Verifying clinical benefit of new anticancer drugs after regulatory approval based on exploratory studies

Verifying clinical benefit of new anticancer drugs after regulatory approval based on exploratory studies | 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 Verifying clinical benefit of new anticancer drugs after regulatory approval based on exploratory studies Akira Ito, Mamoru Narukawa This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5248134/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Feb, 2025 Read the published version in Therapeutic Innovation & Regulatory Science → Version 1 posted 9 You are reading this latest preprint version Abstract Background : In Japan, anticancer drugs are often approved based on the Objective Response Rate (ORR) when the conduct of a confirmatory study is difficult or expected to take a considerably long time. However, it remains unclear how frequently post-marketing confirmatory studies are conducted and for which indications they are implemented. We aimed to understand the status of post-marketing confirmatory studies for approved anticancer drugs. Methods : We investigated the status of post-marketing confirmatory studies on anticancer drug indications approved based on ORR in Japan between 2015 and 2022. Results : We found that 60% of the indications did not have planned confirmatory studies, with many receiving “orphan drug” designations. This observation is consistent with the Japanese regulations thatallow the approval of anticancer drugs based on the ORR, for which confirmatory studies are difficult to conduct or expected to take a long time. Post-marketing confirmatory studies were less commonly requested from the regulatory authority in Japan than in the US. Although the results of post-marketing confirmatory studies were often utilized in regulatory actions in Japan (including modifications to approved indications), no indications were found where these results led to withdrawal of approval or additional confirmatory study requirements, and the evaluations of the results were not disclosed when they did not lead to regulatory actions. Conclusions : To enhance transparency in the regulatory review process and facilitate smoother regulatory actions based on the results of post-marketing confirmatory studies, it may be beneficial to require the submission of the results of postmarketingconfirmatory studies if it is feasible following the approval based on ORR. Pharmaceuticals and Medical Devices Agency Cancer Conditional Approval Accelerated Approval US Food and Drug Administration Figures Figure 1 INTRODUCTION Randomized controlled trials (RCTs) that use overall survival (OS) as an endpoint are considered the gold standard in the development of anticancer drugs. Regulatory agencies often require positive OS results from well-conducted RCTs to approve new anticancer drugs [ 1 ]. The accelerated approval (AA) system, which was introduced in the United States (US) in 1992 to expedite the availability of drugs for patients with highly unmet medical needs, allows the approval of drugs based on surrogate endpoints that are reasonably likely to predict clinical benefits. After an AA, companies must complete confirmatory studies in a timely manner to confirm the clinical benefits of the drug. The AA is then converted into regular approval [ 2 ]. Recently, AA has been widely applied for the approval of anticancer drugs owing to the serious and life-threatening nature of the disease [ 3 ]. Furthermore, in Japan, marketing approvals have been granted to certain types of anticancer drugs based on surrogate endpoints, such as the objective response rate (ORR). The guideline for the clinical evaluation of anticancer drugs states that clear efficacy based on endpoints such as prolonged survival is required for common cancers and that this may not be applicable to rare cancers [ 4 ]. More than 20% of the anticancer drugs were approved in Japan based on single-arm studies mainly using ORR as an endpoint between 2006 and 2019 [ 5 ]. In addition, a conditional approval system was introduced in 2017 to ensure rapid patient access to drugs with high medical needs [ 6 ]. This system allows the approval of drugs for serious diseases with limited treatment options, for which the conduct of confirmatory studies is difficult or expected to take a considerably long time owing to the small number of patients, based on limited data on efficacy and safety in nonconfirmatory clinical studies. Conditional approval requires post-marketing surveillance to monitor drug safety and efficacy; however, confirmatory clinical studies are not always required. Although product approval based on surrogate endpoints provides an opportunity for patients to have early access to promising new treatments, it involves risks and uncertainties, as the clinical benefits of drugs via this pathway may not be fully established at the time of approval [ 7 ]. Therefore, timely and appropriate confirmatory studies are important to ensure patient benefits. In the US, concerns have been raised regarding the delay in post-marketing confirmatory studies after AA and the undue continuation of AA after failure to verify the clinical benefit by post-marketing confirmatory studies [ 8 ]. This led to the enactment of the Consolidated Appropriations Act, which includes the Food and Drug Omnibus Reform Act of 2023, to give the Food and Drug Administration (FDA) more authority to require companies to conduct confirmatory studies at the time of drug approval [ 9 ]. There may also be challenges in Japan regarding the verification of the clinical benefit of a drug after approval based on ORR. However, the status of confirmatory studies after approval based on ORR and regulatory actions based on these study results have rarely been investigated in Japan. Thus, we aimed to understand the status of post-marketing confirmatory studies for approved anticancer drugs based on ORR in Japan. In addition, to investigate the background of post-marketing confirmatory studies, the characteristics of the products and their indications approved based on ORR were compared between the drugs for which post-marketing confirmatory studies were conducted and drugs without such studies. We also compared the post-marketing requirements and regulatory actions based on the results of post-marketing confirmatory studies in Japan and the US to understand the differences in approaches by the regulatory agencies in these two countries. METHODS Target drugs and indications New drugs and biologics with indications for malignant neoplasms approved in Japan between January 1, 2015, and December 31, 2022, were identified through the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) website. Among these, drug indications approved based on ORR were selected for this study. Data collection For the target drugs, we collected the following information from the PMDA website: submission type, approval year, indication (including diagnosis based on biomarkers), special regulatory pathway status, development strategy (global/local), sponsor of the pivotal study, and post-marketing requirements. We also reviewed the approval status of the target drugs in the US and collected the same information from Drugs@FDA, if available. As for information on special regulatory pathways, we examined the status of “orphan drug” designation and conditional approval in Japan and orphan drug designation and AA in the US. Subsequently, to determine the status of post-marketing confirmatory studies for the target drugs, we searched for confirmatory studies for the same tumor type as the approved indications using ClinicalTrials.gov. The search option was employed for conditions/diseases (approved tumor type for each target indication) and other terms (drug names). The search results were refined by selecting “Phase 3” and “Phase 4” for the study phase. If no relevant studies were found on ClinicalTrials.gov, we searched the Japan Registry of Clinical Trials, considering the possibility of local studies in Japan. The search was conducted in December 2023. Data analysis To investigate the background of the post-marketing confirmatory studies conducted for target drug indications in Japan, we compared the characteristics of indications between drugs with and without such studies. Drug indications approved only in Japan were determined as local developments, and those approved based on the same ORR data in the US were determined as global developments. We also calculated the time from approval to the date of completion of the post-marketing confirmatory study for the indications for which the post-marketing confirmatory studies were completed to evaluate the time to verify clinical benefit in Japan. Subsequently, we compared the status of conditional approval in Japan and AA in the US, the post-marketing requirements, and the regulatory actions based on the results of post-marketing confirmatory studies for indications commonly approved in Japan and the US to understand the approaches of the regulatory agencies in the two countries. Fisher's exact test was used to compare the characteristics of drug indications, post-marketing confirmatory study status, and the frequency of regulatory actions. All analyses were conducted using StatsDirect version 3.3.5 (StatsDirect Ltd., Altrincham, UK). RESULTS Drugs investigated Between 2015 and 2022, 205 anticancer drug indications were approved in Japan. Of these, 45 approved indications based on ORR were selected for this analysis (Fig. 1 ). Of the 45 indications, post-marketing confirmatory studies were completed or ongoing for 18; no post-marketing confirmatory studies were planned for the remaining 27 indications. Characteristics of anticancer drug indications approved based on ORR The characteristics of the targeted anticancer drugs are summarized in Table 1 . Orphan drug designation and local development were more common in the indications for which post-marketing confirmatory studies were not planned. Table 1 Comparison of the anticancer drug indications with or without a confirmatory study plan Confirmatory studies ongoing/completed Confirmatory studies not planned P-value Number of indications 18 27 Submission type -n NDA/BLA 12 14 0.3472 Supplemental NDA/BLA 6 13 Approved year -n 2015–18 9 8 0.3005 2019–22 11 19 Indication -n Solid tumor 12 15 0.4790 Hematological malignancy 6 12 Biomarker -n Yes 9 12 0.7264 No 9 15 Orphan drug designation -n Yes 9 23 0.0155 No 9 4 Global/Local development -n Global 16 11 0.0013 Local 2 16 Sponsor of the pivotal study -n Company 18 22 0.0661 Investigator 0 5 Differences were evaluated using Fisher exact test. NDA/BLA; new drug application/biologics license application The median time from approval to completion of the post-marketing confirmatory study was 2.4 years for the eight indications for which post-marketing confirmatory studies were completed. Status of conditional approval/AA, post-marketing requirements, and subsequent regulatory actions in Japan and US Of the 45 indications approved based on ORR in Japan, 27 were also approved in the US based on ORR. Among the common 27 indications, post-marketing confirmatory studies were completed for 8, ongoing for 8, and not planned for 11. Three indications were approved under the conditional approval system in Japan, and 22 were approved under the AA system in the US (P < 0.0001; Table 2 ). The remaining five indications received regular approval in the US based on ORR without post-marketing confirmatory study requirements. Table 2 Status of conditional approval in Japan and AA in the US, post-marketing requirements and regulatory actions in Japan and the US. based on the results of post-marketing confirmatory studies. Japan US P-value Number of indications 27 Submission type -n NDA/BLA 18 17 0.7847 Supplemental NDA/BLA 9 10 Approval year -n -2018 13 14 0.7933 2019-22 14 13 Orphan drug designation -n Yes 18 23 0.1279 No 9 4 Conditional approval (Japan) / Accelerated approval (U.S.) -n Yes 3 22 < 0.0001 No 24 5 Postmarketing requirement for confirmatory study -n Yes 1 14 < 0.0001 No 26 13 Regulatory action based on the postmarketing confirmatory study -n Modification to approved indication / Label change 6 6 0.6555 No regulatory action 21 19 Withdrawal / Additional confirmatory study requirement 0 2 Differences were evaluated using Fisher exact test. AA, accelerated approval; US, The United States ; NDA/BLA, new drug application/biologics license application While confirmatory studies were requested as an approval condition for one indication in Japan, they were requested as AA post-marketing requirements for 14 indications in the US (P < 0.0001; Table 2 ). Of the 22 AA indications in the US, 8 were approved without post-marketing requirements for confirmatory studies. In these cases, follow-up of studies on which the AA was based were requested as post-marketing requirements to describe the clinical benefit through a more precise estimation of the ORR and mature response duration. Regulatory actions based on results of post-marketing confirmatory studies in Japan and US In Japan, of the eight indications for which post-marketing confirmatory studies were completed, supplemental new drug aplications for modification of the approved indication were approved based on the results of the post-marketing confirmatory studies for five, and the label was changed without indication change for one. For the remaining two indications, regulatory actions were not taken in Japan, while the AA was withdrawn or an additional confirmatory study was requested based on the results of post-marketing confirmatory studies in the US (Table 3 ). Table 3 Regulatory actions in Japan and the US. based on the results of post-marketing confirmatory study. Drug Original indication in Japan Regulatory action (year) Japan US Osimertinib mesilate Inoperable or recurrent EGFR T790M mutation positive NSCLC with resistance to EGFR tyrosine kinase inhibitors. Modification to approved indication (2018) RA Conversion (2017) Ceritinib Unresectable advanced/relapsed ALK-positive NSCLC with resistance or intolerance to crizotinib. Modification to approved indication (2017) RA Conversion (2017) Romidepsin R/R peripheral T-cell lymphoma. No actions Withdrawal (2021) Pembrolizumab R/R classical Hodgkin's lymphoma. Label change (2023) RA Conversion (2020) Lorlatinib Unresectable or recurrent ALK-positive NSCLC with resistance or intolerance to ALK tyrosine kinase inhibitors. Modification to approved indication (2021) RA Conversion (2021) Trastuzumab deruxtecan Unresectable or recurrent HER2-positive breast cancer in patients who have previously been treated with chemotherapy (for use only if refractory or intolerant to standard therapies). Modification to approved indication (2022) RA Conversion (2022) Polatuzumab vedotin R/R diffuse large B-cell lymphoma. Modification to approved indication (2022) RA Conversion (2023) Sotorasib Unresectable advanced or recurrent KRAS G12C NSCLC that has progressed after cancer chemotherapy. No actions Additional confirmatory study results were requested at ODAC (2023) US, The United States; EGFR, epidermal growth factor receptor; NSLCL, non-small-cell lung cancer; ALK, anaplastic lymphoma kinase; R/R, Relapsed or refractory; RA, regular approval; ODAC, oncology drugs advisory committee DISCUSSION We found that post-marketing confirmatory studies were not conducted for more than half of the anticancer drug indications approved based on ORR in Japan. Such studies were conducted less frequently for indications with orphan drug designations or those developed locally in Japan, and many locally developed indications obtained orphan drug designations. Thus, the main reason why post-marketing confirmatory studies were not conducted is assumed to be the small number of patients. This finding aligns with the Japanese regulations that allow for the approval of anticancer drugs based on ORR, for which confirmatory studies are difficult to conduct or expected to take a considerably long time [ 4 ]. For locally developed indications targeting rare patient populations, participation in a global confirmatory study could be a potential solution to verify the clinical benefits of the drug. However, if conducting a confirmatory study is not feasible, even as a global study, it may be reasonable not to mandate it considering the balance between the available evidence and medical needs. In our study, 40% (18/45) of the indications had completed or were ongoing post-marketing confirmatory studies, indicating that approvals based on ORR were granted even when conducting a confirmatory study was feasible. Among these, only one indication had a post-marketing requirement for a confirmatory study in Japan. It is assumed that companies often plan a post-marketing confirmatory study, even when it is not a post-marketing requirement by the Ministry of Health, Labour and Welfare (MHLW)/PMDA. The median time from approval based on ORR to the completion of the post-marketing confirmatory study was 2.4 years in Japan, which is comparable to the duration (3.1 years) reported in a similar study in the US [ 8 ]. Among the 27 indications commonly approved in Japan and the US, 3 were approved under the conditional approval system in Japan, whereas 22 were approved under the AA system in the US. This difference indicates the narrower scope of the conditional approval system in Japan, which is generally limited to indications for which conducting a confirmatory study is difficult or expected to take a considerably long time. In Japan, approvals based on ORR are granted either as regular or conditional approvals; however, the distinction between these two types of approvals remains unclear, potentially hindering the use of a conditional approval system [ 10 ]. Only 1 indication out of 27 was required to conduct a confirmatory study as a post-marketing requirement in Japan. In contrast, in the US, confirmatory studies were requested for more than half of the indications. This suggests different views on the necessity of post-marketing confirmatory studies between the MHLW/PMDA and FDA. In Japan, post-marketing confirmatory studies were conducted for an additional 15 indications, even when not explicitly required by the MHLW/PMDA, whereas in the US, such studies were rarely conducted in cases where they were not requested by the FDA. In Japan, post-marketing confirmatory studies are typically not required as an approval condition regardless of the feasibility, although it is recommended in the guidelines for clinical evaluation of anticancer drugs that high-quality, adequate, and appropriate data be collected after approval. In contrast, the FDA seems to require a confirmatory study as long as it is feasible and grants approval without a post-marketing confirmatory study requirement only when conducting such studies is particularly difficult. The results of post-marketing confirmatory studies led to regulatory actions, such as supplemental applications for modification to approved indications and label changes, in both Japan and the US. However, in Japan, no regulatory actions were taken for two indications for which post-marketing confirmatory studies had failed, whereas in the US, one indication was withdrawn and an additional confirmatory study was requested for the other after discussion at the Oncologic Drugs Advisory Committee. Regulatory actions based on common data may differ owing to factors such as differences in medical circumstances between Japan and the US. It is likely that the PMDA and companies discussed the results of post-marketing clinical studies for these two indications, but the evaluation results were not publicly disclosed. When conducting a post-marketing confirmatory study is feasible after approval based on ORR, requiring the submission of the study results would enhance the transparency of the regulatory review process and facilitate smoother regulatory action based on the results of the post-marketing confirmatory study. Under the conditional approval system, regulatory actions are taken as needed based on post-marketing data agreed upon at the time of conditional approval, and these actions are generally easier to implement compared to regular approval. The conditional approval system is expected to further promote streamlined regulatory actions based on the results of post-marketing studies. As we have previously reported, the PMDA is likely to require more robust clinical evidence for anticancer drugs approved under the AA system in the US, indicating the potential for more indications to be approved in Japan based on surrogate endpoints [ 11 ]. Facilitating regulatory actions based on post-marketing studies, such as modification or withdrawal of approvals, could potentially lower the regulatory hurdles to granting approval based on ORR. Therefore, the active use of conditional approval can expedite the development of drugs targeting serious diseases in Japan. This study had some limitations. First, regarding the time from approval to the completion of the post-marketing confirmatory study, our study had a bias toward observing indications, with their clinical benefit being verified earlier because only those for which post-marketing confirmatory studies had been completed were included in the analysis. Second, for the analysis of regulatory actions based on post-marketing confirmatory studies, some actions may be taken in the future. CONCLUSION Among the 45 anticancer drug indications approved based on ORR in Japan, 27 (60%) did not have a planned post-marketing confirmatory study, many of which received orphan drug designation. This observation is consistent with the Japanese regulations allowing the approval of anticancer drugs based on ORR, for which confirmatory studies are difficult to conduct or expected to take a considerably long time. Additionally, post-marketing confirmatory studies were requested less frequently in Japan than in the US. Although the post-marketing confirmatory study results were utilized in regulatory actions to a certain extent, there were no indications for which unfavorable results led to the withdrawal of approval or additional study requirements in Japan, and the evaluation results were not disclosed. Increased transparency of the regulatory review process and more streamlined regulatory actions based on post-marketing confirmatory study results are needed. Declarations FUNDING The authors received no financial support for the research, authorship, or publication of this manuscript. CONFLICT OF INTEREST Akira Ito is an employee of Daiichi Sankyo, Inc., Basking Ridge, NJ, United States AUTHOR CONTRIBUTIONS I.A. wrote the manuscript; I.A. and N.M. designed the study; I.A. conducted the experiments; I.A. and N.M. analyzed the data. References U.S. Food and Drug Administration. Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer – Drugs and Biologics https://www.fda.gov/media/71195/download Published December 2018. Accessed 14 June2024. U.S. Food and Drug Administration. Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics https://www.fda.gov/media/86377/download Published May 2014. Accessed 14 June 2024. Beaver JA, Howie LJ, Pelosof, et al. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol. 2018;4(6):849–56. Ministry of Health, Labour and Welfare. Guidelines for clinical evaluation of anti-cancer drugs https://www.mhlw.go.jp/web/t_doc?dataId=00tc5801&dataType=1&pageNo=1 Published Mar 31, 2021. Accessed 21 June 2024. Ken Hatogai Y, Kato C, Hirase. Efficacy evaluation of anticancer agents in single-arm clinical trials: analysis of review reports from Pharmaceuticals and Medical Devices Agency. Acta Oncol. 2021;60(2):143–8. Ministry of Health, Labour and Welfare. Implementation of a Conditional Early Approval System for Pharmaceutical Products (the Pharmaceuticals and Medical Devices Agency) https://www.pmda.go.jp/english/review-services/regulatory-info/0003.html Published October 20, 2017. Accessed Mar 13, 2024. U.S. Department of Health and Human Services. Delays in Confirmatory Trials for Drug Applications Granted FDA's Accelerated Approval Raise Concerns https://oig.hhs.gov/oei/reports/OEI-01-21-00401.asp Published 29 September 2022. Accessed 14 June 2024. Beaver JA, Pazdur R. Dangling Accelerated Approvals in Oncology. N Engl J Med. 2021;384(18):e68. Fashoyin-Aje LA, Mehta GU, Beaver JA, et al. The On- and Off-Ramps of Oncology Accelerated Approval. N Engl J Med. 2022;387(16):1439–42. Tanaka M, Miyazawa H, Terashima R, et al. Conditional early approval for new drug applications in Japan: Current and emerging issues. Clin Transl Sci. 2023;16(8):1289–93. Ito A, Narukawa M. Impact of the US Accelerated Approval for New Anticancer Drugs on Time to Verification of Benefit and Regulatory Approval in the EU and Japan. Ther Innov Regul Sci. 2024;58(1):136–42. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 10 Feb, 2025 Read the published version in Therapeutic Innovation & Regulatory Science → Version 1 posted Editorial decision: Revision requested 06 Dec, 2024 Reviews received at journal 26 Nov, 2024 Reviews received at journal 25 Nov, 2024 Reviewers agreed at journal 12 Nov, 2024 Reviewers agreed at journal 11 Nov, 2024 Reviewers invited by journal 28 Oct, 2024 Editor assigned by journal 14 Oct, 2024 Submission checks completed at journal 12 Oct, 2024 First submitted to journal 11 Oct, 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. 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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-5248134","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":387256864,"identity":"44e99acc-2150-4ffc-8d26-4ecfe0ca0f30","order_by":0,"name":"Akira Ito","email":"data:image/png;base64,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","orcid":"","institution":"Kitasato University","correspondingAuthor":true,"prefix":"","firstName":"Akira","middleName":"","lastName":"Ito","suffix":""},{"id":387256866,"identity":"7694d17e-2612-41af-9114-f4a39ddc40f8","order_by":1,"name":"Mamoru Narukawa","email":"","orcid":"","institution":"Kitasato University","correspondingAuthor":false,"prefix":"","firstName":"Mamoru","middleName":"","lastName":"Narukawa","suffix":""}],"badges":[],"createdAt":"2024-10-11 19:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5248134/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5248134/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s43441-025-00757-3","type":"published","date":"2025-02-10T15:57:19+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":72165506,"identity":"2dbe1dce-0d2d-4a2b-8d86-2cea2a96853e","added_by":"auto","created_at":"2024-12-23 10:18:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":18447,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of selecting anticancer drug indications in this study\u003c/p\u003e\n\u003cp\u003eORR, objective response rate\u003c/p\u003e","description":"","filename":"Fig120241004.png","url":"https://assets-eu.researchsquare.com/files/rs-5248134/v1/3647157319df3962f3e5cda8.png"},{"id":76487476,"identity":"0f51dd28-e232-458b-834c-d0b7aad82096","added_by":"auto","created_at":"2025-02-17 16:08:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":680196,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5248134/v1/ae563e8a-3dd9-49c4-939b-f663635f1dc5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Verifying clinical benefit of new anticancer drugs after regulatory approval based on exploratory studies","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eRandomized controlled trials (RCTs) that use overall survival (OS) as an endpoint are considered the gold standard in the development of anticancer drugs. Regulatory agencies often require positive OS results from well-conducted RCTs to approve new anticancer drugs [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe accelerated approval (AA) system, which was introduced in the United States (US) in 1992 to expedite the availability of drugs for patients with highly unmet medical needs, allows the approval of drugs based on surrogate endpoints that are reasonably likely to predict clinical benefits. After an AA, companies must complete confirmatory studies in a timely manner to confirm the clinical benefits of the drug. The AA is then converted into regular approval [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Recently, AA has been widely applied for the approval of anticancer drugs owing to the serious and life-threatening nature of the disease [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, in Japan, marketing approvals have been granted to certain types of anticancer drugs based on surrogate endpoints, such as the objective response rate (ORR). The guideline for the clinical evaluation of anticancer drugs states that clear efficacy based on endpoints such as prolonged survival is required for common cancers and that this may not be applicable to rare cancers [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. More than 20% of the anticancer drugs were approved in Japan based on single-arm studies mainly using ORR as an endpoint between 2006 and 2019 [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In addition, a conditional approval system was introduced in 2017 to ensure rapid patient access to drugs with high medical needs [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This system allows the approval of drugs for serious diseases with limited treatment options, for which the conduct of confirmatory studies is difficult or expected to take a considerably long time owing to the small number of patients, based on limited data on efficacy and safety in nonconfirmatory clinical studies. Conditional approval requires post-marketing surveillance to monitor drug safety and efficacy; however, confirmatory clinical studies are not always required.\u003c/p\u003e \u003cp\u003eAlthough product approval based on surrogate endpoints provides an opportunity for patients to have early access to promising new treatments, it involves risks and uncertainties, as the clinical benefits of drugs via this pathway may not be fully established at the time of approval [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Therefore, timely and appropriate confirmatory studies are important to ensure patient benefits. In the US, concerns have been raised regarding the delay in post-marketing confirmatory studies after AA and the undue continuation of AA after failure to verify the clinical benefit by post-marketing confirmatory studies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This led to the enactment of the Consolidated Appropriations Act, which includes the Food and Drug Omnibus Reform Act of 2023, to give the Food and Drug Administration (FDA) more authority to require companies to conduct confirmatory studies at the time of drug approval [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. There may also be challenges in Japan regarding the verification of the clinical benefit of a drug after approval based on ORR. However, the status of confirmatory studies after approval based on ORR and regulatory actions based on these study results have rarely been investigated in Japan.\u003c/p\u003e \u003cp\u003eThus, we aimed to understand the status of post-marketing confirmatory studies for approved anticancer drugs based on ORR in Japan. In addition, to investigate the background of post-marketing confirmatory studies, the characteristics of the products and their indications approved based on ORR were compared between the drugs for which post-marketing confirmatory studies were conducted and drugs without such studies. We also compared the post-marketing requirements and regulatory actions based on the results of post-marketing confirmatory studies in Japan and the US to understand the differences in approaches by the regulatory agencies in these two countries.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTarget drugs and indications\u003c/h2\u003e \u003cp\u003eNew drugs and biologics with indications for malignant neoplasms approved in Japan between January 1, 2015, and December 31, 2022, were identified through the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) website. Among these, drug indications approved based on ORR were selected for this study.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eFor the target drugs, we collected the following information from the PMDA website: submission type, approval year, indication (including diagnosis based on biomarkers), special regulatory pathway status, development strategy (global/local), sponsor of the pivotal study, and post-marketing requirements. We also reviewed the approval status of the target drugs in the US and collected the same information from Drugs@FDA, if available. As for information on special regulatory pathways, we examined the status of \u0026ldquo;orphan drug\u0026rdquo; designation and conditional approval in Japan and orphan drug designation and AA in the US.\u003c/p\u003e \u003cp\u003eSubsequently, to determine the status of post-marketing confirmatory studies for the target drugs, we searched for confirmatory studies for the same tumor type as the approved indications using ClinicalTrials.gov. The search option was employed for conditions/diseases (approved tumor type for each target indication) and other terms (drug names). The search results were refined by selecting \u0026ldquo;Phase 3\u0026rdquo; and \u0026ldquo;Phase 4\u0026rdquo; for the study phase. If no relevant studies were found on ClinicalTrials.gov, we searched the Japan Registry of Clinical Trials, considering the possibility of local studies in Japan. The search was conducted in December 2023.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eTo investigate the background of the post-marketing confirmatory studies conducted for target drug indications in Japan, we compared the characteristics of indications between drugs with and without such studies. Drug indications approved only in Japan were determined as local developments, and those approved based on the same ORR data in the US were determined as global developments. We also calculated the time from approval to the date of completion of the post-marketing confirmatory study for the indications for which the post-marketing confirmatory studies were completed to evaluate the time to verify clinical benefit in Japan.\u003c/p\u003e \u003cp\u003eSubsequently, we compared the status of conditional approval in Japan and AA in the US, the post-marketing requirements, and the regulatory actions based on the results of post-marketing confirmatory studies for indications commonly approved in Japan and the US to understand the approaches of the regulatory agencies in the two countries.\u003c/p\u003e \u003cp\u003eFisher's exact test was used to compare the characteristics of drug indications, post-marketing confirmatory study status, and the frequency of regulatory actions. All analyses were conducted using StatsDirect version 3.3.5 (StatsDirect Ltd., Altrincham, UK).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eDrugs investigated\u003c/h2\u003e \u003cp\u003eBetween 2015 and 2022, 205 anticancer drug indications were approved in Japan. Of these, 45 approved indications based on ORR were selected for this analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Of the 45 indications, post-marketing confirmatory studies were completed or ongoing for 18; no post-marketing confirmatory studies were planned for the remaining 27 indications.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of anticancer drug indications approved based on ORR\u003c/h2\u003e \u003cp\u003eThe characteristics of the targeted anticancer drugs are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Orphan drug designation and local development were more common in the indications for which post-marketing confirmatory studies were not planned.\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\u003eComparison of the anticancer drug indications with or without a confirmatory study plan\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\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\u003eConfirmatory studies ongoing/completed\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eConfirmatory studies not planned\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of indications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18\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\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubmission type -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNDA/BLA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.3472\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSupplemental NDA/BLA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApproved year -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2015\u0026ndash;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.3005\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019\u0026ndash;22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndication -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSolid tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.4790\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematological malignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\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\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiomarker -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.7264\u003c/em\u003e\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrphan drug designation -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.0155\u003c/em\u003e\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\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\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlobal/Local development -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlobal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.0013\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSponsor of the pivotal study -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.0661\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvestigator\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eDifferences were evaluated using Fisher exact test.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNDA/BLA; new drug application/biologics license application\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe median time from approval to completion of the post-marketing confirmatory study was 2.4 years for the eight indications for which post-marketing confirmatory studies were completed.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatus of conditional approval/AA, post-marketing requirements, and subsequent regulatory actions in Japan and US\u003c/h3\u003e\n\u003cp\u003eOf the 45 indications approved based on ORR in Japan, 27 were also approved in the US based on ORR. Among the common 27 indications, post-marketing confirmatory studies were completed for 8, ongoing for 8, and not planned for 11. Three indications were approved under the conditional approval system in Japan, and 22 were approved under the AA system in the US (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The remaining five indications received regular approval in the US based on ORR without post-marketing confirmatory study requirements.\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\u003eStatus of conditional approval in Japan and AA in the US, post-marketing requirements and regulatory actions in Japan and the US. based on the results of post-marketing confirmatory studies.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of indications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubmission type -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNDA/BLA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.7847\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSupplemental NDA/BLA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApproval year -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e-2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7933\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019-22\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\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrphan drug designation -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.1279\u003c/em\u003e\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConditional approval (Japan) / Accelerated approval (U.S.) -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\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\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e\u0026lt;\u0026thinsp;0.0001\u003c/em\u003e\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostmarketing requirement for confirmatory study -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e\u0026lt;\u0026thinsp;0.0001\u003c/em\u003e\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegulatory action based on the postmarketing confirmatory study -n\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModification to approved indication / Label change\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e0.6555\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo regulatory action\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithdrawal / Additional confirmatory study requirement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eDifferences were evaluated using Fisher exact test.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAA, accelerated approval; US, The United States ; NDA/BLA, new drug application/biologics license application\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWhile confirmatory studies were requested as an approval condition for one indication in Japan, they were requested as AA post-marketing requirements for 14 indications in the US (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Of the 22 AA indications in the US, 8 were approved without post-marketing requirements for confirmatory studies. In these cases, follow-up of studies on which the AA was based were requested as post-marketing requirements to describe the clinical benefit through a more precise estimation of the ORR and mature response duration.\u003c/p\u003e\n\u003ch3\u003eRegulatory actions based on results of post-marketing confirmatory studies in Japan and US\u003c/h3\u003e\n\u003cp\u003eIn Japan, of the eight indications for which post-marketing confirmatory studies were completed, supplemental new drug aplications for modification of the approved indication were approved based on the results of the post-marketing confirmatory studies for five, and the label was changed without indication change for one. For the remaining two indications, regulatory actions were not taken in Japan, while the AA was withdrawn or an additional confirmatory study was requested based on the results of post-marketing confirmatory studies in the US (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\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\u003eRegulatory actions in Japan and the US. based on the results of post-marketing confirmatory study.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOriginal indication in Japan\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eRegulatory action (year)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOsimertinib mesilate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInoperable or recurrent EGFR T790M mutation positive NSCLC with resistance to EGFR tyrosine kinase inhibitors.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModification to approved indication (2018)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRA Conversion\u003c/p\u003e \u003cp\u003e(2017)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCeritinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnresectable advanced/relapsed ALK-positive NSCLC with resistance or intolerance to crizotinib.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModification to approved indication (2017)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRA Conversion (2017)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRomidepsin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR/R peripheral T-cell lymphoma.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo actions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWithdrawal\u003c/p\u003e \u003cp\u003e(2021)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePembrolizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR/R classical Hodgkin's lymphoma.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLabel change (2023)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRA Conversion (2020)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLorlatinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnresectable or recurrent ALK-positive NSCLC with resistance or intolerance to ALK tyrosine kinase inhibitors.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModification to approved indication (2021)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRA Conversion (2021)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrastuzumab deruxtecan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnresectable or recurrent HER2-positive breast cancer in patients who have previously been treated with chemotherapy (for use only if refractory or intolerant to standard therapies).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModification to approved indication (2022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRA Conversion (2022)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolatuzumab vedotin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR/R diffuse large B-cell lymphoma.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModification to approved indication (2022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRA Conversion (2023)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSotorasib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnresectable advanced or recurrent KRAS G12C NSCLC that has progressed after cancer chemotherapy.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo actions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdditional confirmatory study results were requested at ODAC (2023)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eUS, The United States; EGFR, epidermal growth factor receptor; NSLCL, non-small-cell lung cancer; ALK, anaplastic lymphoma kinase; R/R, Relapsed or refractory;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eRA, regular approval; ODAC, oncology drugs advisory committee\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eWe found that post-marketing confirmatory studies were not conducted for more than half of the anticancer drug indications approved based on ORR in Japan. Such studies were conducted less frequently for indications with orphan drug designations or those developed locally in Japan, and many locally developed indications obtained orphan drug designations. Thus, the main reason why post-marketing confirmatory studies were not conducted is assumed to be the small number of patients. This finding aligns with the Japanese regulations that allow for the approval of anticancer drugs based on ORR, for which confirmatory studies are difficult to conduct or expected to take a considerably long time [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. For locally developed indications targeting rare patient populations, participation in a global confirmatory study could be a potential solution to verify the clinical benefits of the drug. However, if conducting a confirmatory study is not feasible, even as a global study, it may be reasonable not to mandate it considering the balance between the available evidence and medical needs.\u003c/p\u003e \u003cp\u003eIn our study, 40% (18/45) of the indications had completed or were ongoing post-marketing confirmatory studies, indicating that approvals based on ORR were granted even when conducting a confirmatory study was feasible. Among these, only one indication had a post-marketing requirement for a confirmatory study in Japan. It is assumed that companies often plan a post-marketing confirmatory study, even when it is not a post-marketing requirement by the Ministry of Health, Labour and Welfare (MHLW)/PMDA. The median time from approval based on ORR to the completion of the post-marketing confirmatory study was 2.4 years in Japan, which is comparable to the duration (3.1 years) reported in a similar study in the US [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong the 27 indications commonly approved in Japan and the US, 3 were approved under the conditional approval system in Japan, whereas 22 were approved under the AA system in the US. This difference indicates the narrower scope of the conditional approval system in Japan, which is generally limited to indications for which conducting a confirmatory study is difficult or expected to take a considerably long time. In Japan, approvals based on ORR are granted either as regular or conditional approvals; however, the distinction between these two types of approvals remains unclear, potentially hindering the use of a conditional approval system [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOnly 1 indication out of 27 was required to conduct a confirmatory study as a post-marketing requirement in Japan. In contrast, in the US, confirmatory studies were requested for more than half of the indications. This suggests different views on the necessity of post-marketing confirmatory studies between the MHLW/PMDA and FDA. In Japan, post-marketing confirmatory studies were conducted for an additional 15 indications, even when not explicitly required by the MHLW/PMDA, whereas in the US, such studies were rarely conducted in cases where they were not requested by the FDA. In Japan, post-marketing confirmatory studies are typically not required as an approval condition regardless of the feasibility, although it is recommended in the guidelines for clinical evaluation of anticancer drugs that high-quality, adequate, and appropriate data be collected after approval. In contrast, the FDA seems to require a confirmatory study as long as it is feasible and grants approval without a post-marketing confirmatory study requirement only when conducting such studies is particularly difficult.\u003c/p\u003e \u003cp\u003eThe results of post-marketing confirmatory studies led to regulatory actions, such as supplemental applications for modification to approved indications and label changes, in both Japan and the US. However, in Japan, no regulatory actions were taken for two indications for which post-marketing confirmatory studies had failed, whereas in the US, one indication was withdrawn and an additional confirmatory study was requested for the other after discussion at the Oncologic Drugs Advisory Committee. Regulatory actions based on common data may differ owing to factors such as differences in medical circumstances between Japan and the US. It is likely that the PMDA and companies discussed the results of post-marketing clinical studies for these two indications, but the evaluation results were not publicly disclosed.\u003c/p\u003e \u003cp\u003eWhen conducting a post-marketing confirmatory study is feasible after approval based on ORR, requiring the submission of the study results would enhance the transparency of the regulatory review process and facilitate smoother regulatory action based on the results of the post-marketing confirmatory study. Under the conditional approval system, regulatory actions are taken as needed based on post-marketing data agreed upon at the time of conditional approval, and these actions are generally easier to implement compared to regular approval. The conditional approval system is expected to further promote streamlined regulatory actions based on the results of post-marketing studies. As we have previously reported, the PMDA is likely to require more robust clinical evidence for anticancer drugs approved under the AA system in the US, indicating the potential for more indications to be approved in Japan based on surrogate endpoints [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Facilitating regulatory actions based on post-marketing studies, such as modification or withdrawal of approvals, could potentially lower the regulatory hurdles to granting approval based on ORR. Therefore, the active use of conditional approval can expedite the development of drugs targeting serious diseases in Japan.\u003c/p\u003e \u003cp\u003eThis study had some limitations. First, regarding the time from approval to the completion of the post-marketing confirmatory study, our study had a bias toward observing indications, with their clinical benefit being verified earlier because only those for which post-marketing confirmatory studies had been completed were included in the analysis. Second, for the analysis of regulatory actions based on post-marketing confirmatory studies, some actions may be taken in the future.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eAmong the 45 anticancer drug indications approved based on ORR in Japan, 27 (60%) did not have a planned post-marketing confirmatory study, many of which received orphan drug designation. This observation is consistent with the Japanese regulations allowing the approval of anticancer drugs based on ORR, for which confirmatory studies are difficult to conduct or expected to take a considerably long time. Additionally, post-marketing confirmatory studies were requested less frequently in Japan than in the US. Although the post-marketing confirmatory study results were utilized in regulatory actions to a certain extent, there were no indications for which unfavorable results led to the withdrawal of approval or additional study requirements in Japan, and the evaluation results were not disclosed. Increased transparency of the regulatory review process and more streamlined regulatory actions based on post-marketing confirmatory study results are needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors received no financial support for the research, authorship, or publication of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAkira Ito is an employee of Daiichi Sankyo, Inc., Basking Ridge, NJ, United States\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI.A. wrote the manuscript; I.A. and N.M. designed the study; I.A. conducted the experiments; I.A. and N.M. analyzed the data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eU.S. Food and Drug Administration. Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer \u0026ndash; Drugs and Biologics \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.fda.gov/media/71195/download\u003c/span\u003e\u003cspan address=\"https://www.fda.gov/media/71195/download\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Published December 2018. Accessed 14 June2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eU.S. Food and Drug Administration. Guidance for Industry Expedited Programs for Serious Conditions \u0026ndash; Drugs and Biologics \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.fda.gov/media/86377/download\u003c/span\u003e\u003cspan address=\"https://www.fda.gov/media/86377/download\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Published May 2014. Accessed 14 June 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeaver JA, Howie LJ, Pelosof, et al. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol. 2018;4(6):849\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMinistry of Health, Labour and Welfare. Guidelines for clinical evaluation of anti-cancer drugs \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.mhlw.go.jp/web/t_doc?dataId=00tc5801\u0026amp;dataType=1\u0026amp;pageNo=1\u003c/span\u003e\u003cspan address=\"https://www.mhlw.go.jp/web/t_doc?dataId=00tc5801\u0026amp;dataType=1\u0026amp;pageNo=1\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Published Mar 31, 2021. Accessed 21 June 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKen Hatogai Y, Kato C, Hirase. Efficacy evaluation of anticancer agents in single-arm clinical trials: analysis of review reports from Pharmaceuticals and Medical Devices Agency. Acta Oncol. 2021;60(2):143\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMinistry of Health, Labour and Welfare. Implementation of a Conditional Early Approval System for Pharmaceutical Products (the Pharmaceuticals and Medical Devices Agency) \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.pmda.go.jp/english/review-services/regulatory-info/0003.html\u003c/span\u003e\u003cspan address=\"https://www.pmda.go.jp/english/review-services/regulatory-info/0003.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Published October 20, 2017. Accessed Mar 13, 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eU.S. Department of Health and Human Services. Delays in Confirmatory Trials for Drug Applications Granted FDA's Accelerated Approval Raise Concerns \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://oig.hhs.gov/oei/reports/OEI-01-21-00401.asp\u003c/span\u003e\u003cspan address=\"https://oig.hhs.gov/oei/reports/OEI-01-21-00401.asp\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Published 29 September 2022. Accessed 14 June 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeaver JA, Pazdur R. Dangling Accelerated Approvals in Oncology. N Engl J Med. 2021;384(18):e68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFashoyin-Aje LA, Mehta GU, Beaver JA, et al. The On- and Off-Ramps of Oncology Accelerated Approval. N Engl J Med. 2022;387(16):1439\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTanaka M, Miyazawa H, Terashima R, et al. Conditional early approval for new drug applications in Japan: Current and emerging issues. Clin Transl Sci. 2023;16(8):1289\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIto A, Narukawa M. Impact of the US Accelerated Approval for New Anticancer Drugs on Time to Verification of Benefit and Regulatory Approval in the EU and Japan. Ther Innov Regul Sci. 2024;58(1):136\u0026ndash;42.\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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"therapeutic-innovation-and-regulatory-science","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tirs","sideBox":"Learn more about [Therapeutic Innovation \u0026 Regulatory Science](https://link.springer.com/journal/43441)","snPcode":"43441","submissionUrl":"https://www.editorialmanager.com/tirs/default.aspx","title":"Therapeutic Innovation \u0026 Regulatory Science","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Pharmaceuticals and Medical Devices Agency, Cancer, Conditional Approval, Accelerated Approval, US Food and Drug Administration","lastPublishedDoi":"10.21203/rs.3.rs-5248134/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5248134/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: In Japan, anticancer drugs are often approved based on the Objective Response Rate (ORR) when the conduct of a confirmatory study is difficult or expected to take a considerably long time. However, it remains unclear how frequently post-marketing confirmatory studies are conducted and for which indications they are implemented. We aimed to understand the status of post-marketing confirmatory studies for approved anticancer drugs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We investigated the status of post-marketing confirmatory studies on anticancer drug indications approved based on ORR in Japan between 2015 and 2022.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: We found that 60% of the indications did not have planned confirmatory studies, with many receiving “orphan drug” designations. This observation is consistent with the Japanese regulations thatallow the approval of anticancer drugs based on the ORR, for which confirmatory studies are difficult to conduct or expected to take a long time. Post-marketing confirmatory studies were less commonly requested from the regulatory authority in Japan than in the US. Although the results of post-marketing confirmatory studies were often utilized in regulatory actions in Japan (including modifications to approved indications), no indications were found where these results led to withdrawal of approval or additional confirmatory study requirements, and the evaluations of the results were not disclosed when they did not lead to regulatory actions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: To enhance transparency in the regulatory review process and facilitate smoother regulatory actions based on the results of post-marketing confirmatory studies, it may be beneficial to require the submission of the results of postmarketingconfirmatory studies if it is feasible following the approval based on ORR.\u003c/p\u003e","manuscriptTitle":"Verifying clinical benefit of new anticancer drugs after regulatory approval based on exploratory studies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-23 10:18:00","doi":"10.21203/rs.3.rs-5248134/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-06T19:25:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-27T02:58:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-25T19:37:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196561202011943413197621566030055543444","date":"2024-11-13T01:15:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"209788115489530175996443291198135527365","date":"2024-11-11T17:57:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-28T16:26:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-14T13:44:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-12T04:20:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Therapeutic Innovation \u0026 Regulatory Science","date":"2024-10-11T19:15:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"therapeutic-innovation-and-regulatory-science","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tirs","sideBox":"Learn more about [Therapeutic Innovation \u0026 Regulatory Science](https://link.springer.com/journal/43441)","snPcode":"43441","submissionUrl":"https://www.editorialmanager.com/tirs/default.aspx","title":"Therapeutic Innovation \u0026 Regulatory Science","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3aa17c94-ba54-44d8-94c1-f6d4ae172c97","owner":[],"postedDate":"December 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-17T16:00:38+00:00","versionOfRecord":{"articleIdentity":"rs-5248134","link":"https://doi.org/10.1007/s43441-025-00757-3","journal":{"identity":"therapeutic-innovation-and-regulatory-science","isVorOnly":false,"title":"Therapeutic Innovation \u0026 Regulatory Science"},"publishedOn":"2025-02-10 15:57:19","publishedOnDateReadable":"February 10th, 2025"},"versionCreatedAt":"2024-12-23 10:18:00","video":"","vorDoi":"10.1007/s43441-025-00757-3","vorDoiUrl":"https://doi.org/10.1007/s43441-025-00757-3","workflowStages":[]},"version":"v1","identity":"rs-5248134","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5248134","identity":"rs-5248134","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}