting that drug development is driven by medical needs. On the other hand, Japan\u0026rsquo;s participation in MRCTs for pancreatic cancer, which is one of the main causes of cancer death among Japanese, tended to be low. And the number of MRCTs themselves was also low. This indicates the unmet medical need in pancreatic cancer and the need for further improvement in Japan.\u003c/p\u003e \u003cp\u003eAlso, differences in Japan\u0026rsquo;s participation rated in MRCT were observed by drug modality. The number of small molecule and monoclonal antibody trials for molecular targets has increased since the MHLW/PMDA measures to promote international joint clinical trials, and Japan\u0026rsquo;s participation rate in phase III MRCT has been considered high, while Japan\u0026rsquo;s participation in phase III MRCT is low when it comes to cytotoxic agents because many cytotoxic agents have been approved through bridging or public knowledge-based application in Japan [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In fact, in the MRCT analysis of all diseases, the odds ratio (OR) for Japan\u0026rsquo;s participation in MRCT was 2.19 (1.33\u0026ndash;3.62, P\u0026thinsp;=\u0026thinsp;0.002) for biological drugs, while the OR for chemical compounds was 0.63 (0.39\u0026ndash;0.99), a trend similar to that of the present study [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are limitations in our study. Including only phase III trials as a target is a limitation since the number of approvals based on early-stage trials such as phase I and II studies as pivotal trials has increased in Japan for mainly rare cancers in recent years. In the U.S., the FDA often grants accelerated approval based on early-stage trials and then grants full approval with the results of the phase III trial as a confirmation trial. In Japan, SAKIGAKE designation and conditional early approval for new drug applications are equivalent to the FDA's Breakthrough Therapy designation and Accelerated Approval [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], however, there are not yet many examples of use, and it is hoped that the early approval system will be expanded to the same level as that of the FDA.\u003c/p\u003e \u003cp\u003eMany previous reports have analyzed the drug lag resulting from drug approval dates in the US and Japan [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. On the other hand, this study is significant in that it can predict the possibility of a lag not only in past trends but also in drugs/indications scheduled for approval in the future, based on the inclusion rate of Japan in phase III MRCTs.\u003c/p\u003e \u003cp\u003eThe number of Japan\u0026rsquo;s non-participation in phase III MRCTs continues to increase, and future expansion of drug lag and drug loss was anticipated. Promotion of Japan's inclusion in the MRCTs and expansion of the early approval system are desirable.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eWe would like to thank TWIns (Joint Graduate School of Tokyo Women\u0026apos;s Medical University and Waseda University) members for their valuable suggestions and assistance in data interpretation.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eKaname Shiga is an employee of Janssen Pharmaceutical K.K., a subsidiary of Johnson \u0026amp; Johnson Innovative Medicine, Raritan, NJ, USA. Taro Shibata and Toshio Miyata have no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMinistry of Health, Labour and Welfare (2022) Summary of Vital Statistics Monthly Report Annual Total\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCancer and Disease Control Division, Ministry of Health, Labor and Welfare (2019) Cancer Incidence of Japan\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsuji K, Tsutani K (2008) Follow the leader. 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Invest New Drugs 29:706\u0026ndash;712. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s10637-011-9638-0\u003c/span\u003e\u003cspan address=\"10.1007/s10637-011-9638-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDirector of Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, MHLW (2007) Basic principles on Global Clinical Trials\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEvaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, MHLW (2012) Basic principles on Global Clinical Trials (Reference Cases)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEvaluation and Licensing Division, Pharmaceutical and, Bureau FS (2014) MHLW Basic principles for Conducting Phase1 Trials in the Japanese Population Prior to Global Clinical Trials\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaeda H, Kurokawa T (2015) Recent trends for drug lag in clinical development of oncology drugs in Japan: does the oncology drug lag still exist in Japan? 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Clin Transl Sci 16:1289\u0026ndash;1293. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/cts.13536\u003c/span\u003e\u003cspan address=\"10.1111/cts.13536\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Drug lag, drug loss, anticancer drug development, MRCT, phase III","lastPublishedDoi":"10.21203/rs.3.rs-5456839/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5456839/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Despite efforts to mitigate drug lag, discrepancies in drug approval timelines persist between Japan and the US, and increase in unapproved drugs has become a significant challenge. This study aimed to evaluate potential drug lag and drug loss by assessing Japan's participation in global phase III multinational/multiregional clinical trials (MRCTs) targeted cancers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Phase III MRCTs of anticancer drugs initiated between 2008 and 2022 were collected. Information of participant countries, study sponsor, study design, and cancer type were collected and analyzed by. logistic regression analysis to identify factors affected Japan’s participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Of 999 phase III MRCTs, Japan's participation every 5 year increased over 15 years (2008-2012: 34.3%, 2013-2017: 51.6%, 2018-2022: 60.2%), while Japan’s non-participation numbers didn’t change (2008-2012: 157, 2013-2017: 167, 2018-2022: 165). In the multivariate logistic regression analysis, the absence of an operational base in Japan and minor cancers were negatively associated with Japan’s participation in phase III MRCTs. Japan’s participation was also associated with some cancer organs and drug modalities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Potential future drug lag and increases of unapproved drug were expected to increase. Since inclusion of Japan in MRCTs results in shorter or no approval lag, Japan should promote to make the circumstances where small overseas companies can include Japan in MRCTs.\u003c/p\u003e","manuscriptTitle":"Evaluation of Drug Lag and Drug Loss in Japan: Participation in Global Phase III Oncology Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-24 16:32:20","doi":"10.21203/rs.3.rs-5456839/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2025-01-01T05:10:39+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-11-24T02:53:00+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-24T02:48:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-15T11:12:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2024-11-14T20:37:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e78d8e0a-4f24-490e-a0a9-276ffa3fc7d7","owner":[],"postedDate":"December 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-14T16:10:34+00:00","versionOfRecord":{"articleIdentity":"rs-5456839","link":"https://doi.org/10.1007/s10147-025-02756-8","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2025-04-11 16:05:39","publishedOnDateReadable":"April 11th, 2025"},"versionCreatedAt":"2024-12-24 16:32:20","video":"","vorDoi":"10.1007/s10147-025-02756-8","vorDoiUrl":"https://doi.org/10.1007/s10147-025-02756-8","workflowStages":[]},"version":"v1","identity":"rs-5456839","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5456839","identity":"rs-5456839","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}