AS-1411

同写意20岁庆！第五届全球生物医药前沿技术大会报名开启！“意”同创新，穿越周期。7月中旬，苏州金鸡湖畔，让我们与“新药写意人”一起为中国医药创新“同写意”！目前，越来越多的创新药趋向中美双报或全球申报等国际策略。当前国内尚没有专门的、系统的药品和生物制品法规标准体系。从事新药产品工作的监管专业人员需要了解世界各地的法规、要求、途径和流程。在美国有专门的法规事务协会Regulatory Affairs Professionals Society（RAPS），其对药品和生物制品的监管有着至关重要的作用。该协会2023年出版了适用于全球的书籍《药品和生物制品法规基础（全球视觉）》（Fundamentals of Pharmaceutical and Biologics Regulations A GLOBAL PERSPECTIVE），该书结合新旧法规、药品及生物制品、监管体系的变化，每年月底左右进行系统更新并出版最新书籍。为了支持他们的工作，RAPS在编辑咨询委员会的建议和指导下重新调整了《基础知识》的内容。本书扩大了《基础知识》的范围，以纳入了更多有关药物开发的内容，以帮助读者了解监管申报流程。来自全球四大洲的14个国家的50多位监管专业人士为本书各章节的撰写做出了贡献，涉及该行业的各个专业领域。笔者现针对该书籍进行粗浅的翻译/解析，笔者看到这本书籍作为注册人我是欣喜的，其为药品和生物制品的全球申报至少提供了某种意义上的标准或者方向。本书共有六大部分，将分别从一般概述、非临床、药学、临床、上市许可、上市后等逐一介绍。希望此系列推文供致力于国内药品和生物制品的发展的监管事务专业人员参考。如有任何建议或者纠正，请私信联系我们。1前言药品和生物制品在治疗和预防疾病方面发挥着至关重要的作用，但它们也有可能产生严重的不良反应。因此，监管对于帮助确保医药产品的安全性、有效性和质量至关重要。药品和生物制品法规基础（Fundamentals of Pharmaceutical and Biologics Regulations：由美国法规事务协会(RAPS) ）出版，旨在全面介绍全球医药产品的监管要求。本书是RAPS推出的一系列权威性基础知识读物中的最新一本。我们于1999年出版了第一版《RAPS美国监管事务基础》，但自那以后，医疗产品及其监管发生了巨大变化。药品开发和营销流程：从前期筛选到批准后的要求，现已真正全球化。监管要求的国际协调取得了长足进步，但全球仍有数十个监管机构拥有独特的流程和途径。从事新药产品工作的监管专业人员需要了解或知道在哪里可以找到世界各地的法规、要求、途径和流程。为了支持他们的工作，RAPS在编辑咨询委员会的建议和指导下重新调整了《基础知识》的内容。本书扩大了《基础知识》的范围，以纳入了更多有关药物开发的内容，以帮助读者了解监管申报流程。关于医疗器械和诊断的监管类似的综合书籍预计将于2024年出版。50多位监管专业人士为本书各章节的撰写做出了贡献。这些志愿者来自全球四大洲的14个国家，涉及该行业的各个专业领域。他们供职于各种组织--从大型制药公司到小型咨询公司。他们为Linda McBride, RPh, RAC-US，Siegfried Schmitt, PhD，以及章节编辑Kimberly Belsky, MS, FRAPS、Devanshi Maharaja, MSc, MTech、Daniel G. Mannix, PhD, FRAPS、Flora Siami, MPH、Kip Vought。这些人员共同收集了来自全球各地卫生机构（health authorities）的信息，从而为您提供了一份尽可能完整的资源，帮助您了解众多法律、法规和指南，以及如何在整个产品生命周期内将其应用于医药产品。RAPS非常感谢这些贡献者帮助革新本书。作为最新成员，本书依赖于前几本书的更新内容和贡献这些知识的作者。RAPS感谢这些贡献者帮助我们实现这一新的发展。我谨代表RAPS的工作人员和创建这本书的志愿者，希望一本全球视角有用的书籍《药品和生物制品法规基础》帮助你们支持您所在领域的目标，提高你们的法规监管能力，或帮助你们准备参加药品监管事务认证（RAC-Drugs）考试。随着时间的推移，我们将继续更新和改进这本书，我们欢迎您在editor@raps.org上提供任何反馈或建议。2简介当我们萌生出版这本书的想法时，我们问自己的第一个问题是：监管机构真的需要这本书吗？答案很明确是"需要"，原因就如下：在与朋友和家人聊天时，经常会围绕着疾病和药物展开。而且，作为医疗保健行业的专业人士，我们经常会被问到一些探究性的问题，比如疫苗是否真的像说明书上写的那样有很多副作用；为什么一种药物的价格如此昂贵；又或者为什么开发一种治疗老年痴呆症的药物需要如此长的时间。当然，这本书并不是写给我们的朋友和家人看的，而是真正为需要得到这些问题答案的监管专业人士写的。那么，我们从哪里可以找到答案呢？遗憾的是，这些信息到处都是--这里有一篇文章，那里有一本书的章节。有些是中文，有些是英文，还有些是其他语言。没有一个单一、全面的资料来源可以提供全球药品和生物制品的监管视角。正因如此，本书成为全球监管专业人士的必备之书。这本书能解答所有问题吗？并非如此，然而，亲爱的读者，它确实可以为您提供权威监管信息和指导的最佳来源，我们与50多位全球专家作者和我们作为编辑合作，可以为您带来这些信息和指导。我们衷心希望您能喜欢阅读这本书，并从中获得有用的信息，回答您的问题，甚至是您家人和朋友的问题。如果您有时间，请告诉我们您的反馈意见。3目录第一部分：一般信息第 1 章：医疗蓝图与药物发展第 2 章：药物开发的连续性，从临床前到市场准入第 3 章：通过 ICH、WHO 和其他全球倡议实现国际协调第二部分：非临床研究第 4 章：良好实验室规范和非临床开发原则第 5 章：安全性药理学研究第 6 章：药代动力学和毒代动力学研究第 7 章：遗传毒理学研究第 8 章：致癌性研究第 9 章：发育和生殖毒性评估第 10 章：人用药物的监管环境风险评估第三部分：CMC（药学研究）第 11 章：活性物质（Active substances）的全球监管流程第 12 章：协调临床和非临床开发的药物供应第 13 章：药品开发研究和生产经验第 14 章：分析开发--测试和稳定性第四部分：Clinical Trials临床试验第 15 章：开展临床试验：药物申请类型、数据要求和获得上市批准第 16 章：临床阶段（1、2、3、4期）第 17 章：加强临床试验的多样性第 18 章：药监之间的互动第 19 章：儿科第 20 章：地区性研究第五部分：上市许可第 21 章：效益-风险评估框架第 22 章：eCTD和数字应用第 23 章：快速审批途径第 24 章：文件要求第六部分：上市后授权第 25 章：授权后承诺第 26 章：转让和续期第 27 章：产品扩展、变异和补充第 28 章：合规性第 29 章：召回第 30 章：上市后监测第 31 章：广告和促销第 32 章：市场准入附录各章节的法规和指南 - 对比矩阵缩略语术语表索引4正文第 1 章医疗蓝图与药物发展医疗保健一直是人类生活的一个重要方面，如今更是如此。随着医药产品领域的发展，医疗保健领域也在不断演变和转型，目前受到支付方改革、技术、科学进步、消费者需求等因素的极大影响。这些新的现实和挑战影响着医药产品的开发和审批。以前，我们对许多危及生命的疾病缺乏有效的治疗方法；现在，尽管有了更多的治疗方法，但公众对医疗保健的监督却加强了。患者及其家属希望尽快获得新的治疗方法，并获得准确易懂的使用信息。虽然这导致卫生当局支持创新和科技进步，但也增加了全球监管格局的复杂性。美国食品和药物管理局（FDA）和欧洲药品管理局（EMA）通常是首先审查这些创新治疗方法的监管机构，并引领将有效且具有成本效益的治疗方法带给更广泛的人群。此外，国际人用药品技术要求协调理事会（ICH）在监管机构和制药行业的科学讨论基础上制定指导方针，在全球药物开发中发挥着至关重要的作用。ICH指导方针不断更新，并被全球越来越多的卫生机构所采用。ICH的使命是在全球范围内实现更大程度的协调，确保以最节省资源的方式开发、注册和维护安全、有效和高质量的药品，同时满足高标准的要求。1、FDA（Food and Drug Administration）FDA是美国卫生与公众服务部（HHS）的一个机构，负责通过确保人用药品和生物制品以及本书范围之外的其他产品的安全性，有效性来确保公众健康。FDA的使命包括支持创新，使药品更安全、更有效、更经济实惠，从而促进公众健康（advancing public health by supporting innovations that make medicines safer, more effective, and more affordable）。该局的任务是向公众提供他们在使用医药产品以保持和改善健康时所需的准确、科学的信息。FDA在美国反恐工作中发挥着重要作用。该局与其他美国机构、国际监管机构、学术界、行业协会、消费者团体等开展合作。2、FDA在全球监管格局中的作用美国等主要国家人民消费的许多医药产品都是在其他国家生产的。在美国，受 FDA监管的产品由150多个国家的130,000多家工厂生产。FDA在确定和确认其标准和要求是否适用于进口到美国的医药产品的生产、分销和储存方面面临着挑战。鉴于产品的生产可能涉及来自不同国家的多个方面，产品有可能配制或包装不当、受到污染、被转移、被伪造或掺假。因此，由监管机构监督整个产品生命周期的合规性和监督活动是药品开发过程的重要组成部分。FDA监督药品的进出口，以确保FDA监管的产品符合《食品、药品和化妆品法案》（FD&C法案）和根据这些法规颁布的法规的要求。受FDA管制的进口产品，在入境时须接受美国海关及边境保护局（CBP）的检查。不符合美国规例的进口产品会被扣留。此外，FDA还与CPB核实公司的进口许可证，可能进行随机抽样，并对不符合规定的产品发出进口警报。外国制造商必须持有美国许可证才能向美国进口生物制品。FDA与外部组织和外国政府密切合作，促进药品安全和监管的一致性。其工作包括：- 开发新的执法和监管工具；- 进行更多的外国检查；- 与外国监管机构和其他利益干系人合作；- 制定统一标准和标准趋同；- 教育行业代表了解其要求；以及- 提高供应链的透明度和问责制FDA内有几个办公室负责处理全球问题。监管事务办公室（ORA）负责检查和审查进入美国的产品。该机构的产品中心执行涉及其产品组合的政策和外联活动。全球政策与战略办公室（OGPS）是泛机构协调者、信息发布者，也是世界卫生组织等多边组织的联络点。全球政策和战略办公室还负责处理受管制产品的国际贸易和相互承认协议，促进与全球同行的信息共享，并管理食品及药物管理局在世界各地的驻外办事处。国际产品办公室（OIP）负责协调食品及药物管理局的国际工作，帮助促进与对口外国机构和国际组织的伙伴关系。国际产品办公室在世界各地的办事处侧重于特定地区：拉丁美洲（哥斯达黎加）、欧洲（布鲁塞尔、伦敦）、中国（北京）和印度（新德里）。3、国际安排FDA使用各种工具与其他国家建立伙伴关系，以促进产品安 全，这些工具可分为两类国际安排：合作安排和保密承诺（Confidentiality Commitments）。保密承诺为FDA与国际组织和其他国家的监管机构共享某些类型的非公开信息建立了法律框架，作为合作执法或监管活动的一部分。合作安排（Cooperative Arrangement）是一份书面文件，说明FDA、其他监管机构和国际组织参与合作活动的诚意。4、并行科学建议（Parallel Scientific Advice）欧洲药品管理局 (EMA) 和美国食品和药品监督管理局（FDA）共同采用的另一种全球化方法是建立一种机制，让专家在新医药产品（药物、生物制品、疫苗、先进疗法、纳米技术和儿科药物开发）的开发阶段就关键问题与申办者同时进行科学讨论。这有助于制药业和监管机构在产品开发的早期阶段主动参与。5、集群呼叫（Cluster Calls）包括美国食品药品监督管理局（FDA）、欧洲药品管理局（EMA）、加拿大卫生部、日本药品和医疗器械管理局（PMDA）以及澳大利亚治疗用品管理局（TGA）在内的多个卫生管理机构也制定了一项名为 "集群呼叫 "（Cluster Calls）的程序，以便在先进疗法（advanced therapies）（如细胞和组织产品）、生物类似药（biosimilars）、血液安全（blood safety）、肿瘤血液学产品（oncology-hematology products）和非临床肿瘤学产品（nonclinical oncology products）、孤儿产品（orphan products）、患者参与（patient engagement）、儿科产品（pediatric products）、药物基因组学（pharmacogenomics）、药物计量学（建模和模拟）（pharmacometrics (modeling and simulation)）、药物警戒（ pharmacovigilance）、罕见病（ rare diseases）、疫苗（ vaccines）和兽医医疗产品（veterinary medical products）。(并非所有这些机构都参与了所有集群）。FDA还是多个国际组织的成员或参与者，其中包括国际协调理事会、药品检查公约、药品检查合作计划、国际医疗器械监管者论坛以及推广国际食品标准的食品法典。除了自身的计划外，FDA还就国际问题与其他HHS和联邦机构广泛合作。在HHS（Health and Human Services (美国卫生与公众服务部）） 内部，Office of Global Affairs（OGA）全球事务办公室（OGA）与FDA及其他机构就贸易与健康、新兴传染病与全球健康安全、药品定价与报销、烟草控制与营养等问题开展合作。用他们自己的话说，"他们促进重要的全球关系，协调整个 HHS 和美国政府的国际参与，并提供全球卫生外交和政策方面的领导力和专业知识，为建设一个更安全、更健康的世界做出贡献"。OGA与美国国务院合作，并担任美国政府与世界卫生组织的联络人。6、欧洲药品管理局（EMA）欧洲药品管理局（EMEA）成立于1995年。它在欧盟（EU）各国开展工作，以评估人用和兽用药品为主要重点，保护人类和动物健康。它还为合作伙伴和利益相关者提供独立、公正、以科学为基础的药品信息。2009年底，该机构更名为欧洲药品管理局（EMA）。建立 EMA 的主要目的是在欧盟不同成员国的监管机构之间建立一个统一的流程。该机构还负责罕见病（rare diseases）、草药（herbal medicines）、儿童药物（medicines for children）和先进治疗药物（advanced therapy medicines）等专业领域的产品开发。直到2020年，英国一直是EMA的东道国。由于英国于2020年1月31日退出欧盟，EMA总部于2019年3月迁至阿姆斯特丹。EMA的独特之处在于药品授权的双重性。在欧盟，所有药品都必须获得上市许可（MA）后才能供患者使用。获得这种授权有两种方式。在集中程序下（Centralised Procedure），EMA会给出意见，从而为整个欧盟颁发单一的上市许可（MA）。根据国家MA程序，各成员国授权药品在其境内使用。大多数人用和兽用医药产品--包括生物技术和其他高科技方法衍生的产品，治疗艾滋病、癌症、糖尿病或神经退行性疾病的人类药物，以及所有指定的孤儿药--都要通过集中程序批准。EMA由一个独立的管理委员会管理，该委员会由 36 名独立成员组成。董事会的职责是确定EMA的预算、制定年度工作计划并确保该机构与合作组织有效合作。7、全球监管舞台上的EMA与FDA一样，EMA也承认国际合作的重要性和必要性。EMA认为这也将确保数据的完整性，以支持临床试验和生产，鼓励对药品的授权和监管采取全球方法，并避免不必要的重复工作。这种合作旨在通过促进全球监管资源的有效利用来提高效率。保密安排或相互承认协议（MRA）对于此类双边活动至关重要，欧洲药品管理局和欧盟委员会在所有国际活动中都大量使用这种安排或相互承认协议。保密安排有助于监管机构之间交流机密信息。关于良好生产规范（GMP）的相互承认协议允许欧盟当局依赖其他监管机构进行的GMP检查，在产品进入欧盟时免除批量测试，并共享与检查相关的信息和质量缺陷信息。欧盟与包括澳大利亚、巴西、加拿大、以色列、日本、新西兰、瑞士和美国在内的许多国家都有互认协议（MRAs）。EMA还通过具体的欧盟框架支持欧盟委员会与俄罗斯、印度和中国的合作。EMA还与国际人用药品技术要求协调委员会（ICH）、国际药品监管当局联盟（ICMRA）、国际药品监管机构论坛（IPRF）、世卫组织、欧洲委员会、经济合作与发展组织（OECD）、食品法典委员会、国际兽疫局（OIE）和欧洲自由贸易协会（EFTA）合作。此外，EMA还参与了多个项目，例如:• 欧盟-美国GMP检查相互依赖倡议;• 加强与中国和印度的合作;• ICH治理和科学改革;• 为孤儿药资格认定制定通用的FDA-EMA申请表和年度报告：• 国际仿制药评估试点;和• 埃博拉治疗方法的国际合作和预防。8、国际协调理事会（ICH）国际协调理事会成立于1990年，旨在建立监管机构与制药行业之间的协调。2015年10月，它根据瑞士法律改革为非营利性法律实体。其使命包括促进公众健康；为新药的开发、生产、注册和监管做出贡献；以及制定可由监管机构实施的技术指南。ICH的全球成员不断增加，包括成员、观察员和专家。最近，就连非专利药和非处方药行业也加入了ICH。ICH组织包括20个成员和36个观察员，分布在不同的监管机构，包括美国FDA、欧盟委员会、日本药品和医疗器械管理局、瑞士医疗器械管理局等，以及EFPIA（欧洲制药工业和协会联合会）和PhRMA（美国药品研究和制造商协会）等行业成员。准则的协调和制定是一个多步骤的过程，需要监管机构就准则的主题和内容达成共识，并在不同的ICH地区通过和实施。截至2023年3月，围绕安全、质量、疗效和多学科技术要求起草的 ICH 指导方针已超过70项。ICH的一些主要优势/成功之处包括:通用技术文件（CTD）和电子CTD（eCTD），将所有质量、安全性和有效性信息以通用、统一的格式汇集在一起，为所有ICH地区的监管机构所接受。- 通过制定科学和伦理方面的共同标准，在一个ICH地区进行的临床试验可用于其他ICH地区。- 监管活动医学字典（MedDRA）是一种高度特定的标准化医学术语，用于促进共享监管信息，这些信息用于医疗产品上市授权前后的注册、记录和安全监控。9、总论随着全球卫生机构认识到药物开发过程的全球化，并致力于支持安全、有效和具有成本效益的此类产品的开发，监管环境也在不断演变。FDA和EMA法规及ICH指南不断发展，以反映受监管产品的复杂性并实现公共卫生目标。它们在确保质量管理以及无偏见和无腐败地批准和使用这些药品方面发挥着关键作用，无论这些药品是进口还是出口到特定地区。英文原文（上下滑动查看更多）IntroductionThe first question we asked ourselves when the idea came up for this book was: Does the regulatory community really need it?The answer was an unequivocal “yes,” and here is why. We are both of an age at which chats with friends and family revolve around ailments and medication more often than we would like to admit. And, as healthcare industry professionals, we are often asked probing questions such as whether a vaccine really has as many side effects as the label says; why a drug costs so much; or why it has taken so long to develop an Alzheimer’s drug.Of course, this book is not written for our friends and family members, but really for the regulatory professionals who need to have the answers to such questions.So where do we find the answers? Sadly, the information is all over the place – there is an article here, a book chapter there. Some are in Chinese; some are in English; and others in yet another language. There was no single, comprehensive source for a global regulatory perspective on drugs and biologics.And that is why this book is an absolute necessity for regulatory professionals globally. Does it give you the answers to all and everything?That would be wishful thinking. It does, however, give you, dear reader, the single best source of authoritative regulatory information and guidance that our collaborative of more than 50 global expert authors and we, as editors, can bring you.We sincerely hope you will enjoy reading it and glean helpful bits of information that answer your questions – and maybe even those of your families and friends. And if you have a minute, do let us know your feedback.Table of ContentsSection I: General InformationChapter 1: Healthcare Landscape and Drug DevelopmentRuchi Gupta, MSChapter 2: The Drug Development Continuum, Preclinical to Market AccessDarlene Rosario, MBA, RAC-US; Pragnesh Donga, MPharm, MBA, RAC-Drugs; Kathrin Schalper, PhD, RAC-US, RAC-EU, RAC-Canada, RAC-DevicesChapter 3: International Harmonization via ICH, WHO, and other Global InitiativesAnu Gaur, PhD, MBA, MSRA, RAC-US, RAC-GlobalSection II: Nonclinical StudiesChapter 4: Principles of Good Laboratory Practice and Nonclinical DevelopmentKurt Stahl, BS; Jennifer G. Brown, PhD, RAC-USChapter 5: Safety Pharmacology StudiesCharlene F. Barroga PhD, DABT; Brian M. Roche, PhD, DSP, DABT; Simon Authier, DVM, PhD, MSc, MBAChapter 6: Pharmacokinetic and Toxicokinetic StudiesTyler Vandivort, PhD, RAC-Drugs, DABTChapter 7: Genotoxicity StudiesTyler Vandivort, PhD, RAC-Drugs, DABTChapter 8: Carcinogenicity StudiesTyler Vandivort, PhD, RAC-Drugs, DABTChapter 9: Developmental and Reproductive Toxicity AssessmentsCharlene F. Barroga, PhD, DABT; Alan M. Hoberman, PhD, DABT, ATSChapter 10: Regulatory Environmental Risk Assessment of Human PharmaceuticalsMargaret L. Fleming, PhD; Jennifer K. Saxe, PhDSection III: Chemistry, Manufacturing, and ControlsChapter 11: The Global Regulatory Process for the Registration of Active SubstancesDarlene Rosario, MBA, RAC-US; Yuwei Zhang, MD, PhD, MPH, MBA; Robert Falcone, PhD, FRAPS, FTOPRAChapter 12: Coordinating Drug Supply for Clinical and Nonclinical DevelopmentAjay Babu Pazhayattil, DBA, MPharm; Payal Shah, MS, RAC-USChapter 13: Pharmaceutical Development Studies and Manufacturing ExperienceKomalkumar Patel, MS; Nikolaos Zacharias, MSc; Kingman Ng, PhD; Beat U. Steffen, MSc, MBA, FRAPS; Nicole Beard, PhD, MScChapter 14: Analytical Development – Testing and StabilitySection IV: Clinical TrialsChapter 15: Conducting Clinical Trials: Drug Application Types, Data Requirements and Obtaining Marketing ApprovalSharry Arora, MPharm, RAC-DrugsChapter 16: Phases of Development (1,2,3,4)Rowena Cook, MS, RAC-Global; Amanda McEwen, MRes; Shuli Cui, MS, RAC-US; Stefanie Fasshauer, MBAChapter 17: Enhancing Diversity in Clinical TrialsMonique Carter, MS, RAC, FRAPS; Zaida Recinos-Vasquez, MSPS, MSRAQA; Leonor Pessanha Saldanha, PhD, MScChapter 18: Health Authority InteractionsChauneen Leah Wood, MS, RAC-US; Azzurra Ravizza, MSChapter 19: PediatricsLinda McBride, RPh, RAC-USChapter 20: Regional-Specific StudiesMantej (Nimi) Chhina, PhD, JD, MSc; Marjorie Zettler, PhD, MPHSection V: Marketing AuthorizationChapter 21: Framework for Benefit-Risk AssessmentCristina Damatarca, MD, PgDipChapter 22: eCTD and Digital ApplicationsAmrita Ghosh, RAC-US; Danini Marin, MSc; Katelyn Mulligan, MSChapter 23: Expedited Approval PathwaysYingying Liu, MS; Kathrin Schalper, PhD, RAC-CAN, RAC-Devices, RAC-EU, RAC-US; Ching Li, PhD; Christinne V. Villanueva, MS; Hongbo Pan, MBA;Grzegorz Podrygajlo, PhDChapter 24: Dossier RequirementsJesshanie Tabaniag, RPh; Kholoud Mamdouh Abdelfattah, MSc; Stefanie Fasshauer, MBA; Danini Marin, MSc; and Prashant Bhatia, MScSection VI: Postmarketing AuthorizationChapter 25: Postauthorization CommitmentsLinda McBride, RPh, RAC-USChapter 26: Transfers and RenewalsLinda McBride, RPh, RAC-USChapter 27: Product Extensions, Variations, and SupplementsLinda McBride, RPh, RAC-USChapter 28: ComplianceSiegfried Schmitt, PhD; Barbara Rusin, MS; Anne Marie Woodland, MS, RAC-EU, RAC-USChapter 29: RecallsChapter 30: Postmarket SurveillanceLinda McBride, RPh, RAC-USChapter 31: Advertising and PromotionTimothy A. Candy, PharmD, MS, BCPSChapter 32: Market Access: Reimbursement and PricingAnu Gaur, PhD, MBA, MSRA, RAC-US, RAC-Global; Parvarsha Nafees, PharmDAppendicesRegulations and Guidelines Across Chapters – Comparative MatrixAbbreviations and AcronymsGlossary of TermsIndexchapter 1 Healthcare Landscape and Drug DevelopmentHealthcare always has been – and is even more so today– a vital aspect of human life. The healthcare landscape continues to evolve and transform hand in hand with evolution in the medicinal product development field, now highly influenced by payer reform, technology, scientific advances, consumer demand, and more.These new realities and challenges impact how medicinal products are developed and approved. Previously, we lacked effective treatments for many life-threatening diseases; now, despite having many more treatments available, public scrutiny of healthcare has intensified. Patients and their families want new treatments sooner with accurate and understandable information on how to use them. While this has led health authorities to support innovation and advances in science and technology, it has also increased the complexity in the global regulatory landscape.The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) often are the regulators who first review these innovative treatments and lead the way in bringing efficacious and cost-effective treatments to the general and broader population.In addition, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) plays a critical role in global drug development by developing guidelines based on scientific discussions among regulatory authorities and the pharmaceutical industry. ICH guidelines are updated continuously and applied by an increasing number of health authorities worldwide. The mission of ICH is to achieve greater harmonization worldwide and ensure that safe, effective, and high-quality medicines are developed, registered, and maintained in the most resource-efficient manner while meeting high standards.Food and Drug AdministrationFDA, an agency of the US the Department of Health and Human Services (HHS), is responsible for protecting the public health by assuring the safety, efficacy, and security of human drugs and biological products, as well as other products outside the scope of this book. FDA’s mission includes advancing public health by supporting innovations that make medicines safer, more effective, and more affordable. The agency is tasked with providing the public with the accurate, science-based information they need to use medicinal products to maintain and improve their health. FDA plays a significant role in US counterterrorism efforts. The agency collaborates with other US agencies, international regulators, academia, trade associations, consumer groups, and others.Role in Global Regulatory LandscapeMany of the medicinal products consumed by people of leading nations such as the US are produced in other countries. In the US, FDA-regulated products are produced in over 130,000 facilities in more than 150 countries. The agency faces challenges in determining and confirming that its standards and requirements have been applied in the manufacture, distribution, and storage of medicinal products imported into the US. Given that the manufacture of a product may involve multiple parties from different countries, there are chances for the product to be improperly formulated or packaged, contaminated, diverted, counterfeited, or adulterated. Thus, compliance and surveillance activities overseen by regulatory bodies across the product life cycle are a critical part of the drug development process.FDA oversees the import and export of medicinal products to ensure that the FDA-regulated products comply with the requirements of the Food, Drug, and Cosmetics Act (FD&C Act) and the regulations promulgated under these statutes. Imported products regulated by FDA are subject to inspection at the time of entry by the US Customs and Border Protection (CBP). Imported products not in compliance with US regulations are subject to detention. Moreover, FDA verifies with CPB a company’s licensure for imports, may perform random sampling, and will issue import alerts for noncompliant products. A foreign manufacturer must have a US license to import a biological product into the US.FDA works closely with external organizations and foreign governments to promote product safety and regulatory consistency.Its efforts include:• developing new enforcement and regulatory tools;• conducting more foreign inspections;• collaborating with foreign regulators and other stakeholders;• developing harmonized standards and standards convergence;• educating industry representatives about its requirements; and• increasing transparency and accountability in the supply chainSeveral offices within FDA address global issues. The Office of Regulatory Affairs (ORA) inspects and reviews products offered for entry into the US. The agency’s product centers implement the policies and outreaches that touch their product portfolios.The Office of Global Policy and Strategy (OGPS) serves as a pan-agency coordinator, information distributor, and access point for multilateral organizations like the World Health Organization.OGPS also addresses international trade of regulated products and mutual recognition agreements, facilitates information sharing with its global counterparts, and manages FDA’s foreign offices worldwide.The Office of International Products (OIP) coordinates the FDA’s international work, which helps foster partnerships with counterpart foreign agencies and international organizations. OIP offices around the world focus on specific regions: Latin America (Costa Rica), Europe (Brussels, London), China (Beijing), and India (New Delhi).International ArrangementsFDA uses various tools to set up partnerships with other nations to promote product safety, and they fall into two categories of international arrangements: Cooperative Arrangements and Confidentiality Commitments. A Confidentiality Commitment sets up the legal framework for the FDA to share certain kinds of non-public information with international organizations and regulators in other countries as part of cooperative law enforcement or regulatory activities.A Cooperative Arrangement is a written document that describes the good-faith intentions of the FDA, other regulators, and international organizations to engage in cooperative activities.Parallel Scientific AdviceAnother globalized approach shared by the EMA and the FDA is establishing a mechanism for experts to concurrently engage in scientific discourse with sponsors on key issues during the development phase of new medicinal products (drugs, biologicals, vaccines, advanced therapies, nanotechnology, and pediatric drug development). It helps the pharmaceutical industry and regulatory agencies proactively engage early in product development.Cluster CallsVarious health authorities, including FDA, EMA, Health Canada, the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), and Australian Therapeutic Goods Administration (TGA), also have developed a process called ‘cluster calls’ to allow for increased collaboration and discussion of important topics in areas such as advanced therapies (e.g., cell and tissue products), biosimilars, blood safety, oncology-hematology products and nonclinical oncology products, orphan products, patient engagement, pediatric products, pharmacogenomics, pharmacometrics (modeling and simulation), pharmacovigilance, rare diseases, vaccines, and veterinary medical products. (Not all of these agencies necessarily participate in all clusters.)FDA also is a member or participant in several international organizations, including the International Council for Harmonisation,Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-operation Scheme, International Medical Device Regulators Forum, and Codex Alimentarius, which promotes international food standards.In addition to its own programs, FDA collaborates extensively with other HHS and federal agencies on international issues. Within HHS, the Office of Global Affairs (OGA) works with FDA and other agencies on such issues as trade and health, emerging infectious diseases and global health security, pharmaceutical pricing and reimbursement, and tobacco control and nutrition. In their own words, “they foster critical global relationships, coordinate international engagement across HHS and the U.S. government, and provide leadership and expertise in global health diplomacy and policy to contribute to a safer, healthier world.” OGA collaborates with the US Department of State and serves as the US government’s liaison to the World Health Organization.European Medicines AgencyThe European Medicines Evaluation Agency (EMEA) was founded in 1995. It worked across the European Union (EU) nations to protect human and animal health by evaluating human and veterinary medicines as their primary focus. It also provided partners and stakeholders with independent, unbiased, science-based information on medicines. The name was changed to European Medicines Agency (EMA) in late 2009.The main objective for establishing EMA was to have a harmonized process among the regulatory bodies of different member states within the EU. The agency also is responsible for products developed in the specialized areas of medicines for rare diseases, herbal medicines, medicines for children, and advanced therapy medicines. Up until 2020, the UK hosted EMA. Because the UK left the EU on 31 January 2020, the EMA headquarters moved to Amsterdam in March 2019.What is unique about EMA is the dual nature in which a medicinal product may be authorized. In the EU, all medicines must have a marketing authorization (MA) before they can be used by patients. There are two ways of obtaining this authorization.Under the Centralised Procedure, EMA gives an opinion, resulting in a single MA for the whole of the EU. Under national MA procedures, individual member states authorize the medicines for use in their territory.11 Most medicinal products for human and veterinary use – including those derived from biotechnology and other high-technology methods, human medicines for HIV/AIDS, cancer, diabetes, or neurodegenerative diseases, and all designated orphan medicines – are to be approved by the Centralised Procedure.EMA is governed by an independent Management Board composed of 36 independent members. The board’s role is to define EMA’s budget, develop the yearly work plan and ensure the agency works effectively with partnering organizations.EMA on the Global Regulatory StageLike FDA, EMA acknowledges the importance and requirement for international collaboration. It believes this will also ensure data integrity to support clinical trials and manufacturing, encourages a global approach to authorization and supervision of medicines, and avoid unnecessary duplication of efforts. Such a collaboration aims to create efficiencies by promoting the effective use of global regulatory resources.13 Confidentiality arrangements or mutual recognition agreements (MRAs) are critical for such bilateral activities and heavily used by EMA and European Commission to work closely in all international activities. Confidentiality arrangements facilitate the exchange of confidential information between regulators. MRAs on good manufacturing practice (GMP) allow EU authorities to rely on GMP inspections performed by other regulators, waive batch testing of products on entry into the EU and share information on inspection-related information and quality defects.The EU has MRAs with various countries, including Australia, Brazil, Canada, Israel, Japan, New Zealand, Switzerland, and the US. EMA also supports European Commission collaborations with Russia, India, and China through specific EU frameworks.EMA also works with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the International Coalition of Medicines Regulatory Authorities (ICMRA), the International Pharmaceutical Regulators Forum (IPRF), WHO, the Council of Europe, the Organisation for Economic Co-operation and Development (OECD), Codex Alimentarius, the Office International des Epizooties (OIE), and the European Free Trade Association (EFTA).Additionally, EMA is involved in multiple initiatives, such as:• EU-US Mutual Reliance Initiative on GMP inspection;• Increasing collaboration with China and India;• Reform of ICH governance and science;• Common FDA-EMA application form and annual report fororphan designation;• International Generic Medicines Assessment pilot; and• International cooperation on approaches to Ebola treatmentand prevention.International Council for HarmonisationICH was founded in 1990 to build harmonization between regulators and the pharmaceutical industry. It was reformed into a non-profit legal entity under Swiss law in October 2015. Its mission includes promoting public health; contributing to the development, manufacturing, registration, and supervision of new medicines; and developing technical guidelines that can be implemented by the regulatory authorities. ICH17 has grown in terms of its global membership, including members, observers, and experts.More recently, even the generic and over-the-counter industries have joined ICH. The ICH organization includes 20 members and 36 observers spread across various regulatory agencies, including the US FDA, EC, Pharmaceuticals and Medical Devices Agency (Japan), Swissmedic (Switzerland), etc., and industry members like EFPIA (European Federation of Pharmaceutical Industries and Association) and PhRMA (Pharmaceutical Research and Manufacturers of America.18 It also has numerous working groups with many experts working towards the process of harmonization and creation and implementation of ICH guidelines. The process of harmonization and development of guidelines is a multi-step process requiring consensus between regulators on the guideline topic and content to its adoption and implementation in various ICH regions. As of March 2023, over 70 ICH guidelines have been drafted on technical requirements around Safety, Quality, Efficacy, and Multidisciplinary. Some of the major advantages/successes of ICH include:Common Technical Document (CTD) and electronic CTD (eCTD), which brings together all Quality, Safety, and Efficacy information in a common, harmonized format accepted by regulators in all ICH regions.• Clinical trials conducted in one ICH region can be used in other ICH regions by setting the common standards on science and ethics.• Medical Dictionary for Regulatory Activities (MedDRA) is a highly specific, standardized medical terminology used to facilitate sharing of regulatory information used for registration, documentation, and safety monitoring of medical products before and after marketing authorization.ConclusionThere is an ongoing evolution in the regulatory landscape as health authorities worldwide acknowledge the globalization of drug development processes and are working towards supporting the safe, efficacious, and cost-effective development of such products. FDA and EMA regulations and ICH guidelines continue to evolve to reflect the complexity of regulated products and fulfill public health goals. They play a key role in ensuring quality management and bias- and corruption-free approval and use of these drugs, whether being imported or exported to their specific regions.更多优质内容，欢迎关注↓↓↓