Glycopin

同写意20岁庆！中国医药创新未来之路！“意”同创新，穿越周期，赢得未来。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”！本章重点介绍当前国际上的医药产品监管环境，包括全面概述国际人用药品技术要求协调理事会（ICH）和世界卫生组织（WHO）的关键作用，后者是联合国（UN）领导全球卫生生态系统倡议与合作的唯一机构。本章还讨论了致力于协调和持续改进全球监管流程以提高效率的国际组织。1历史遗产与法规对医药产品的监管源于使用不安全的产品以及由此引发的公共健康风险和悲剧。15世纪英国颁布的《药剂师器皿、药品和物品法》是早期颁布便于允许检查医药产品的生产来合法管制药品的典型例子。在美国，1902年的《生物制品管制法》（又称《病毒毒素法》）授权美国政府卫生实验室（美国国立卫生研究院的前身）监管生物制品（包括血清和疫苗）的生产。随后，1906年又颁布了《纯净食品和药品法》，禁止在州际贸易中对食品、饮料和药品进行掺假和掺杂。美国农业部化学局被授权执行这项法律，并于1930年更名为食品药品监督管理局（FDA）。1938年的《联邦食品、药品和化妆品法》（FD&C）规定，新药在上市前必须经证明安全有效，并扩大了FDA的权限，使其有权监管医疗器械和化妆品。在这些法律颁布之前，消费者面临着潜在的不安全、无效和掺假产品的风险。公共卫生悲剧，包括1937年美国的Elixir Sulfanilamide事件以及20世纪50年代欧盟和加拿大的沙利度胺悲剧，加速了现代有效法规的实施。根据1938年《食品药品管制法》，生物制剂（或生物制品）被视为药物，虽然该法的某些部分适用于生物制剂，但该法并未修改或取代最初的1902年《生物制品管制法》的规定；因此，这两部法律的规定都被用于监管生物制剂，监管权力由FDA和卫生实验室/NIH分担。1972年，包括疫苗和血清在内的生物制剂的监管工作由NIH移交给FDA。2监管机构的作用虽然不同地区和市场目前的发展水平（发达、发展中或新兴）可能会有不同的监管规定，但监管机构的作用始终如一：保护公众健康。监管机构的责任声明说明了这一点，下面举几个例子：印度中央药品标准控制组织 (CDSCO)：通过确保药品、化妆品和医疗器械的安全性、有效性和质量，保障并提高公众健康水平。澳大利亚治疗用品管理局（TGA）：通过有效、及时地监管治疗用品，保障并提高澳大利亚社会的健康水平。日本药品和医疗器械管理局 (PMDA)：通过确保药品和医疗器械的安全性、有效性和质量，保护公众健康。中国国家药品监督管理局 (NMPA)：负责药品（包括中药和民族药）、医疗器械和化妆品的安全监管。3药物尽管各个市场/地区的申报要求各不相同，但监管机构一般要求申办方提交数据和资料，表明研究疗法具有合理、令人满意的效益-风险比，以便获得市场批准。就非专利药而言，生产商必须提供证据，证明拟议产品与其前身创新药具有相同的疗效、安全性和性能特征。生产商必须能够满足其计划在其销售产品的每个国家的个别监管要求。其还必须遵守上市后的监控要求，以确保根据药品的风险概况对关键问题进行评估，并根据要求采取相应的行动。对药品的风险概况进行评估，并按要求采取行动。世卫组织将药物警戒（PV）定义为 "与检测、评估、了解和预防不良反应或任何其他药品/疫苗相关问题有关的科学和活动"。ICH药物警戒E2E准则也引用了这一定义，该准则指出，药物警戒 "描述了一种总结已确定的药物重要风险、重要的潜在风险和重要的缺失信息的方法，包括潜在的高危人群和可能使用该产品但尚未进行批准前研究的情况"。该指南还建议 "应对所有药物产品进行常规药物警戒"，并建议除特定地方要求外，还应满足常规药物警戒的要求：制定标准系统和流程，确保以可获取的方式收集和整理并向相关人员报告的所有可疑不良反应信息。为监管机构准备报告。快速报告药品不良反应。定期更新安全更新报告（PSUR）持续监测已批准产品的安全性概况，包括信号检测、问题评估、更新标签以及与监管机构联络。4生物制品生物制剂或生物产品是一类从生物体中提取的治疗产品。在生物制剂的生产过程中，这些原生生物/原液是通过生物反应器中的大规模细胞培养进行培育和纯化的。起源生物可以是病毒、细菌、酵母、植物细胞或动物细胞。生物制品比药品用途更广，可用于开发复杂的疗法，如疫苗、生长因子、免疫调节剂、单克隆抗体以及从人血和血浆中提取的产品。FDA将人体细胞、组织以及细胞和组织类产品（HCT/P's）区分为由其器械和放射卫生中心（CDRH）作为医疗器械监管的产品和由其生物制品评估与研究中心（CBER）监管的产品。5国际协调理事会（ICH）国际药品协调理事会成立于1990年，其宗旨是 "就如何进一步协调药品注册技术指南和要求的解释和应用提出建议，从而减少或避免在研究和开发人类新药过程中进行重复试验"。监管协调为全球监管机构和制药业保护公众健康带来了诸多益处。这种协调效应的主要好处包括：在不影响安全性和有效性的前提下，防止重复进行人体临床试验，最大限度地减少动物试验的使用；简化新药申请的监管评估程序；缩短药物开发时间，减少药物开发资源。这进一步强调了向全球利益相关者发出的关键和重要信息，即有必要开发安全有效的高效疗法，使患者能够获得治疗。ICH 的创始成员是来自美国、欧盟和日本等发达国家的监管机构和制药业代表。成员已扩大到许多其他国家和具有观察员地位的组织（见Table 3-1） 。ICH将其协调工作的透明度作为建立和维护公众信任的优先事项。ICH大会和管理委员会努力确保ICH过程保持透明，并认识到所有利益相关者都应了解有关重要决策的最新信息以及ICH指南制定的实时进展情况。2005年和2012年，该委员会分别采取措施，确保指南制定过程的所有部分都能尽快、清晰地在其网站上公开反映。ICH协调活动分为四类：正式的ICH程序（formal ICH procedures）、问答程序（Q&A procedures）、修订程序（revision procedures）和维护程序（maintenance procedures）。每项活动都可能需要一份概念文件（concept paper）和/或业务计划（business plan）（见Figure 3-1）。正式的ICH程序包括五个步骤。所有新的ICH主题的协调都遵循该程序。成立一个专家工作组（expert working group ,EWG），负责实施以下步骤和程序。步骤 1：达成共识• 工作小组根据概念文件中确定的目标，编写技术文件的共识草案。步骤 2a：确认关于技术文件的共识• 当大会根据EWG报告一致认为有足够的科学共识可使技术文件进入下一阶段的监管磋商时，即进入该步骤。步骤 2b：监管成员通过准则草案• 在技术文件的基础上，ICH监管成员将采取其认为必要的行动来制定准则草案。• 监管成员批准准则草案。步骤 3：监管磋商和讨论• 包括三个不同阶段৹ 阶段 I - 适用于区域监管磋商阶段。৹ 第 II 阶段--适用于在从咨询过程中获得所有意见后对区域咨询意见的讨论。৹ 第三阶段--是步骤3专家指南草案的定稿阶段。步骤3专家指南草案经监管EWG 签名后，提交给大会监管成员，请求通过。步骤 4：通过 ICH 协调准则• 大会一致认为已就指南草案达成充分共识。ICH监管成员通过步骤4的最终文件，将其作为ICH指南。步骤 5：实施• 按照适用于ICH对其他地区监管准则和要求的相同国家/地区程序实施。指导方针一旦进入正式程序的第5步，即由各自国家或地区的ICH监管成员和观察员实施。监管成员应根据ICH章程实施所有ICH指南/准则。监管观察员是ICH的无表决权成员；执行某些ICH指南是成为监管成员的先决条件。总体而言，ICH指南根据适用的国家、地区和/或地方规则实施，所有ICH指南的实施阶段也取决于成员或观察员加入ICH的时间。此外，ICH还对监管成员和观察员国家/地区进行调查，以了解ICH指南的实施和遵守水平及其适用性。ICH 指南主题分为四类，每类都有一个字母代码：1. Quality Guidelines (Q) 质量指南涉及稳定性研究的开展、杂质测试相关阈值的定义，以及基于现行良好生产规范（cGMP）风险管理的更灵活的药品质量方法。2.   Safety Guidelines (S) 安全指南 旨在通过体内和体外动物研究，揭示潜在的风险，如致癌性、遗传毒性和生殖毒性。3.    Efficacy Guidelines (E)疗效指 涉及人体临床试验的设计、实施、安全性和报告。这些指南还包括生物技术过程中产生的新型药物，以及利用药物遗传学/基因组学技术生产更有针对性的药物。4.   Multidisciplinary Guidelines (M) 多学科指南 为不完全或单一属于质量、安全和疗效类别的交叉主题提供指导。这些多学科指南包括ICH医学术语 （MedDRA）、通用技术文件（CTD），以及监管信息传输电子标准（ESTRI）的制定。全球数据协调工作ICH工作取得的一项具有里程碑意义的重要成就是，各方同意将所有与质量、安全性和有效性相关的数据信息以一种名为 "通用技术文件"（CTD）的标准格式进行整合。CTD在很大程度上消除了向不同ICH监管机构提交信息时重新格式化的需要。在许多国家，已被ICH监管成员接受的CTD可作为在相应市场审查研究产品的先例。CTD分为五个模块：- 模块1 针对特定地理区域，包括行政管理信息。- 模块2 包括质量、非临床和临床数据摘要。- 模块3 包括质量（CMC）数据。- 模块4 包括非临床数据。- 模块5 包括临床数据。ICH M4指导方针为提交纸质CTD提供指导，而M8指导方针则为提交电子CTD要求提供指导。2003年7月，CTD成为欧盟和日本新药申请的强制格式，并被强烈推荐用于提交给美国FDA的新药申请（NDA）。6世界卫生组织世界卫生组织（世卫组织，World Health Organization (WHO)）成立于1948年。世卫组织是联合国（United Nations， UN）唯一的机构，它将全球各国、合作伙伴和人民联系在一起，以促进健康，同时维护世界安全，为弱势群体服务，确保世界人口获得最高水平的健康。WHO的使命是围绕全球公共卫生提供全球领导和指导，并维护全球卫生生态系统。目前，世卫组织有194个成员国。世卫组织秘书处包括专家、工作人员和外勤人员，设在瑞士日内瓦。世卫组织在150多个国家设有区域办事处，这些办事处分布在以下全球区域：- 非洲- 美洲- 东地中海- 欧洲- 东南亚- 西太平洋世卫组织计划《第十三个工作总规划》（The Thirteenth General Programme of Work (GPW 13)）确定了世卫组织2019-2023年五年期战略。该方案侧重于实现三个十亿目标，以便在国家一级对人民健康产生可衡量的影响。基于COVID-19全球大流行对公共卫生造成的破坏，世卫组织将GPW 13延长至2025年。世卫组织参与了意义重大、影响深远的全球和区域公共卫生倡议。最近的一个例子是2020年4月启动的ACT（获取COVID-19工具）加速器伙伴关系。该伙伴关系是一项 "具有里程碑意义的合作，旨在加快COVID-19疫苗、诊断和治疗方法的开发、生产和公平分配"，汇集了十个主要的公共卫生和发展机构以及各国政府和非政府组织，以应对不断发展的大流行病形势。7国际组织、合作协议和伙伴关系下文概述了几个地区的国际和地区合作努力。药品检查合作计划药品检查合作计划（Pharmaceutical Inspection Co-operation Scheme (PIC/S)）成立于1995年，是1970年《药品检查公约》（PIC）的延伸。它是监管机构之间在人用或兽用医药产品良好生产规范（GMP）领域的一种不具约束力的非正式合作安排。PIC/S的主要任务是 "在国际范围内领导制定、实施和维护统一的药品生产质量管理规范（GMP）标准和检查机构的质量体系"。作为一个先驱组织，PIC/S在药品检查和GMP领域处于领先地位。自成立以来，PIC/S已成功地适应了不断变化的环境，特别是全球化环境，目前仍是全球唯一专门从事GMP工作的组织。自2023年起，PIC/S的任务将扩展到non-good practice（GxP，主要侧重于培训和标准领域的良好生产工艺 (GMDP)），这也符合PIC/S的新使命，即通过统一标准和为全球监管检查员提供世界一流的培训，领导制定和实施人用和兽用药品检查框架，努力改善公众健康。PIC/S愿意与全球任何拥有类似GMP检查系统的监管机构开展合作。目前，PIC/S有50多个全球监管机构参与。国际药品监管机构计划国际药品监管机构计划（International Pharmaceutical Regulators Programme (IPRP)）成立于2018年，旨在促进人用药品监管方法的趋同。IPRP的宗旨是为其监管成员和观察员创造一个环境，就共同关心的问题交流信息，促成合作，促进人用医药产品监管方法的趋同。其目标侧重于协助最大限度地提高潜在效率，以应对日益复杂的全球监管环境，促进ICH和其他国际协调的人用医药产品技术准则的实施。IPRP为其成员和观察员提供实实在在的好处，并致力于促进信息共享与合作，以推动公共卫生事业的发展，促进药品的获取，并应对共同关心的新出现的监管挑战。IPRP成员包括世卫组织和多个全球监管机构（见表 3-2）。国际药品监管机构联盟国际药品监管机构联盟 (International Coalition of Medicines Regulatory Authorities (ICMRA)）是一个由世界各个地区的主要监管机构自愿组成的行政级别联盟。它为药品监管机构提供全球战略焦点，并在共同的监管问题和挑战方面发挥战略领导作用。ICMRA的成立旨在应对全球当前和新出现的监管和安全挑战。国际制药商协会联合会国际制药商协会联合会（International Federation of Pharmaceutical Manufacturers and Associations (IFMPA)）是一家位于瑞士日内瓦的全球性非营利组织，代表以研究为基础的制药公司和协会。该组织与联合国有正式关系，并提供行业专业知识，帮助全球卫生界找到改善全球健康的解决方案。经济合作与发展组织经济合作与发展组织（Organisation for Economic Co-operation and Development (OECD)）成立于1961年，是一个拥有37个成员国的政府间经济组织，旨在促进经济进步和世界贸易。经合组织与各国政府、政策制定者和公民一起，致力于建立以证据为基础的国际标准，并为一系列社会、经济和环境挑战寻找解决方案。它为数据和分析、经验交流、最佳做法分享以及公共政策和国际标准制定方面的建议提供了一个独特的论坛和知识中心。伊斯兰合作组织伊斯兰合作组织（Organisation of Islamic Cooperation (OIC)）的前身是伊斯兰会议组织，是一个成立于1969年的国际组织，由57个成员国组成，其中49个是穆斯林占多数的国家。伊斯兰合作组织是 "穆斯林世界的集体声音"，致力于 "本着促进国际和平与和谐的精神，捍卫和保护穆斯林世界的利益"。8美洲泛美药品监管协调网络泛美药品监管协调网络 (Pan American Network for Drug Regulatory Harmonization）成立于1999年，并于2000年获得泛美卫生组织（PAHO）的正式认可。PANDRH的使命是 "促进药品质量、安全和疗效各方面的药品监管协调，为提高美洲成员国公民的生活质量和医疗保健水平做出贡献"。其协调工作包括处方药和非处方药（OTC）、非专利产品、类似生物制品、疫苗和草药。PANDRH 目前的成员包括泛美卫生组织所有成员国的药品监管机构、地区制药行业协会（ALIFAR、FIFARMA）、学术界、消费者团体和专业协会的代表。美洲五个次区域贸易一体化集团，如安第斯共同体、加共体（加勒比共同体）、中美洲一体化体系（中美洲）、南方共同市场（南美洲/南方共同市场）和北美自由贸易协定（北美自由贸易协定）的代表也加入了 PANDRH"。9欧洲欧亚经济联盟欧亚经济联盟（Eurasian Economic Union，EAEU/EEU）由白俄罗斯共和国、哈萨克斯坦共和国和俄罗斯联邦成立，旨在建立 "一个经济联盟，提供货物、服务、资本和劳动力的自由流动，并在联盟内由文件和国际协定确定的部门奉行协调、统一和单一的政策"。自2014年成立以来，欧亚经济联盟的成员已扩大到亚美尼亚共和国和吉尔吉斯共和国。欧亚经济联盟的协调工作正在取得进展。10亚太地区日本制药工业协会日本制药工业协会（JPMA）是一个自愿组织，目前拥有71家研发型制药公司会员。JPMA成立于1968年，以 "实现患者参与的医疗 "为宗旨，通过开发创新型新药为全球医疗保健事业做出了贡献。JMPA的目标是开发多方面的项目，重点解决影响制药行业的共同问题，加深对制药的理解，促进国际合作。作为ICH的创始行业成员，JMPA非常活跃。该集团还领导着亚洲制药协会会议（APAC）。东南亚国家联盟东南亚国家联盟Association of Southeast Asian Nations (ASEAN)（东盟）由印度尼西亚、马来西亚、菲律宾、新加坡和泰国的外交部长于1967年成立，此后又增加了以下成员国：文莱、柬埔寨。东盟在文化、经济和政治发展方面开展合作，包括监管协调方面的工作。东盟医药产品工作组（PPWG）成立于1999年，旨在制定 "东盟成员国医药法规协调计划， 以补充和促进[东盟自由贸易区]目标的实现"。该倡议特别注重消除法规对贸易造成的技术壁垒，同时不影响药品的质量、疗效和安全"。PPWG致力于新化学实体（NCE）生物制品、主要和次要变异产品以及非专利药品的协调工作。亚太经济合作组织亚太经济合作组织（Asia-Pacific Economic Cooperation (APEC)）成立于 1989年，由来自澳大利亚、文莱、加拿大、印度尼西亚、日本、韩国、马来西亚、新西兰、菲律宾、新加坡、泰国和美国的代表组成。目前，亚太经合组织成员包括澳大利亚、文莱达鲁萨兰国、加拿大、智利、中华人民共和国、中国香港、印度尼西亚、日本、韩国、马来西亚、墨西哥、新西兰、巴布亚新几内亚、秘鲁、菲律宾、俄罗斯联邦、新加坡、中国台北、泰国和美国以及越南。亚太经合组织的主要目标是 "支持亚太地区的可持续经济增长和繁荣"。亚太经合组织生命科学创新论坛（APEC Life Sciences Innovation Forum）成立于 2002 年，旨在引领医疗保健和健康科学创新。亚太经合组织生命科学创新论坛有来自政府、行业和学术界的代表参与。一年后，亚太经合组织LSIF监管协调指导委员会（RHSC）成立，目的是 "到2020年实现医疗产品监管审批程序的区域趋同。"LSIF是一个三方论坛，由来自政府最高行政级别、行业和学术界的代表共同参与，为生命科学创新创造正确的政策环境。目前，它有三个主要目标：1. 与国际标准和医疗服务相协调2. 促进经济和技术合作，包括能力建设3. 探索促进公私部门在生命科学创新方面合作的途径。目前正在亚太经合论坛 LSIF 和区域健康服务中心下实施的项目之一是 "促进多区域临床试验（MRCT）路线图"。在日本的倡导下，多区域临床试验路线图旨在 "促进多区域临床试验（MRCT）以及监管机构接受这些临床试验结果的审查"。亚洲协调工作组亚洲协调工作组（Asian Harmonization Working Party (AHWP)）成立于1996-97年，旨在加强亚洲地区的监管协调。AHWP的目标是 "研究和建议协调亚洲和其他地区医疗器械法规的方法，并与全球医疗器械监管论坛、亚太经合组织和其他相关国际组织协调工作，以建立统一的要求、程序和标准"。AHWP目前由来自31个成员经济体的监管机构和医疗器械行业的代表组成。最近，继2020年3月发布预公告之后，AHWP领导层正准备将亚洲协调工作组（AHWP）转变为全球协调工作组（Global Harmonization Working Party (GHWP)）。11非洲非洲药品监管协调组织许多非洲国家法律基础薄弱，缺乏专业技术知识，无法支持适当或有效的监管审查。因此，非洲药品监管协调组织（African Medicines Regulatory Harmonisation(AMRH)）应运而生，"以建立和完善与非洲人口安全、优质药品的监管和获取相关的标准和要求"。自2014年以来，非洲药品监管协调组织一直由非洲各国卫生部长领导，旨在通过监督 "选定药品清单的注册和协调非洲大陆的区域协调系统 "来实现其目标。西非国家经济共同体 西非国家经济共同体（Economic Community of West African States (ECOWAS)）由位于西非地区的15个成员国组成。它于1975年通过《拉各斯条约》成立。西非经共体的使命是促进成员国所有活动领域的经济一体化。西非经共体的愿景是建立一个无国界地区，在这个地区，人民可以获得丰富的资源，并能够在可持续的环境下通过创造机会利用这些资源。西非经共体成员国包括贝宁、布基纳法索、佛得角、科特迪瓦、冈比亚、加纳、几内亚、几内亚比绍、利比里亚、马里、尼日尔、尼日利亚、塞内加尔、塞拉利昂和多哥。— 结论 —  全球监管立法和法规影响着制药和医疗保健行业，也影响着患者对新兴和创新疗法的获取。近几十年来，监管框架和要求进一步发展，以保护公众健康，防止不安全产品的出现。世界各地的监管规定因多种因素而异，包括产品类别/类型、风险概况和分类以及当地监管体系的成熟度。监管要求和差异继续给驾驭监管环境带来挑战，并增加了对更好的监管框架和全球统一性的需求。加强和完善协调有助于降低成本，缩短上市时间，促进贸易，加强研发，使患者能够获得安全有效的产品。由政府、行业和学术界代表组成的几个小组和组织已经成立，以启动和继续实现协调目标。在进入自由化和全球化时代之后，发展中经济体的愿望集中于确保进入其市场的产品的安全和性能，这意味着全球统一的法规或基准将成为加强这一目标的重要工具。世界各国政府和监管机构都有责任不断审查本国的法规、监管立法、框架和程序，以确保其能有效促进本国人民的经济和社会福祉，保护公众健康。总之，除了确保患者获得高质量的医疗保健服务外，全球医疗保健、监管流程和协调工作中引入更新和创新疗法的全球基准仍是当务之急。这需要全球监管机构和组织以一致和快速的方式不断努力。英文原文（上下滑动查看更多）Chapter 3. International Harmonization via ICH, WHO, and other Global InitiativesThis chapter focuses on the current international environments for the regulation of medicinal products, including a comprehensive overview of the critical roles of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the World Health Organization (WHO,) which is the sole United Nations (UN) agency leading the initiatives and collaborations for the global health ecosystem. The chapter also discusses international organizations focused on harmonization and continuous improvements for efficiencies in the global regulatory processes.Historical Legacy and RegulationsThe regulation of medicinal products derives from the use of unsafe products and the resultant public health risks and tragedies. The Apothecary Wares, Drugs and Stuffs Act, enacted in 15th century England, is a classic example of an early effort to legally control medicines by allowing the inspection of medicinal product manufacturing.In the US, the Biologics Control Act of 1902, also known as the Virus-Toxin Law, provided the authority to the US government’s Hygienic Laboratory (a precursor of the National Institutes of Health) to regulate the manufacture of biological products, including serums and vaccines. It was followed in 1906by the Pure Food and Drugs Act, prohibiting misbranded and adulterated foods, drinks, and drugs in interstate commerce. Authority to enforce this law was given to the US Department of Agriculture’s Bureau of Chemistry, which became the Food and Drug Administration (FDA) in 1930. The Federal Food, Drug, and Cosmetic (FD&C) Act of 1938 required that new drugs must be proven to be safe and effective before marketing and extended the FDA’s authority, giving it purview over the regulation of medical devices and cosmetics.Prior to the enactment of those laws, consumers were exposed to risks from potentially unsafe, ineffective, and adulterated products. Public health tragedies, including the 1937 Elixir Sulfanilamide incident in the US and the thalidomide tragedy in the EU and Canada in the 1950s, fast-tracked the implementation of modern and effective regulations.Under the FD&C Act of 1938, a biologic (or biological product) was considered to be a drug, and while some parts of the law were applicable to the biologics, the law did not modify or supersede the provisions of the original Biologics Control Act of 1902; therefore, provisions of both laws were used to regulate biologics, and regulatory authority was split between FDA and the Hygienic Laboratory/NIH. Regulation of biologics, including vaccines and serums, was transferred from NIH to FDA in 1972.Role of RegulatorsWhile regulations may vary by region and by a market’s current level of development (developed, developing, or emerging), the role of the regulator remains the same: To protect the public health. This is illustrated in the statements of responsibility by regulators, as presented with a few examples below:• India’s Central Drugs Standard Control Organization (CDSCO): To safeguard and enhance the public health by assuring the safety, efficacy, and quality of drugs, cosmetics, and medical devices.• Australia’s Therapeutic Goods Administration (TGA): Safeguards and enhances the health of the Australian community through effective and timely regulation of therapeutic goods.• Japan’s Pharmaceuticals and Medical Devices Agency (PMDA): Protects the public health by assuring the safety, efficacy, and quality of pharmaceuticals and medical devices.• China’s National Medical Products Administration (NMPA): To supervise the safety of drugs (including traditional Chinese medicines [TCMs] and ethno-medicines), medical devices, and cosmetics.DrugsAlthough the individual market/region submission requirements vary, regulatory authorities generally require the sponsors to submit data and information indicating that the investigational therapy has a reasonable and satisfactory benefit-risk ratio for its market approval. In the case of generic drugs, the manufacturers must provide evidence that the proposed product has the same therapeutic efficacy, safety, and performance characteristics as its predecessor innovator drug.Manufacturers must be able to meet the individual regulatory requirements of each country in which they intend to market the product. They also must comply with postmarket monitoring requirements to ensure critical issues are assessed against thedrug’s risk profile and actioned, as required. WHO defines pharmacovigilance (PV) as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other medicine/vaccine-related problem.” This definition is also referenced in the ICH Pharmacovigilance E2E guideline, which notes that PV “describes a method for summarizing the important identified risks of a drug, important potential risks, and important missing information, including the potentially at-risk populations and situations where the product is likely to be used that have not been studied pre-approval.”The guideline also advises that “routine pharmacovigilance should be conducted for all medicinal products” and recommends that the requirements for routine PV, in addition to any local requirements:• Systems and processes to ensure information about all suspected adverse reactions reported to company personnel are collected and collated in an accessible manner.• Preparing reports for regulatory authorities.• Expedited Adverse Drug Reaction Reports.• Periodic Safety Update Reports (PSURs)• Continuous monitoring of approved products’ safety profile, including signal detection, issue evaluation, updating labeling, and liaising with regulatory authorities.BiologicsBiologics or biological products are a class of therapeutic products derived from living organisms. In the biologics manufacturing process, these origination organisms are grown and then purified using large-scale cell cultures in bioreactors. Originating organisms may be viruses, bacteria, yeasts, plant cells, or animal cells. Biologics are more versatile than pharmaceuticals and can be used to develop complex therapies such as vaccines, growth factors, immune modulators, monoclonal antibodies, as well as products derived from human blood and blood plasma. The FDA distinguishes between the human cells, tissues, and cellular and tissue-based products (HCT/P’s) that are regulated by its Centerfor Devices and Radiological Health (CDRH) as medical devices and those that are regulated by its Center for Biologics Evaluation and Research (CBER).International Council for HarmonisationEstablished in 1990, ICH aims “to make recommendations toward achieving greater harmonization in the interpretation and application of technical guidance and requirements for pharmaceutical product registration, thereby reducing or obviating duplication of testing carried out during the research and development for new human medicines.”Regulatory harmonization offers many benefits to both the global regulatory authorities and the pharmaceutical industry for protecting public health. The key benefits of this harmonization effects include the prevention of duplication of clinical trials in humans and minimizing the use of animal testing without compromising safety and effectiveness, streamlining the regulatory assessment process for new drug applications, and reducing the development times and resources for drug development. This further emphasizes the critical and vital message to the global stakeholders regarding the need for developing safe and effective efficiency in allowing patient access to therapies.Founding members of ICH were regulatory and pharmaceutical industry representatives from developed nations including the US, EU, and Japan. Membership has expanded to many other countries and organizations holding observer status (See Table 3-1).ICH prioritizes transparency regarding its harmonization work as one way to build and maintain public trust. The ICH Assembly and Management Committee works to ensure that the ICH process remains transparent and has recognized that all stakeholders should have current information on the important decisions and real-time progress of ICH guideline development. In 2005 and again in 2012, the council took measures to ensure all parts of the guideline development process were reflected publicly on its website as quickly and clearly as possible.ICH harmonization activities fall into four categories: formal ICH procedures, Q&A procedures, revision procedures, and maintenance procedures. For each activity, a concept paper and/or a business plan may be required (see Figure 3-1).The formal ICH procedure consists of five steps. It is followed for the harmonization of all new ICH topics. An expert working group (EWG) is established, which works on the following steps and procedures for implementation.Step 1: Consensus building• The EWG prepares a consensus draft of the technical document based on the objectives set out in the concept paper.Step 2a: Confirmation of consensus on the technical document• This step is approached when the assembly agrees, per the EWG report, that there is sufficient scientific consensus for the technical document to proceed to the next stage of regulatory consultation.Step 2b: Adoption of the draft guideline by regulatory members• Based on the technical document, the ICH regulatory members will take the actions they deem necessary to develop the draft guideline.• Regulatory members endorse the draft guideline.Step 3: Regulatory consultation and discussion• Comprised of three distinct stages৹ Stage I – This applies to the regional regulatory consultation stage.৹ Stage II – This applies to the discussion of regional consultation comments after ৹ btaining all comments from the consultation process.৹ Stage III – This is the finalization of Step 3 expert draft guideline. The Step 3 expert draft guideline with regulatory EWG signatures is submitted to the regulatory members of the assembly to request adoption.Step 4: Adoption of an ICH Harmonised Guideline• The assembly agrees that there is sufficient consensus on the draft guideline. The ICH regulatory members adopt the Step 4 final document as an ICH harmonised guideline.Step 5: Implementation• Implementation s carried out according to the same national/regional procedures that apply to other regional regulatory guidelines and requirements in the ICH regions.ICH Guidelines Implementation Once a guideline has reached Step 5 of the formal procedure, it is implemented by ICH regulatory members and observers in their respective country or region. Regulatory members are expected to implement all ICH guidelines based on the ICH Articles of Association. Regulatory observers are non-voting members of ICH; implementation of certain ICH guidelines is a prerequisite to becoming a regulatory member.Overall, ICH Guidelines are implemented under the applicable national, regional, and/or local rules, with the stage of implementation of all ICH Guidelines also being dependent on when a member or observer joined ICH. Further, ICH surveys the regulatory member and observer countries/regions to understand the level of implementation and adherence to the ICH guidelines and their applicability.ICH guidance topics are divided into four categories, and each is assigned a letter code:1.Quality Guidelines (Q) address the conduct of stability studies, define relevant thresholds for impurities testing, and foster a more flexible approach to pharmaceutical quality based on current good manufacturing practice (cGMP) risk management.2.Safety Guidelines (S) seek to uncover potential risks such as carcinogenicity genotoxicity, and reproductive toxicity in animal studies at both in vivo and in vitro levels.3.Efficacy Guidelines (E) are concerned with the design, conduct, safety, and reporting of human clinical trials. These guidelines also cover the novel types of medicines derived from biotechnological processes and the use of pharmacogenetics/genomics techniques to produce better-targeted medicines.4.Multidisciplinary Guidelines (M) provide guidance on the cross-cutting topics which do not entirely or uniquely fit into one of the Quality, Safety, and Efficacy categories. These multidisciplinary guidelines include the ICH medical terminology (MedDRA), the Common Technical Document (CTD), and the development of Electronic Standards for the Transfer of Regulatory Information (ESTRI).Global Data Harmonization EffortAn important and landmark achievement stemming from ICH efforts is the agreement to assemble all Quality, Safety, and Efficacy related data information in a standard format called the Common Technical Document (CTD).22 The CTD submission process has revolutionized the regulatory review processes, reduced time, and has led to harmonized electronic submission acceptance and good review practices. The CTD has largely eliminated the need to reformat the information for submission to the different ICHregulatory authorities. In many countries, a CTD that has been accepted by an ICH regulatory member can serve as precedent for the review of investigational products in the respective marketThe CTD is organized into five modules:• Module 1 is geographic region specific and includes administrative information.• Module 2 includes quality, non-clinical, and clinical data summaries.• Module 3 includes quality data.• Module 4 includes non-clinical data.• Module 5 includes clinical data.The ICH M4 guideline provides guidance on the paper submission of a CTD, whereas the M8 guideline provides guidance on the electronic CTD submission requirements.In July 2003, the CTD became the mandatory format for new drug applications in the EU and Japan and is strongly recommended for new drug applications (NDA) submitted to the US FDA.World Health OrganizationThe World Health Organization (WHO) was founded in 1948. WHO is the United Nations (UN) sole agency that connects global nations, partners, and people to promote health while keeping the world safe and serving the vulnerable to ensure that the world population has access to attain the highest level of health.WHO’s mission is to provide global leadership and guidance around global public health and to maintain the global health ecosystem. Currently, WHO includes 194 member states. The WHO Secretariat includes experts, staff, and field workers and is in Geneva, Switzerland. WHO operates regional offices in more than 150 countries, organized into the following global regions:• Africa• Americas• Eastern Mediterranean• Europe• South-East Asia• Western PacificWHO ProgrammeThe Thirteenth General Programme of Work (GPW 13) defines WHO’s strategy for the five-year period, 2019-2023. This programme focuses on triple billion targets to achieve measurable impacts on people’s health at the country level. Based on public health disruptions from the COVID-19 global pandemic, WHO extended GPW 13 to 2025.WHO has engaged in significant and impactful global and regional public health initiatives. A recent example is the ACT (Access to COVID-19 Tools) Accelerator partnership, launched in April 2020. The partnership, a “landmark collaboration to accelerate the development, production, and equitable distribution of vaccines, diagnostics, and therapeutics for COVID-19,” brought together ten leading public health and development agencies, as well as national governments, non-governmental organizations, in response to the developing pandemic situation. International Organizations, Cooperation Agreements, and PartnershipsThe following section outlines international and regional collaboration efforts in several regions.Pharmaceutical Inspection Co-operation SchemePharmaceutical Inspection Co-operation Scheme (PIC/S) was established in 1995 as an extension to the Pharmaceutical Inspection Convention (PIC) of 1970. It is a non-binding, informal cooperative arrangement between regulatory authorities in the field of good manufacturing practice (GMP) of medicinal products for human or veterinary use. The PIC/S primary mission is “to lead the international development, implementation, and maintenance of harmonised good manufacturing practice (GMP) standards and quality systems of inspectorates in the field of medicinal products”.As a pioneer organization, PIC/S leads in the field of pharmaceutical inspections and GMP. Since its establishment, PIC/S has successfully adapted to a constantly changing environment, particularly globalization, and it remains the sole organization worldwide that exclusively deals with GMP. PIC/S’ mandate from 2023 will be expanded to GxP with a primary focus on good manufacturing process (GMDP) in the field of training and standards, in line with the PIC/S new mission to strive to improve public health by leading the development and implementation of inspection frameworks for human and veterinary medicines, through harmonization of standards and offering world-class training to the regulatory inspectors around the globe.The PIC/S is open to collaborating with any global regulatory authority which has a comparable GMP inspection system. Currently, the PIC/S presently comprises more than 50 participating global regulatory authorities.International Pharmaceutical Regulators ProgrammeInternational Pharmaceutical Regulators Programme (IPRP) was established in 2018 to promote the convergence of regulatory approaches for pharmaceutical medicinal products for human use. The purpose of IPRP is to create an environment for its regulatory members and observers to exchange information on issues of mutual interest, enable cooperation and promote convergence of regulatory approaches for pharmaceutical medicinal products for human use. Their aim focuses on assisting in maximizing potential efficiencies in addressing the increasingly complex global regulatory environment to facilitate the implementation of ICH and other internationally harmonized technical guidelines for pharmaceutical products intended for human use. IPRP offers tangible benefits for its members and observers and is committed to promoting information sharing and collaboration to advance public health, facilitate access to medicines, and address emerging regulatory challenges of mutual interest.  IPRPmembers include WHO and multiple global regulatory authorities (see Table 3-2).Table 3-2. Members and Observers of the International Pharmaceutical Regulators ProgrammeInternational Coalition of Medicines Regulatory AuthoritiesThe International Coalition of Medicines Regulatory Authorities (ICMRA) is a voluntary, executive-level coalition of key regulators from every region in the world. It provides a global strategic focus for medicines regulators and gives strategic leadership on shared regulatory issues and challenges. ICMRA was created to address current and emerging regulatory and safety challenges globally.International Federation of Pharmaceutical Manufacturers and AssociationsThe International Federation of Pharmaceutical Manufacturers and Associations (IFMPA) is a global non-profit organization in Geneva, Switzerland, representing research-based pharmaceutical companies and associations. The group has official relations with the UN and contributes industry expertise to help the global health community find solutions that improve global health.Organisation for Economic Co-operation and DevelopmentThe Organisation for Economic Co-operation and Development (OECD) is an intergovernmental economic organization with 37 member countries, founded in 1961 to stimulate economic progress and world trade. Together with governments, policymakers, and citizens, the OECD works on establishing evidence-based international standards and finding solutions to a range of social, economic, and environmental challenges. It provides a unique forum and knowledge hub for data and analysis, exchange of experiences, best-practice sharing, and advice on public policies and international standard-setting.Organisation of Islamic CooperationThe Organisation of Islamic Cooperation (OIC), formerly the Organisation of the Islamic Conference, is an international organization founded in 1969, consisting of 57 member states, 49 of which are Muslim-majority countries. OIC is “the collective voice of the Muslim world” and works to “safeguard and protect the interests of the Muslim world in the spirit of promoting international peace and harmony.”The AmericasPan American Network for Drug Regulatory HarmonizationPan American Network for Drug Regulatory Harmonization (PANDRH) was established in 1999 and officially recognized by the Pan American Health Organization (PAHO) in 2000.PANDRH’s mission is to “promote drug regulatory harmonization for all aspects of quality, safety, and efficacy of pharmaceutical products as a contribution to the quality of life and health care of the citizens of the Member Countries of the Americas. Their harmonization efforts include prescription and over-the-counter (OTC) medicines, generic products, similar biologics, vaccines, and herbal medicines.The current PANDRH members are pharmaceuticals regulatory authorities of all PAHO member states, representatives of the regional pharmaceutical industry associations (ALIFAR, FIFARMA), academia, consumer groups, and professional associations. They are joined by representatives from the five sub-regional trade integration groups within the Americas, such as the Andean Community, CARICOM (Caribbean Community), SICA (Central America), MERCOSUR (South America/ Southern Common Market), and NAFTA (North American Free Trade Agreement).”EuropeEurasian Economic UnionEurasian Economic Union (EAEU/EEU) was established by the Republic of Belarus, the Republic of Kazakhstan, and the Russian Federation to create “an economic union that provides free movement of goods, services, capital, and labor and pursues coordinated, harmonized, and single policy in the sectors determined by the document and international agreements within the Union.” Since its establishment in 2014, the membership of the EAEU has expanded to include the Republic of Armenia and the Kyrgyz Republic. EAEU harmonization efforts are in progress.Asia-Pacific RegionJapan Pharmaceutical Manufacturers AssociationJapan Pharmaceutical Manufacturers Association (JPMA) is a voluntary organization with 71 research- and development-oriented pharmaceutical company members currently. Established in 1968, JPMA has contributed to global healthcare through the development of innovative new drugs under the motto of “realizing patient-participating medicine.” The JMPA aims to develop multifaceted projects focused on solving common problems affecting the pharmaceutical industry, deepening the understanding of pharmaceuticals, and fostering international cooperation. JMPA is active as a founding industry member of ICH. The group also leads the Asian Pharmaceutical Association Conference (APAC).Association of Southeast Asian NationsThe Association of Southeast Asian Nations (ASEAN) was established in 1967 by the Foreign Ministers of Indonesia, Malaysia, Philippines, Singapore, and Thailand and has since expanded to include the following additional member states: Brunei, Cambodia,Laos, Myanmar, and Vietnam. ASEAN collaborates in cultural, economic, and political development, including work in regulatory harmonization.36The ASEAN Pharmaceutical Product Working Group (PPWG) was established in 1999 to develop “harmonisation schemes of pharmaceutical regulations of the ASEAN member countries to complement and facilitate the objective of [ASEAN Free Trade Area]. The initiative was particularly focused on the elimination of technical barriers to trade posed by regulations, without compromising on drug quality, efficacy, and safety.” PPWG works on harmonization efforts for new chemical entities (NCEs) biotechnological products, major and minor variation products, and generic pharmaceutical products.Asian-Pacific Economic CooperationAsia-Pacific Economic Cooperation (APEC) was founded in 1989 by representatives from Australia, Brunei, Canada, Indonesia, Japan, South Korea, Malaysia, New Zealand, the Philippines, Singapore, Thailand, and the US. Currently, the APEC membershipincludes Australia; Brunei Darussalam; Canada; Chile; People’s Republic of China; Hong Kong, China; Indonesia; Japan; South Korea; Malaysia; Mexico; New Zealand; Papua New Guinea; Peru; the Philippines; the Russian Federation; Singapore; Chinese Taipei; Thailand; and the US; Vietnam. APEC’s primary goal “is to support sustainable economic growth and prosperity in the Asia-Pacific region.”The APEC Life Sciences Innovation Forum (APEC LSIF) was formed in 2002 to lead healthcare and health sciences innovation. APEC LSIF engages representatives from government, industry, and academia. A year later, the APEC LSIF Regulatory Harmonization Steering Committee (RHSC) was established to “achieve regionalconvergence on regulatory approval procedures for medical products by 2020.”The LSIF is a tripartite forum that engages representatives from the highest administrative levels of government, industry, and academia to create the right policy environment for life sciences innovation. Currently, it has three main objectives:1. Harmonization with international standards and health services2. To promote economic and technical cooperation, including capacity building3. To explore avenues to promote public-private sector collaboration in life sciences innovation.One of the projects currently being implemented under APEC LSIF and RHSC is the Roadmap to Promote Multi-Regional Clinical Trial (MRCT). Championed by Japan, MRCT aims to “facilitate multi-regional clinical trials (MRCT) and the acceptanceof these clinical trial results for review by regulatory authorities.”Asian Harmonization Working PartyThe Asian Harmonization Working Party (AHWP) was formed in 1996–97 to achieve greater regulatory harmonization in Asia. AHWP’s goals are “to study and recommend ways to harmonize medical device regulations in the Asian and other regions and to work in coordination with the GHTF, APEC, and other related international organizations aiming for establishing harmonized requirements, procedures, and standards.” AHWP currently is comprised of representatives from regulatory authorities and the medical device industry from 31 member economies. Most recently, following the pre-announcement issued in March 2020, the AHWP leadership is preparing the transformation of the Asian Harmonization Working Party (AHWP) into the GlobalHarmonization Working Party (GHWP).AfricaAfrican Medicines Regulatory Harmonisation Many African countries have insufficient legal foundations and lack the technical expertise to support adequate or efficient regulatory reviews. Therefore, African Medicines Regulatory Harmonisation (AMRH) was created “to establish and improve standards and requirements related to the regulation of and access to safe, high-quality medicines for the African population.” AMRH, which has been led by African health ministers since 2014, aims to achieve its objective by overseeing “the registration of a selected list of medicines and coordinate regional harmonization systems on the continent.” Economic Community of West African States The Economic Community of West African States (ECOWAS) is made up of 15 member countries located in the Western African region. It was established in 1975 via the treaty of Lagos. The ECOWAS mission is to promote economic integration in all fields of activity of the constituting countries. Its vision is the creation of a borderless region where the population has access to its abundant resources and is able to exploit the same through the creation of opportunities under a sustainable environment. The ECOWAS Member States include Benin, Burkina Faso, Cabo Verde, Côted’Ivoire, the Gambia, Ghana, Guinea, Guinea Bissau, Liberia, Mali, Niger, Nigeria, Senegal, Sierra Leone, and Togo. ConclusionGlobal regulatory legislation and statutes impact the pharmaceutical and healthcare industries and patient access to newer and innovative therapies. In recent decades, the regulatory framework and requirements have evolved further to protect public health and protect against unsafe products. Regulations vary worldwide based upon several factors, including product category/type, risk profile and classification, and maturity of the local regulatory system. Regulatory requirements and variations continue to create challenges in navigating the regulatory environment and increase the demand for a better regulatory framework and harmonization globally.Greater and well-integrated harmonization could help reduce cost and market time, facilitate trade, enhance research and development, and allow patient access to safe and efficacious products. Several groups and organizations comprising representatives fromgovernment, industry, and academia have been established to initiate and continue the harmonization objectives.After the era of liberalization and globalization, the desires of developing economies have been focused on ensuring the safety and performance of the product brought to their markets, which signifies that a globally harmonized regulation or benchmark would be an important tool for strengthening the same. All governments and regulatory authorities worldwide have a constant responsibility to review their country regulations, regulatory legislations, frameworks, and processes to ensure that they promote efficiently and effectively the economic and social well-being of their people and the protection of public health.In summary, the need for global benchmarks in global healthcare, regulatory processes, and harmonized efforts in bringing newer and innovative therapies apart from ensuring patient access to quality healthcare remains at the forefront. It requires continuous efforts from global regulatory authorities and organizations in a consistent and expedited manner.参考文献：（上下滑动查看更多）All references verified 31 January 2023.1.van Boxtel CJ, Santoso B, Edwards IR. Drug Regulation: History, Present and Future. In: Drug Benefits and Risks: International Textbook of Clinical Pharmacology, Revised 2nd Ed. IOS Press and Uppsala Monitoring Centre, 2008: 6 –77.2.Food and Drug Administration. 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