为促进替代终点等创新药物研发工具的广泛使用,首先从FDA药品审评评价中心(CDER)开始,于2015年建立了“药物研发工具资格认定程序(qualification process for drug development tools,QPDDT)”[4],旨在通过鼓励认定申请人公开获得认定的创新药物研发工具,促进创新生物标记物在药物研发过程中的普及应用,减少新型研发工具的重复审评。生物标记物日益成为治疗特定疾病医药产品研发的重要组成部分,因此QPDDT中最重要的就是生物标记物资格认定项目(biomarkers qualification program,BQP),医药产品研发中作为有效指标的生物标记物,经该程序获FDA审评通过后即认定为合格的生物标记物。
2.3.1资格认定程序沟通框架 2015年CDER发布的《药品开发工具资格认定程序》指南建立了CDER和药物开发工具(drug development tool, DDT)申请人的沟通框架[4],将资格认定分为起始阶段、咨询和建议阶段、审评阶段。通过CDER和申请人积极沟通,能够获得足以支持特定使用背景下(Content of Use, COU)下DDT的完整数据资料。当然DDT的适用情况不是一成不变的,随着申请人对日益增多的数据继续展开收集、上交和分析活动,COU可能会发生变动,其范围可能扩大。COU变动的申请不一定由初始申请人提交,可由其他人员提交。当科学证据不再支持COU时,DDT资格可能会被撤销。
第一阶段:起始阶段。申请人首先联系CDER,获得DDT追踪号。CDER收到申请后,将指定联系人,同时将DDT追踪号录入数据库,为方便后续提交资料如意向书(a letter of intent, LOI)等能直接与该申请号联系在一起。意向书是申请人首次向CDER提交的,用以描述DDT价值的简要文字说明。意向书包括DDT、COU描述以及阐述资格认定的合理性。CDER收到意向书后,通常根据请求是否具备科学价值以及CDER现有审评资源是否充足,以及DDT其他发展路径的建议等进行评价,并决定是否开始咨询和建议阶段。
5结论 美国是药品创新和审评效率居世界首位的国家,全世界近60%的创新药选择在美国作为首选市场上市,2015年FDA批准的45个创新药(包括NME和BLA)平均审评中位时间仅需8.5个月[17]。美国FDA与制药企业、行业协会、学术界及其他监管部门合作,致力于发展生物标记物等创新的药品研发工具[18],并将其融入监管科学设计,从而有效地提高监管效率和药品审评速度,值得我国借鉴。 请输入标题 abcdefg REFERENCES [1] EFPIA. The Pharmaceutical Industry in Figures Key Data 2012[EB/OL]. [2012-06-15]. http://www.efpia.eu/sites/www.efpia.eu/files/EFPIA Figures 2012 Final.pdf. [2] Silver S. Bethesda. BEST(Biomarkers,EndpointS,and other Tools) Resource [EB/ OL]. [2016-04-28]. http://www.ncbi.nlm.nih.gov/book ... helf_NBK326791.pdf. [3] LIU B L. Classification of efficacy endpoints in a clinical trial of the new drug[J]. Chin J New Drugs(中国新药杂志). 2016,25(10) :1104-1105. [4] FDA. Guidance for Industry and FDA Staff Qualification Process for Drug Development Tools[EB/OL]. [2014-01-01]. http://www.fda.gov/downloads/dru ... ances/ucm230597.pdf [5] FDA. 21st-Century Cures:Modernizing Clinical Trials and Incorporating the Patient Perspective[EB/OL]. [2014-07-11]. http://www.fda.gov/newsevents/testimony/ucm404647.htm. [6] Downing N S,Amina wung J A,Shah N D, et al.. Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005–2012[J]. JAMA,2014, 311(4):368–377 [7] S Amur,L LaVange,I Zineh, et al.. Biomarker Qualification: Toward a Multiple Stakeholder Framework for Biomarker Development,Regulatory Acceptance,and Utilization[J]. CLINICAL PHARM & THER,2015,98(1):311 [8] FDA Facts;Biomarkers and Surrogate Endpoints [EB/OL]. [2016-07-22]. http://www.fda.gov/aboutfda/innovation/ucm512503.htm. [9] FDA. Joint FDA/ EMA Letter of Intent (LOI) Submissions for Biomarker and Clinical Outcome Assessment Qualification Programs [EB/OL]. [2016-03-04]. http://www.fda.gov/drugs/develop ... gram/ucm422888.htm. [10] XU X G,JIANG M. The Use and Limitation of Surrogate End Points in Clinical Trials[J]. Chin J Clin Pharmacol Ther(中国临床药理学与治疗学),2006 ,11(10):1195 [11] Frank R and Hargreaves R. 2003.Clinical biomarkers in drug discovery and development[J]. Nature Reviews Drug Discovery. 2(7):566-580 [12] FANG X H. The Use and Limitation of Surrogate End Points in the Cardiovascular Diseases Clinical Trials[J]. J Evidence-Based Medicine(循证医学).2005,5(6):365 [13] FDA. Novel Drugs Approved Using Surrogate Endpoints [EB/OL]. [2015-01-01]. http://www.fda.gov/downloads/newsevents/testimony/ucm445375.pdf. [14] FDA. Guidance for Industry Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention [EB/OL]. [2008-02-13]. http://www.fda.gov/downloads/Drugs/ Guidances/ucm071624.pdf. [15] Antiretroviral Drugs Using Plasma HIVRNA Measurements – Clinical Considerations for Accelerated and Traditional Approval (2002) [EB/OL]. [2002-05-13]. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070968.pdf. [16] FDA. Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics[EB/OL]. [2007-05-01]. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071590.pdf. [17] John K. Jenkins CDER New Drug Review 2015 Update. CDER new drug review:2015 update [EB/OL]. [2016-03-27]. http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm477020.pdf. [18] TAO X M,DONG J P,HUANG L,et al. Relationship of Ecosystems and Resolution of New Drug Research and Development[J].Chin Pharm J(中国药学杂志),2016,51(7):592 文章来源:孙宇昕,魏芬芳,杨悦.美国FDA药品审评中替代终点开发与应用[J].中国药学杂志,2017,52(5):414-419.转载此版本请保留出处,并注明转载自“国际药政通”(SYPHU-IFDPL)。 (责任编辑:郑永侠、王艺芳)