目的: 旨在探寻中美附条件批准药品上市后确证性研究政策的完善方向,以及研发企业在制定上市后确证性研究研发策略时的考量点,以供业界参考。方法: 通过对比中美两国附条件批准药品上市后确证性研究的相关法规政策要求,以及中美两国在附条件批准上市后确证性研究上的实践情况,结合实际案例,对两国上市后确证性研究设计方案进行分类汇总,进而深入探讨中美两国在政策及实施上的优化方向。结果与结论: 中美两国对附条件批准上市后确证性研究的启动和完成时间、研究结果解读的要求在同步收紧,标准也愈发清晰,但确证性研究开展进度缓慢仍然是两国监管部门面临的挑战。虽然随机对照试验被美国食品药品管理局（Food and Drug Administration,FDA）和国家药品监督管理局药品审评中心（Center for Drug Evaluation,CDE）推荐用于确证性研究设计,但研发企业在单臂试验的使用上仍有可尝试和突破的空间。
Objective: To explore the improvement direction of the regulations and policies on confirmatory studies on post-marketing of conditional approval of drug in China and the United States, as well as the considerations of research and development (R&D) enterprises in building development strategies of confirmatory studies, and for the industry's reference. Methods: By comparing the requirements of relevant regulations and policies of confirmatory studies on post-marketing of conditional approval of drug in China and the United States, and the practice of the studies in the two countries, with the analyzing of real cases, the design schemes of post-marketing confirmatory studies in China and the United States were classified and summarized, and then the optimization direction of the policy and implementation in China and the United States was further discussed. Results and Conclusion: The requirements for the initiation time, completion time and the interpretation of research results of post-marketing confirmatory studies in China and the United States have been tightened simultaneously, and the criteria have become clearer, however, the slow progress of confirmatory studies is still a challenge faced by the regulatory authorities in both countries. Although randomized controlled trials are recommended by the Food and Drug Administration (FDA) and Center for Drug Evaluation (CDE) of NMPA for confirmatory study design, there is still room for experimentation and breakthrough in the use of single-arm trials for R&D enterprises.
[1] FDA. Guidance for Industry Expedited Programs for Serious Conditions Drugs and Biologics[EB/OL].(2014)[2024-10-04]. https://www.fda.gov/media/86377/download.
[2] FDA. Postmarket Requirements and Commitments Page[EB/OL].[2024-10-04]. https://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm.
[3] FDA. Food and Drug Omnibus Reform Act(FDORA)of2022[EB/OL].(2022)[2024-10-04]. https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/food-and-drug-omnibus-reform-act-fdora-2022.
[4] FDA. 21CFR PART 314.510 Approval Based on a Surrogate Endpoint or on An Effect on a Clinical Endpoint Other Than Survival or Irreversible Morbidity [EB/OL].(2024-04-25) [2024-10-04]. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-H/section-314.510.
[5] Citeline. FDORA Effect? For Accelerated Approval Class of2023,Most Confirmatory Trials at Least Underway[EB/OL].(2024-01-29)[2024-10-04]. https://pink.citeline.com/PS149667/FDORA-Effect-For-Accelerated-Approval-Class-Of-2023-Most-Confirmatory-Trials-At-Least-Underway.
[6] Beakes-Read G,Neisser M,Frey P,et al.Analysis of FDA's Accelerated Approval Program Performance December 1992-December 2021[J]. Therapeutic Innovation & Regulatory Science, 2022,56(5):698-703.
[7] Citeline. The Long and Short of Accelerated Approval Accountability in US[EB/OL].(2022-11-29)[2024-10-04]. https://pink.citeline.com/PS147381/The-Long-And-Short-Of-Accelerated-Approval-Accountability-In-US.
[8] FDA. Food and Drug Omnibus Reform Act (FDORA) of2022[EB/OL].(2022)[2024-10-04]. https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/food-and-drug-omnibus-reform-act-fdora-2022.
[9] 国家市场监督管理总局. 药品注册管理办法[EB/OL].(2020-03-30)[2024-10-04]. https://www.samr.gov.cn/zw/zfxxgk/fdzdgknr/fgs/art/2023/art_3275cb2a929d4c34ac8c0421b2a9c257.html.
[10] 国家药品监督管理局. 药品附条件批准上市申请审评审批工作程序(试行)[EB/OL]. (2020-07-08)[2024-04-25]. https://www.nmpa.gov.cn/xxgk/fgwj/xzhgfxwj/20200708151701834.html.
[11] 国家药品监督管理局药品审评中心. 国家药监局药审中心关于发布《药品附条件批准上市技术指导原则(试行)》的通告(2020年第41号)[EB/OL].(2020-11-19)[2024-10-04]. https://www.cde.org.cn/main/news/viewInfoCommon/d1716db06f90c3adf134de337373b22c.
[12] 国家药品监督管理局药品审评中心.信息公开—附条件批准[EB/OL].(2024)[2024-10-04]. http://www.cde.org.cn/main/xxgk/listpage/c8d79e513a6df98adf05893281ace198.
[13] 国家药品监督管理局. 国家药监局综合司公开征求《药品附条件批准上市申请审评审批工作程序(试行) (修订稿征求意见稿)》意见[EB/OL].(2023-08-25)[2024-10-04]. https://www.nmpa.gov.cn/directory/web/nmpa/xxgk/zhqyj/zhqyjyp/20230825104212129.html.
[14] 齐玥丽,邹丽敏,蒋永麟,等. 我国附条件批准政策梳理及抗肿瘤创新药审评标准浅析[J].中国新药杂志,2023,32(2):189-197.
[15] FDA. Withdrawn:FDA Grants Accelerated Approval to Infigratinib for Metastatic Cholangiocarcinoma[EB/OL].(2023-08-25)[2024-10-04]. https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-fda-grants-accelerated-approval-infigratinib-metastatic-cholangiocarcinoma.
[16] Regeneron Pharmaceuticals,Inc. Regeneron Provides Update on Biologics License Application for Odronextamab[EB/OL].(2024-03-25)[2024-10-04]. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application.
[17] Oncology Nursing News. Copanlisib Will No Longer Be Available in the US for Relapsed Follicular Lymphoma[EB/OL].(2023-11-24)[2024-10-04]. https://www.oncnursingnews.com/view/copanlisib-will-no-longer-be-available-in-the-us-for-relapsed-follicular-lymphoma.
[18] FDA. Withdrawn:FDA Grants Accelerated Approval to Melphalan Flufenamide for Relapsed or Refractory Multiple Myeloma[EB/OL].(2024-02-23)[2024-10-04]. https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-fda-grants-accelerated-approval-melphalan-flufenamide-relapsed-or-refractory-multiple.
[19] 国家药品监督管理局药品审评中心.信迪利单抗注射液(CXSS1800008)申请上市技术审评报告[S]. 2019.
[20] 国家药品监督管理局药品审评中心.瑞基奥仑赛注射液(CXSS2200019)申请上市技术审评报告[S]. 2023.
[21] Q Ribeiro TB,Bennett CL,Colunga-Lozano LE,et al. Increasing FDA-Accelerated Approval of Single-Arm Trials in Oncology(1992 to 2020)[J]. Journal of Clinical Epidemiology,2023,159:151-158.
[22] FDA. Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics Guidance for Industry Draft Guidance[EB/OL].(2023)[2024-10-04]. https://www.fda.gov/media/166431/download.
[23] FDA. Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics [EB/OL].(2018)[2024-10-04]. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trial-endpoints-approval-cancer-drugs-and-biologics.
[24] FDA. Frequently Asked Questions[EB/OL].(2024-08-21)[2024-10-04]. https://www.fda.gov/about-fda/oncology-center-excellence/project-confirm.
[25] FDA. Center for Drug Evaluation and Research.Application Number: 203469Orig1s000MEDICALREVIEW(S)[EB/
OL].(2012-11-19)[2024-10-04]. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000MedR.pdf.
[26] FDA. NDA 203469/S-037 Accelerated Approval Letter[EB/OL].(2024)[2024-10-04]. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/203469Orig1s037ltr.pdf.
[27] FDA. FDA Grants Accelerated Approval to Zanubrutinib for Relapsed or Refractory Follicular Lymphoma[EB/OL].(2024-03-07)[2024-10-04]. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanubrutinib-relapsed-or-refractory-follicular-lymphoma.
[28] FDA. NDA 213217/S-011 Accelerated Approval Letter.[EB/OL].(2024)[2024-10-04]. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/213217Orig1s011ltr.pdf.
[29] FDA. FDA Grants Accelerated Approval to Selpercatinib for Pediatric Patients Two Years and Older With RET-Altered Metastatic Thyroid Cancer or Solid Tumors[EB/OL].(2024-06-17)[2024-10-04]. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-selpercatinib-pediatric-patients-two-years-and-older-ret-altered.
[30] FDA. Prescribing Information of selpercatinib[EB/OL].(2024)[2024-10-04]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213246s012lbl.pdf.
[31] FDA. NDA 213246/S-012 Accelerated Approval Letter[EB/OL].(2024)[2024-10-04]. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/213246Orig1s012ltr.pdf.
[32] 国家药品监督管理局药品审评中心. 肿瘤主动免疫治疗产品临床试验技术指导原则(试行) [EB/OL].(2023-04-25)[2024-10-04]. https://www.cde.org.cn/main/news/viewInfoCommon/311c810ad705f3a0e5538a5e5efb9dae.
[33] 周思源,杨志敏,宋媛媛,等. 我国创新药审评审批的改革与发展——以抗肿瘤药物为例[J].中国食品药品监管,2024(6):4-15.
[34] 国家药品监督管理局药品审评中心. 单臂试验支持上市的抗肿瘤药进入关键试验前临床方面沟通交流技术指导原则[EB/OL].(2020-12-02)[2024-10-04]. https://www.cde.org.cn/main/news/viewInfoCommon/2a6d7894c0ee2aaa37fd1ca8e941cdab.
[35] 国家药品监督管理局药品审评中心. 盐酸安罗替尼胶囊(CXHS1800039-41)申请上市技术审评报告[S]. 2021.
[36] 国家药品监督管理局药品审评中心. 盐酸安罗替尼胶囊临床试验公示信息[EB/OL].(2024)[2024-10-04]. http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml.
[37] 国家药品监督管理局药品审评中心. 阿替利珠单抗注射液(JXSS2000033)申请上市技术审评报告[S]. 2022.
[38] NIH's National Library of Medicine. A Study of Atezolizumab in High PD-L1 Expression, Chemotherapy-Naïve Patients With Stage IV Non-Squamous or Squamous Non-Small Cell Lung Cancer [EB/OL].(2024)[2024-10-04]. https://clinicaltrials.gov/study/NCT05047250?term=ML42606&rank=1.
[39] 国家药品监督管理局药品审评中心. 注射用维博妥珠单抗(JXSS2101036)申请上市技术审评报告[S]. 2023.
[40] 国家药品监督管理局药品审评中心. 信息公开>>附条件批准品种>>注射用维泊妥珠单抗[EB/OL].(2024)[2024-10-04]. https://www.cde.org.cn/main/xxgk/listpage/b40868b5e21c038a6aa8b4319d21b07d.
[41] 国家药品监督管理局药品审评中心. 达雷妥尤单抗注射液(皮下注射) (JXSS2000050)申请上市技术审评报告[S]. 2021.
[42] 国家药品监督管理局药品审评中心. 信息公开>>附条件批准品种>>达雷妥尤单抗注射液(皮下注射)[EB/OL].(2024)[2024-10-04]. https://www.cde.org.cn/main/xxgk/listpage/b40868b5e21c038a6aa8b4319d21b07d.
[43] 张烁,金思羽,杨莉. 美国抗肿瘤药加速批准程序运行效果分析及对我国的启示[J]. 中国新药杂志,2024,33(6):521-530.
[44] 国家药品监督管理局药品审评中心. 单臂临床试验设计用于支持抗肿瘤药上市申请的适用性技术指导原则[EB/OL].(2023-03-14)[2024-10-04]. https://www.cde.org.cn/zdyz/domesticinfopage?zdyzIdCODE=610bd41855e7c9afeb694271015d3cd8.
[45] 国家药品监督管理局药品审评中心. 晚期肝细胞癌临床试验终点技术指导原则[EB/OL].(2020-11-26)[2024-10-04]. https://www.cde.org.cn/main/news/viewInfoCommon/2ab3ff01edb369c8bbec9285545c79f1.
[46] 国家药品监督管理局药品审评中心. 谷美替尼片(CXHS2200010)申请上市技术审评报告[S]. 2023.
[47] 国家药品监督管理局药品审评中心. 信息公开>>附条件批准品种>>谷美替尼片[EB/OL].(2024)[2024-10-04]. https://www.cde.org.cn/main/xxgk/listpage/b40868b5e21c038a6aa8b4319d21b07d.
[48] 国家药品监督管理局药品审评中心. 用于产生真实世界证据的真实世界数据指导原则[EB/OL].(2021-04-13)[2024-10-04]. https://www.cde.org.cn/main/news/viewInfoCommon/2a1c437ed54e7b838a7e86f4ac21c539.
[49] 国家药品监督管理局药品审评中心. 试点产品附条件获批上市药品临床真实世界数据应用试点开新局[EB/OL].(2021-04-06)[2024-10-04]. https://www.cde.org.cn/main/news/viewInfoCommon/89e868145361fc4ace6765474944a892.
[50] 国家药品监督管理局药品审评中心. 以临床价值为导向的抗肿瘤药物临床研发指导原则[EB/OL].(2021-11-15)[2024-10-04]. https://www.cde.org.cn/main/news/viewInfoCommon/ef7bfde96c769308ad080bb7ab2f538e.
[51] 姚晨. 利用真实世界数据生产高质量真实世界证据支持药械监管[J].中国食品药品监管,2020(2):22-27.
[52] 唐凌,周明,夏琳,等.对单臂试验支持抗肿瘤药物上市策略的再思考[J].中华肿瘤杂志,2022,44(6):587-592.
[53] 国家药品监督管理局药品审评中心. 真实世界证据支持药物研发与审评的指导原则(试行)[EB/OL].(2020-01-07)[2024-10-04]. https://www.cde.org.cn/zdyz/domesticinfopage?zdyzIdCODE=db4376287cb678882a3f6c8906069582.
[54] FDA. Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence Guidance for Industry[EB/OL].(2023)[2024-10-04]. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-one-adequate-and-well-controlled-clinical.
[55] 丁锦希,李苏菊,李鹏辉. 美国快速通道与突破性疗法模式的比较研究与借鉴[J]. 上海医药, 2017,38(5):52-56,59.
[56] 朱越,蒋蓉,邵蓉. 澳大利亚药品注册特殊审评制度简析及启示[J]. 广东药科大学学报, 2018,34(6):765-769.
[57] 张虹,高晨燕,陈晓媛,等. 关于采用单臂临床试验数据用于支持进口药品注册的考虑[J].中国新药杂志,2013,22(18):2126-2129.
[58] Citeline. Pazdur On Accelerated Approval:FDA Needs to Explain Why It Does Not Always Seek Withdrawal When Trials Fail[EB/OL].(2024-01-30)[2024-10-04]. https://pink.citeline.com/PS149669/Pazdur-On-Accelerated-Approval-FDA-Needs-To-Explain-Why-It-Does-Not-Always-Seek-Withdrawal-When-Trials-Fail.
[59] 国家药品监督管理局药品审评中心. 抗肿瘤药联合治疗临床试验技术指导原则[EB/OL].(2020-12-30)[2024-10-04]. https://www.cde.org.cn/main/news/viewInfoCommon/e486210418ae46e01cebe7f05067f86c.
[60] 唐凌,周明,夏琳,等. 以患者为核心的抗肿瘤药物临床研发的审评考虑[J]. 临床肿瘤学杂志,2021,26(7):577-582.
[61] 唐辉, 汤立达. 药品附条件批准上市的内涵与风险防控[J]. 中国医药导刊,2021,23(4):289-295.
[62] 梁晨. 新药许可加速的制度实践及其风险规制[J]. 中国市场监管研究,2021(10):46-51.
[63] Beaver JA,Pazdur R.Perspective ‘Dangling' Accelerated Approvals in Oncology[J]. New England Journal of Medicine,2021,384:e68.
[64] Luo XX,Xin D,Lin H.Evidence of Pre-Approval Clinical Trial Supporting the Granted Conditional Approval for Novel Cancer Drugs in China Between 2015 and 2022[J]. The Lancet Discovery Science,2023,63.
[65] 周菁菁,黄梦琴,孙志明,等. 附条件批准上市药品纳入基本医疗保险药品目录的政策风险分析[J]. 医学与社会,2023,36(1):99-104.
[66] 国家药品监督管理局. 国家药监局关于发布真实世界证据支持药物研发与审评的指导原则(试行)的通告(2020年第1号)[EB/OL].(2020-01-03)[2023-08-29]. https://www.nmpa.gov.cn/xxgk/ggtg/ypggtg/ypqtggtg/20200107151901190.html.
[67] FDA. Accelerated Approval Program[EB/OL].(2024-02-24)[2024-10-04]. https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program.
[68] Naci H,Zhang YC,Woloshin S,et al.Overall Survival Benefits of Cancer Drugs Initially Approved by the US Food and Drug Administration on the Basis of Immature Survival Data:A Retrospective Analysis[J]. The Lancet Oncology,2024,25(6):760-769.
[69] 国家药品监督管理局药品审评中心. 信息公开>>附条件批准品种[EB/OL].(2024)[2024-10-04]. https://www.cde.org.cn/main/xxgk/listpage/c8d79e513a6df98adf05893281ace198.
[70] 国家药品监督管理局药品审评中心. 信息公开>>上市药品信息[EB/OL].(2024)[2024-10-04]. https://www.cde.org.cn/main/xxgk/listpage/c8d79e513a6df98adf05893281ace198.
