我国药品注册工作实施eCTD的探讨

目的：为我国药品注册工作实施电子通用技术文档（eCTD）提供参考。方法：介绍eCTD的组成、优势和在全球的实施情况,结合我国实情,从政策、技术层面探讨我国实施eCTD面临的挑战。结果与结论：eCTD在药品注册资料的创建、传输、审阅、检索、存档及文件生命周期管理等方面具备的优势,保证了资料的完整、规范,提高了申报、审评效率,节约了注册成本。但在系统安全性、原辅料与药品注册数据关联、中药制剂注册申报等方面仍需进一步完善,并加强相关专业人才的培养,以加快推进eCTD信息化系统建设和使用。     

我国正式实施eCTD后药品生产企业的注册申报应对策略

研究我国药品生产企业(以下简称为药企)在药品电子通用技术文档(eCTD)正式实施后可能面临的困难，并提出应对策略。介绍eCTD的起源及演进，及其在国外主要国家的情况，并对国家药品监督管理局(NMPA)发布的相关指导原则进行介绍，分析我国药企在进行eCTD注册申报过程中可能遇到的问题并提出应对措施。eCTD已在世界范围内得到广泛应用，我国发布的eCTD指南参考的是ICH发布的V3.2.2版本。eCTD有助于提高药品申报效率，但其制作难度大、专业性强，制药企业应当做好早期规划，尽快完善企业内部eCTD注册申报体系建设，以积极心态迎接eCTD时代的到来。     

药品注册申报资料的整理和分类邮寄介要

新药注册申报过程是申请人报送临床研究资料及其他变更和补充资料,省级药品监督管理部门进行形式审查,组织对生产情况和条件进行现场考察抽取样品,然后提交给国家药监部门受理,技术审评意见随后提交给国家药监部门审批。笔者就其中整理、邮寄分类药品注册申报资料的具体内容进行介要。     

关于实施《药品注册工作程序》(试行)的通知

国药管注 [2 0 0 0 ] 1 2号各省、自治区、直辖市药品监督管理局或卫生厅 (局 )、医药管理部门、解放军总后卫生部 :为进一步加强新药、进口药品、仿制药品审批管理工作 ,完善审评工作机制 ,提高审评水平和工作效率 ,促进新药的发展 ,我局制定了《药品注册工作程序》 (试行 ) ,经局务会审议通过 ,现予发布。本工作程序自 2 0 0 0年 5月 1日起试行。附件 :1、新药申报受理通知书　　　 2、仿制药品申报受理通知书药品注册工作程序(试　行 )1　总则1 1　为加强药品注册管理 ,规范药品注册工作程序 ,维护药品注册申请人的合法权益 ,保证药品审…     

关于规范药品注册工作净化药品注册环境问题的通知

自《药品注册管理办法》实施以来，药品注册工作进度顺利，申请人提交的申请质量不断提高，药品注册的每个环节都做到了依法审评，为建立科学的审评机制取得了良好的开端。但最近我们发现，个别申请人为早日申报获得批准而忽视研究工作的质量，只顾追赶进度。有的单位研发一个药品后大肆兜售技术资料，转卖多家进行申报，甚至产生其他不规范行为，严重影响药品质量。为规范药品注册工作，净化药品注册环境，现将有关问题通知如下：     

药品审评听证程序

首先申请人递交市场准入申请（MAA），有关部门首先对递交申请的有效性进行确证，然后开始初步审评。药品审评委员会组成三个工作小组，各工作小组进行内部审评，向药品审评委员会提交审评报告并发表自己的疑义。     

欧盟药品加速审评政策及实证分析

目的:为我国新药审评审批制度的深入改革提供参考。方法:系统分析欧盟药品加速审评政策的法律基础,并与其他同类政策进行比较;对加速审评流程的关键环节,尤其是加速审评申请的递交前准备、许可前检查、申请的递交和评估等详细流程进行介绍。以Maviret为实例进行个案剖析,实证分析欧盟加速审评政策的应用效果。结果:加速审评是欧盟促进患者尽早获得新药的几项法律条款之一,与条件上市许可、同情用药、优先药物计划、孤儿药认定、医院豁免等政策一样作为在欧盟尽早获得新药的主要途径之一。当药物具备充分的治疗数据、具有重大公共健康利益和治疗创新性时,即有望获得加速审评。在欧盟法规(726/2004/EC)的基础上,欧洲药品管理局(EMA)不断完善加速审评政策体系,相继发布了相关指导原则(指南)与加速审评程序的执行时间表,为该政策的切实落地提供了详细、具体的指导。一旦药物进入加速审评程序,则其审评时间将由标准审评程序的210日缩短至150日。治疗丙型肝炎病毒感染的新药Maviret从2017年1月20日开始加速审评,直到2017年6月22日获得EMA人用药品委员会(CHMP)发布批准其上市许可的肯定意见,整个流程不到半年。结论:欧盟药品加速审评政策既有完善的立法支持,又有详细具体的实施细则和执行时间表,能够加快一些公众急需的、具有特殊医疗优势的药品的上市速度。     

CTD格式申报资料中制剂处方工艺部分解读

本文根据对新药申报的化学药品制剂CTD格式申报资料撰写要求相关内容的理解,结合审评工作体会,针对制剂处方工艺的申报资料进行解读和分析。CTD格式申报资料技术评价的核心是通过对原辅料质量控制、处方研究、关键生产环节研究及有效过程控制、工艺放大研究验证,证明能够建立完整的生产过程质量控制体系,持续稳定生产出符合设计质量要求的药品。     

FDA《新药和生物制品的获益-风险评估供企业用的指导原则》介绍

美国食品药品管理局（FDA）于2021年9月发布了《新药和生物制品的获益-风险评估供企业用的指导原则》（草案），详细介绍了FDA目前采用的新药审评的获益-风险评估的"获益-风险框架"方法。该指导原则用最大的篇幅讨论了新药注册申请人为FDA获益-风险评估提供信息、上市前应采取的行动，也简要介绍了上市后应采取的措施。中国目前还没有类似的指导原则，详细介绍FDA该指导原则，期望对国内药品监管部门的新药和新生物制品的获益-风险评估有所启迪，特别是对药品注册申请人在新药和新生物制品全生命周期，尤其是在开发过程中，为药品监管部门提供获益-风险评估信息的行动有帮助，从而有益于加速药品审评的进程以及对申报药品做出准确审评结论。     

10年来我国新药（西药）的现状和分析

１０年来我国新药（西药）的现状和分析孔英梅（卫生部药品审评中心１０００５０）１９８５年《中华人民共和国药品管理法》和《新药审批办法》颁布执行以来，在卫生部领导下，我国新药审评工作走上了科学化、规范化和法制化的道路，申报资料的质量和审评的水平也不断提高...     

Utilization of electronic resources in the NDA/BLA regulatory review of bioanalytical data: perspectives from US FDA reviewers

The electronic common technical document (eCTD) format is frequently used in submitting bioanalytical information as part of a new drug application (NDA) or biologics license application (BLA). While the use of the eCTD format has many advantages, the potential for further improvement exists. This review highlights issues that are commonly encountered in reviewing bioanalytical information during the review process. In addition, the authors suggest potential strategies that illustrate how the ability to locate bioanalytical data or information can be enhanced and the summary information can be more consistently organized for a NDA or a BLA that is submitted in an eCTD format.     

Implementation strategy for eCTD electronic submission in China based on experiences from ICH countries

With the development of information technology and pharmaceutical science, eCTD (electronic common technical document) has gradually become the main format for pharmaceutical registration dossiers all over the world, especially the ICH (the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) countries. In 2015, CFDA (China Food and Drug Administration) emphasized the significance of establishing a uniform specification for registration applications, extensively applying CTD format in China and enforcing eCTD electronic submissions step by step. In this study, we summarized the international experiences on implementation of eCTD from ICH countries and analyzed China’s current regulatory status. A survey was carried out to investigate the feasibility of implementing eCTD electronic submission in China, the possible problems to be faced with and the related solutions. Finally, recommendation on eCTD implementation strategy in China was proposed.     

我国药品加快上市注册程序的注册情况分析

目的：对2020年新修订的《药品注册管理办法》颁布前后我国纳入药品加快上市注册程序并已批准上市的药品信息进行分析,为完善我国药品加快上市注册程序提供参考。方法：检索国家药品监督管理局药品审评中心发布的2019-2021年度药品审评报告,对通过优先审评和药品加快上市注册程序而上市的相关药品数据资料进行信息整理和汇总分析。结果：通过药品加快上市注册程序的上市药品数量逐年增多,优先审评审批资源向临床优势药品和创新药品倾斜。结论：药品加快上市注册程序可为临床价值显著的药品提高审批效率,在一定程度上激发制药企业研制热情,但药品加快上市注册审批体系仍需进一步完善配套政策,细化实施要求,加快专业指南出台,鼓励以临床价值为导向的药品的研发创制, 不断提升药品监管部门的服务和监管能力。     

药包材生产申请资料的探讨

目的 帮助和指导国内药包材生产企业更好地准备申请产品的注册申报资料,满足技术审评的基本要求;同时,有助于审评机构进行科学规范的审评,提高审评工作的质量和效率.方法 对目前药包材生产申请所需提交的12项资料,重点从3批申报产品的质量检验报告书;申报产品生产、销售、应用情况综述;产品配方;产品的生产工艺及主要生产、检验设备说明;申报产品的质量标准;3批申报产品的企业自检报告书以及与采用申报产品包装的药品相容性研究资料等7个方面,提出了细化注册申报资料的具体内容.结果与结论 结合药包材生产现状,对药包材企业生产申请所需提交的资料进行细化和规范化,有利于药包材生产申请工作的顺利开展.     

The ability of animal studies to detect serious post marketing adverse events is limited

The value of animal studies to assess drug safety is unclear because many such studies are biased and have methodological shortcomings. We studied whether post-marketing serious adverse reactions to small molecule drugs could have been detected on the basis of animal study data included in drug registration files. Of 93 serious adverse reactions related to 43 small molecule drugs, only 19% were identified in animal studies as a true positive outcome, which suggests that data from animal studies are of limited value to pharmacovigilance activities. Our study shows that drug registration files can be used to study the predictive value of animal studies and that the value of animal studies in all stages of the drug development should be investigated in a collaborative endeavour between regulatory authorities, industry, and academia.     

Bayesian Quantitative Disease–Drug–Trial Models for Parkinson’s Disease to Guide Early Drug Development

The problem we have faced in drug development is in its efficiency. Almost a half of registration trials are reported to fail mainly because pharmaceutical companies employ one-size-fits-all development strategies. Our own experience at the regulatory agency suggests that failure to utilize prior experience or knowledge from previous trials also accounts for trial failure. Prior knowledge refers to both drug-specific and nonspecific information such as placebo effect and the disease course. The information generated across drug development can be systematically compiled to guide future drug development. Quantitative disease-drug-trial models are mathematical representations of the time course of biomarker and clinical outcomes, placebo effects, a drug's pharmacologic effects, and trial execution characteristics for both the desired and undesired responses. Applying disease-drug-trial model paradigms to design a future trial has been proposed to overcome current problems in drug development. Parkinson's disease is a progressive neurodegenerative disorder characterized by bradykinesia, rigidity, tremor, and postural instability. A symptomatic effect of drug treatments as well as natural rate of disease progression determines the rate of disease deterioration. Currently, there is no approved drug which claims disease modification. Regulatory agency has been asked to comment on the trial design and statistical analysis methodology. In this work, we aim to show how disease-drug-trial model paradigm can help in drug development and how prior knowledge from previous studies can be incorporated into a current trial using Parkinson's disease model as an example. We took full Bayesian methodology which can allow one to translate prior information into probability distribution.     

The ability of animal studies to detect serious post marketing adverse events is limited

The value of animal studies to assess drug safety is unclear because many such studies are biased and have methodological shortcomings. We studied whether post-marketing serious adverse reactions to small molecule drugs could have been detected on the basis of animal study data included in drug registration files. Of 93 serious adverse reactions related to 43 small molecule drugs, only 19% were identified in animal studies as a true positive outcome, which suggests that data from animal studies are of limited value to pharmacovigilance activities. Our study shows that drug registration files can be used to study the predictive value of animal studies and that the value of animal studies in all stages of the drug development should be investigated in a collaborative endeavour between regulatory authorities, industry, and academia.     

CLINICAL PHARMACOKINETIC REGISTRATION FILE FOR NDA AND ANDA PROCEDURES

Pharmacokinetics is a relatively young branch of the life sciences, which has developed rapidly in the last 15–20 years, thanks to a series of analytical achievements that have allowed drug concentrations to be measured in biological matrices with highly selective and sensitive methods. Most old drugs and all new drugs have been investigated in depth to determine their absorption, distribution, metabolism and elimination. This has produced a huge body of data which have characterized drugs through so-called fingerprint parameters. Today, pharmacokinetics plays a vital role throughout drug development from initial non-clinical studies to clinical trials. In new drug development, simultaneous efforts in pharmacodynamic and pharmacokinetic studies have produced a high degree of synergy, the most useful expression of which is the identification of a therapeutic window, where this can be achieved. Dose linearity/proportionality, gender effect, metabolism and possible polymorphism, studies on neonates/children and on elderly and diseased patients and the population approach, relative and absolute bioavailability, possible interactions and the possible presence of a deep compartment in the distribution are other important applications of pharmacokinetics. Major new developments in pharmaceutical technology which have produced controlled-release delivery systems and the market introduction of generics would never have occurred but for the active contribution of pharmacokinetics. This review is devoted to the investigations needed to prepare appropriate pharmacokinetic registration files for new drug applications (NDAs) and abbreviated or abridged new drug applications (ANDAs) required for generic drugs. Scientific literature, operating guidelines and personal experience are the basis of this review, which describes a number of relevant examples in several specific areas.     

借助Excel实现网上交易系统与医院信息系统间的药品信息传递

目的:借助Excel实现网上交易系统与医院信息系统(HIS)间的药品信息传递。方法:建立药品编码匹配工作薄,利用ExcelVBA编程、自动筛选功能等设计药品编码匹配功能。结果与结论:将HIS采购信息复制到药品编码匹配工作薄中,可自动实现药品编码的匹配。将相关文件导入网上交易系统和HIS,即完成采购信息发布和入库信息输入工作,从而大大提高了工作效率。