Fosdenopterin Hydrobromide

本期导读 在生物制品生产过程中，有可能受到内源性或外源性病毒的污染，从而危及患者的安全。病毒清除验证研究旨在评估生物制品下游纯化工艺在灭活和去除潜在病毒污染物方面的效果，以确保产品的安全性。 药明生物安全性检测团队深耕病毒清除验证领域逾十年，积累了1200多个新药临床试验申请（IND）以及150多个生物制品许可申请（BLA）病毒清除验证研究项目经验。承接上篇《科学制定生物制品病毒清除验证研究策略》，本文将进一步介绍如何高效地执行生物制品病毒清除验证研究。 为了避免将病毒引入GMP厂房，生物制品的病毒清除验证研究通常在第三方实验室进行。一个周密的研究计划对于确保病毒清除验证研究高效和顺利地开展至关重要。 那么，在病毒清除验证研究执行过程中有哪些要点需要关注？哪些工艺步骤具备稳定的病毒清除效果？ 药明生物安全性检测团队分享了他们的洞见。 高品质模型病毒是病毒清除验证研究 成功开展的基础 病毒清除验证研究通常包括预实验和正式加标实验两个阶段。预实验的目的是排除供试品对病毒检测系统的潜在影响和干扰。在加标实验中，模型病毒会添加至工艺中间品中，以评价某一下游工艺步骤的病毒清除效果。 高品质的模型病毒是成功进行病毒清除验证研究的基础。使用高纯度高滴度模型病毒可最大限度降低加标百分比，使缩小模型更能代表实际生产工艺。根据相关法规要求（EMA/CPMP/BWP/268/95），“病毒加标体积应小于10%”。同时，在制备高滴度模型病毒过程中需要避免发生病毒聚集，因为聚集的病毒更容易被过滤等物理方式去除，从而高估实际的病毒清除效果。 药明生物安全性检测团队通过特殊工艺制备的高纯度高滴度模型病毒，被用于除病毒过滤步骤和精纯层析步骤的病毒清除验证研究。研究中的加标百分比通常小于1%，可以显著减少过滤器堵塞、通量衰减等异常现象，从而保证相关研究的顺利进行。 同时，高纯度高滴度的模型病毒有助于稳健的下游工艺步骤获得更高的对数降低值（LRV）。因为对于给定的工艺步骤，LRV是通过工艺处理前后样品间的病毒量差值计算获得的。 病毒清除工艺步骤的选择 在病毒清除验证研究中，不需要对下游工艺中的所有步骤进行评价。如果通过有限的工艺步骤就能获得足够的总体LRV并满足安全性要求，就可以减少其它步骤的验证，从而帮助生产商节约成本和资源。 在生物制品下游纯化工艺中常用的病毒灭活和去除方法包括：低pH孵育、有机溶剂/去污剂处理、层析、除病毒过滤等。 低pH孵育 在抗体类产品下游工艺中，低pH孵育步骤通常衔接在Protein A亲和层析步骤之后，因为Protein A亲和层析大多使用低pH缓冲液进行洗脱。低pH条件会引起病毒表面电荷和蛋白空间结构的不可逆变化，从而使其失去感染性。 低pH孵育是一种有效的包膜病毒灭活步骤。药明生物安全性检测团队完成的超过2100个X-MuLV（异嗜性鼠白血病病毒）灭活实验结果显示，该步骤的平均LRV可达到6.2 log10。当孵育的pH值低于3.6时，所有实验的LRV均大于4 log10。 然而，低pH孵育不适用于大多数细胞和基因疗法（CGT）产品，因为存在损伤细胞或治疗载体的风险。但腺相关病毒（Adeno-associated virus, AAV）载体是一个例外。 有机溶剂/去污剂(S/D)处理 S/D可以破坏病毒包膜的脂质结构，使其丧失感染性。S/D处理是一种重要的包膜病毒灭活方法，尤其适用于不能耐受低pH条件处理的生物制品。 需要注意的是S/D组分对指示细胞有一定的毒性，因此在病毒检测过程中需要进行稀释处理，从而影响最终的LRV。在药明生物执行的近500个S/D灭活实验中，X-MuLV和PrV（伪狂犬病病毒）的平均LRV分别达到5.8 log10和5.9 log10。 在AAV载体下游工艺的前端，通常会使用去污剂（如吐温80）裂解细胞并释放AAV载体。该步骤也可用于包膜病毒的灭活。 除病毒过滤 除病毒过滤是基于体积排阻原理的专用病毒清除步骤。在抗体下游纯化工艺中，通常使用孔径为20nm的除病毒滤器。在药明生物安全性检测团队进行的2600多个MVM（鼠细小病毒）过滤实验中，平均LRV达到6.1 log10，仅有不到1.5%的实验对MVM的截留效果小于4 log10。 对于CGT产品，20nm孔径的滤器并不适用。根据CGT产品的具体特性，可以考虑采用35nm或50nm孔径的除病毒滤器截留大粒径病毒（如：杆状病毒、疱疹病毒、逆转录病毒等）。 层析 层析步骤（包括亲和层析、离子交换层析和混合模式层析等）原本用于纯化目标产品和去除宿主细胞蛋白（host cell proteins, HCPs）等杂质。但层析步骤同时具备一定的病毒去除效果，因此也被用于病毒清除验证研究。在抗体类产品病毒清除验证研究中，亲和层析和阴离子交换（Anion exchange, AEX）层析步骤的应用较为广泛。 在部分病毒载体产品（如AAV载体）的下游工艺中，也包括亲和层析和精纯层析等步骤。可考虑采用这些步骤去除潜在的病毒污染物。 选择经验丰富的第三方病毒清除实验室 病毒清除验证研究的执行涉及生产商、供应商以及第三方实验室，三者间的良好沟通与协作是病毒清除验证研究成功的关键。 经验丰富的第三方实验室掌握病毒学和下游工艺领域的专业知识，熟悉最新的病毒清除技术、病毒检测方法以及全球监管要求。并且能够根据产品及其工艺特点，充分评估相关风险并定制科学的研究方案，确保研究结果得到监管机构的认可。经验丰富的第三方实验室还能提供病毒清除工艺优化、病毒清除数据挖掘等全方位服务，帮助生产商管控和降低产品开发过程中的风险。 关于药明生物安全性检测中心 病毒清除验证研究服务 药明生物安全性检测中心，依托苏州和上海两地的BSL-2实验室，为全球客户提供符合法规要求的研发类（R&D）、新药临床试验申请（IND）和生物制品许可申请（BLA）等不同阶段的病毒清除验证研究服务，服务能力覆盖抗体、融合蛋白、ADC、重组亚单位疫苗、病毒载体、酶以及动物提取物等。 经验丰富的专业团队：120位科研人员，15位专题负责人，累计完成1400+病毒清除验证研究项目； 高标准质量体系：拥有完善的GLP/GMP质量体系，顺利通过全球监管机构和客户的300多次审计（包括30多次EU QP审计）； 高品质模型病毒：拥有12种模型病毒，可满足不同类型产品的病毒清除验证研究需求；制备的高纯度高滴度模型病毒可最大程度的降低对产品和下游工艺的潜在影响，确保病毒清除结果的准确性； 符合国际标准的病毒检测方法：建立了包括噬斑法，TCID50法和qPCR法在内的病毒定量检测方法，所有方法均严格按照ICH Q2的要求完成方法验证。经过验证的大体积样品检测可以显著提高稳健工艺步骤的病毒清除结果（LRV）； 完善的设施设备：拥有30多台AKTA Avant/Pure蛋白纯化系统以及12套客户实验室，随时响应客户需求。相关实验设备严格按照法规要求进行验证和校准，保证实验数据的可靠性。为到访客户提供专属的客户休息室，严格保护客户IP； 快速交付：病毒清除验证研究IND项目最短2个月交付，BLA项目最短3个月交付； 数据挖掘服务：独有的病毒清除验证研究数据库，海量数据助力客户提前预测相关步骤的病毒清除效果； Remote病毒清除支持服务：无需客户亲临现场，由训练有素的下游工艺服务团队根据技术转移方案，执行包括层析装柱、柱效测定、层析/过滤操作、缓冲液配制等各项工作； 客户无忧VIP服务：每个病毒清除验证研究项目均配备有专属项目经理（PM）和专题负责人(SD)，及时更新项目进展，快速响应客户需求。 如需了解更多生物药安全性检测服务 欢迎扫描下方二维码填写 我们的工作人员会尽快联系您 关于药明生物 药明生物（股票代码：2269.HK）是一家全球领先的合同研究、开发和生产（CRDMO）公司。公司通过开放式、一体化生物制药能力和技术赋能平台，提供全方位的端到端服务，帮助合作伙伴发现、开发及生产生物药，实现从概念到商业化生产的全过程，加速全球生物药研发进程，降低研发成本，造福病患。 药明生物在中国、美国、爱尔兰、德国和新加坡拥有超过12000名员工。通过药明生物的专业服务团队，以及先进技术和精深洞见，公司为客户提供高效经济的生物药解决方案。截至2024年6月底，药明生物帮助客户研发和生产的综合项目高达742个，其中包括16个商业化生产项目（不包括新冠项目和非活跃项目）。 药明生物将环境、社会和治理（ESG）视为业务发展和企业精神的重要组成部分，并致力于成为全球生物药CRDMO领域的ESG领导者，例如应用更绿色环保的新一代生物制药技术和能源等引领行业发展。公司成立了由首席执行官领导的ESG委员会，全面落实ESG战略并践行可持续性发展承诺。更多信息，请访问：www.wuxibiologics.com。

不同监管机构在法规要求方面的差异阻碍了药物研发的进程。为解决这一问题，美国食品和药物管理局（FDA）、欧洲药品管理局（EMA）和日本药品和医疗器械管理局（PMDA）已采取多项措施，寻求在法规要求方面达成一致，从而将药物研发项目所受的影响降至最低。 虽然理想的情况是所有监管机构的要求完全一致，但必须认识到，考虑到各监管机构运作所依据的监管和法律框架不同，这可能不是一个现实的期望。 本章将介绍临床试验和上市审批阶段的各种申报类型和数据要求，并指出全球不同市场区域之间的异同。 1 美国的药物申请类型 美国新药开发的两种重要申请类型是研究性新药申请（IND）和新药申请 （NDA）。新分子的临床研究（clinical investigations of a new molecule）必须在研究性新药（IND）申请中进行，以评估其安全性和有效性，而上市批准则通过新药申请程序获得。 01 研究性新药申请 向FDA提交IND是在美国市场开发新药的一个重要里程碑。在开始任何临床试验之前，必须填写并向FDA提交FDA 1571表。事实上，美国联邦法律规定，药品在跨州运输或分销之前，必须提交已获批准的申请（如IND）。因此，提交IND申请使申办者能够在州与州之间运输实验药物，这在进行多中心研究时非常重要。 根据FDA的规定，IND审查程序的主要目标是：“在研究的所有阶段，确保受试者的安全和权利（(assure the safety and rights of subjects）；在2期和3期阶段，帮助确保药物科学评估的质量足以允许对药物的有效性和安全性进行评估”。 ▏IND的类型和类别 FDA认可三种IND--研究者IND、紧急使用IND和治疗IND，以及两类IND--商业 IND和研究IND（The FDA recognizes three types of INDs – Investigator INDs, Emergency Use INDs, and Treatment INDs – and two categories of INDs – Commercial INDs and Research INDs.）。 首先来看不同类型的IND，研究者IND（Investigator IND）是由医生或医生小组提交的，其希望研究一种药物（已批准或未批准）在特定患者群体中或在新适应症中的效果。 如果没有足够的时间完成常规的IND申请程序，则可批准紧急使用IND（Emergency Use IND）；其可能是基于符合公共卫生利益的紧急需求，或病人在没有其他选择的情况下需要紧急治疗。最近批准紧急使用IND的一个例子是，根据《联邦法规汇编》第21卷第312节的规定，授权使用疫苗预防COVID-19。 治疗IND（Treatment IND）的目的是将未经批准的药物用于治疗严重或危及生命的疾病。这类IND在提交NDA或生物许可申请（BLA）之前提交。 至于不同的类别，商业IND是公司为获得新药上市许可而提交的，而研究IND则由研究人员提交。 ▏内容和提交 IND的内容和提交需遵循国际人用药品技术要求协调理事会（ICH）制定的通用技术结构（CTD）。 IND申请中必须包含的详细信息包括： 基于非临床试验（见Drug RA 6章）的研究药物药理学和毒理学信息。包括有关其作用机理和在特定适应症中的可能疗效的信息； 化学、生产和控制（CMC），包括药物成分和稳定性等细节，以及将使用的生产控制； 拟采用的临床方案：首次人体试验方案通常采用单剂量递增设计； 研究者信息，包括监督研究用药的专业人员（一般为医生）的姓名和资格（1572表和CV）； 研究者手册，提供有关研究药物的信息，以便安全地进行临床试验。 ▏开始临床试验 在开始任何临床试验之前，申办者必须在提交IND后等待30个日历日。这使FDA有时间对申请进行审查，并评估是否有足够的数据允许对人体安全施用试验药物。这也使FDA能够衡量试验对象的权利是否得到保障。 IND不会获得批准，而是在FDA收到后30天生效（INDs are not approved; instead, they become effective 30 days after they are received by the FDA）。除非FDA发现有任何理由将拟议的试验置于完全或部分临床暂停状态（place the proposed trial on full or partial clinical hold）。完全临床暂停是指IND申请的所有临床工作都被推迟或暂停，而部分临床暂停是指只有部分临床工作被推迟或暂停。 暂停还可能意味着不得向研究对象提供研究药物，或者如果研究正在进行，则不得招募新的研究对象。申办者应以书面形式对FDA提出的问题作出“完整答复”（‘complete response’）。然后，FDA将审查申办者的答复，并确定所提出的问题是否已得到充分解决，从而使IND申请得以重新开放（re-opened）。如果答复被认为是充分的，申办者就可以根据IND中详细说明的方案进行人体临床试验。 ▏修订和报告 需要向FDA提交年度报告，年度报告应作为报告IND研究状况的重点，并为来年的总体研究计划提供信息。IND后续修正案包含新方案或修订方案，应在先前提交的基础上进行逻辑上的调整，并应辅以更多的信息，包括动物毒理学研究或其他适当的人体研究结果。(Subsequent amendments to the IND that contain new or revised protocols should build logically on previous submissions and should be supported by additional information, including the results of animal toxicology studies or other human studies as appropriate)。 02 新药申请 新药申请是药品申办者请求FDA批准新药在美国销售和上市的正式途径。 新药申请必须包含有关研究药物的所有信息，包括非临床和临床试验结果及其生产细节，以便FDA能够评估该药物作为药品的安全性、有效性和质量。 申办者必须提供关于所有研究、数据和分析的报告，并且必须提供以下方面的详细信息： 拟议的标签（Proposed labeling） 安全性更新（Safety updates） 药物滥用的可能性（Drug misuse potential） 专利信息（Patent information） 任何在美国境外进行的研究数据（Any data from studies that may have been conducted outside of the US） 机构审查委员会合规信息（Institutional review board compliance information） 使用说明（Directions for use） NDA包括一封封面信（cover letter）和一份填写完整的FDA-356h表，以及其他辅助文件。21 CFR第314.50节描述了NDA的内容和格式；对于新化学实体，该节规定，NDA“一般包括一份申请表、一份索引、一份摘要、五或六个技术部分、患者数据的病例报告表、病例报告表、药物样品和标签”。NDA还应包括在非临床和临床试验中获得的数据，这些数据已包含在之前的IND中。(见表15-1）。 提交后，申办者最多需要等待60天，以便FDA对NDA进行初步评估，确定其是否“足够完整，可以进行实质性审查。如果FDA认为NDA不够完整，申请将被拒绝，并向申办者发出“拒绝申报 ”函（‘Refuse to File’ letter）。 这封信将具体说明申请未满足NDA的具体要求。然而，如果FDA发出“完整答复函”（‘Complete Response Letter’），这意味着NDA因实质性原因而不能批准。如果申请被接受提交，FDA将决定NDA是否需要标准或加速审查。该决定将在74天内通知申办者，并将根据《处方药用户费法》（PDUFA）VII中列出的绩效目标日期对申请进行审查。 2 在欧盟进行临床试验 欧洲药品管理局（EMA）的人用医药产品委员会（CHMP）负责评估在欧盟开展临床试验和获得上市许可的研究药物。申办者需要遵守EudraLex10第10卷规定的法律，并提交临床试验申请（CTA）。在欧盟提交CTA相当于在美国提交 IND。研究用医药产品档案（IMPD）是CTA的基本文件之一。 01 欧盟临床试验立法 有关在欧盟进行临床试验的立法最近发生了变化。欧盟临床试验条例536/2014 （EU-CTR）于2022年1月31日生效，取代了欧盟临床试验指令（EU-CTD）2001/20/EC。法规之间有3年的切换期，计划于2025年1月结束（表 15-2）。EU-CTR 536/2014规定的变更导致了EudraLex第10卷的修订和更新，其中包括与其使用相关的具体文件和与较早的EUCTD 2001/20/EC相关的其他文件。 02 临床试验申请和批准 根据EU-CTD 2001/20/EC，临床试验在欧盟国家层面获得批准，即由将开展临床试验的成员国主管机构批准。因此，在启动人体临床研究之前，研究用医药产品（IMP）的申办者需要提交临床试验申请（CTA），并获得其成员国主管机构的批准。2014年4月16日欧洲议会和欧盟理事会关于人用医药产品临床试验的第536/2014号欧盟法规就提交文件包中应包括的内容提供了指导。 在欧盟，CTA文件分为两部分（见表15-3）： - 第 I 部分包含提交给监管机构的文件（其中一些文件还需要伦理委员会审查）； - 第 II 部分只包含提交给伦理委员会的文件。 根据EMA13的规定，初始CTA评估的第I部分从提交审定决定后1天开始。整个第 I 部分评估可能需要45到76天，具体取决于EMA是否要求提供进一步信息。 03 研究药物档案 研究用医药产品卷宗（IMPD）是作为CTA卷宗的一部分提交的，应包括当时与临床试验相关的最新信息。IMP卷宗分为两部分--一部分涉及IMP的质量，另一部分涉及其安全性和有效性。质量部分包含活性药物的信息，如适用，还包括安慰剂和/或参比产品的信息。 安全和疗效部分包含所有非临床和临床研究的数据，并进行了风险效益评估。非临床和临床部分经常与试验研究者手册中的数据相互参照（Non-clinical and clinical sections are frequently cross-referenced to data in the trial’s investigator brochure）。 3 世界其他地区的数据要求 欧洲和北美仍在临床试验领域占据主导地位，截至2021年，世界卫生组织国际临床试验注册平台（ICTRP）所列的活跃商业临床试验机构中，70%以上位于这两个地区。然而，由于全球化程度的提高，临床试验目前正在更广泛的国家开展，尤其是在新兴市场。表15-4和表15-5对巴西、俄罗斯、印度、中国、南非（金砖五国）、亚太（APAC）和中东/北非（MENA）地区的临床试验和上市许可申请情况进行了比较。 01 巴西、俄罗斯、印度、中国和南非 巴西、俄罗斯、印度、中国和南非被视为发展中经济体，统称为金砖国家。在过去二十年里，这些国家的医药市场发展迅速，在临床试验和药品注册监管方面也发生了重大变化。 ▏金砖国家临床试验申请和批准情况 根据单一方案在一个以上国家或地区进行的临床试验越来越受欢迎。这是因为其使来自一个国家或地区的数据能够帮助在另一个国家或地区获得批准。这反过来又有助于在全球成功和及时地开发和注册药物。 在一些金砖国家开展多区域临床试验可能面临挑战。例如，在俄罗斯，除孤儿药外，所有新药的临床研究都必须在当地进行。直到最近，中国还规定必须在当地进行临床试验，然而，改革意味着现在有可能在中国进行全球I期试验。为了使海外数据能够用于中国的临床试验注册，申请人必须能够证明这些数据是可靠的、真实的和可追溯的。 试验必须遵循ICH制定的良好临床实践指导，并按照赫尔辛基宣言的规定保护受试者的安全、权利和福祉。研究药物的安全性和有效性数据必须在目标适应症中提供，申请人必须确保不存在可能影响这些数据的种族敏感性。最后，申请人必须确保数据符合中国药品注册的所有要求。 虽然巴西、印度和南非不要求在当地进行临床试验，但在欧盟委员会审查并批准CTA之前，总部设在欧洲的申请人不能在这些国家之一启动多地区临床试验。不过，监管机构和伦理委员会的审查可以在金砖五国和欧盟国家同时进行。 要在中国或印度开展临床试验，申请人必须在国内设有机构或代表处（To be able to conduct a clinical trial in China or India, the sponsor must have an in-country presence or representation）。药品稳定性研究需要根据各国的稳定性要求进行，巴西为IVb区，俄罗斯为I区，印度和南非为IV区，中国为II区。 ▏巴西的要求 在巴西，负责临床试验申请（CTA）审查和批准的监管机构是国家卫生监督局 （Agência Nacional de vigilica Sanitária，ANVISA）。为获得临床试验批准，申办者必须提交药物临床开发档案（DDCM）。机构伦理委员会审查并批准所有临床试验。DDCM应包括以下文件： - CTA表格 - 卫生监督检查费付款证明（或豁免证明） - 临床试验方案 - 试验已在世卫组织ICTRP或其他公认数据库中注册的证明 - 药物开发计划、 - 研究者手册 - 现有安全性信息摘要 - 研究药物和安慰剂的说明 - 研究药物的标签 - 非临床研究和以往任何临床研究的摘要 - 申办者与临床研究机构之间临床协议（clinical agreement）的认证副本 ANVISA有90天的时间对CTA进行审查，如果该机构未在此期限内做出答复，则可开始临床试验，前提是已获得所有伦理方面的批准。 ANVISA根据ICH成员国或英国药品和保健产品监管机构（MHRA）已批准的信息提交，发布了巴西药品快速通道审查指南。 ▏俄罗斯的要求 俄罗斯是欧亚经济联盟（EEU）的一部分，该联盟包括其他四个成员国：欧亚经济联盟包括白俄罗斯、哈萨克斯坦、吉尔吉斯斯坦和亚美尼亚。俄罗斯审批所需的CTA卷宗与欧盟的卷宗相似，必须包括申请书、国家税款缴纳证明、试验方案副本、研究者手册、研究者证书详情、知情同意书、分析证书和良好生产规范证书。不过，法律并未规定非临床和临床研究报告的格式。 不过，其内容与欧洲的IMPD类似，应包括研究产品的成分、临床前数据和任何临床数据、毒理学报告和任何疗效数据（包括非临床和临床数据）。审批时间大致为2至4个月。 ▏印度的要求 印度的国家监管机构是中央药品标准控制组织（CDSCO），该组织由印度药品总监（DCGI）或中央许可机构领导。根据美国国立卫生研究院（NIH）国家过敏与传染病研究所（NIAID）ClinRegs网站，CDSCO负责审批新药、开展临床试验、制定药品标准、监督进口药品质量、提供专家建议，以及协调各邦负责监管药品生产、销售和分销的许可机构。 CDSCO有90个日历日来决定全球临床试验申请（即在印度境外开发的药物），有30个日历日来决定本地试验。所有临床试验还必须获得机构伦理委员会的批准，批准时间为30天。如果试验对象是在印度境外（如美国或加拿大、英国、欧盟、澳大利亚或日本）已获批准的药物，则可免于进行本地试验。 ▏中国的要求 中国负责国家药品注册和临床试验的监管机构是国家医药产品监督管理局（NMPA）。更具体地说，国家药品监督管理局药品审评中心（CDE）负责评估临床试验申请和上市许可申请。一般来说，如果申请人在60个工作日后没有收到CDE的拒绝或澄清询问，则临床试验申请将被视为已获批准。在受理申请后，中国境外新药的CTA审批可能需要3-6个月的时间，这取决于该新药是否已在其他国家获得批准或是否满足了尚未满足的紧急医疗需求。 ▏南非的要求 南非健康产品管理局（SAHPRA）负责南非临床试验的监督、审批和检查。临床试验开始前必须获得SAHPRA和注册伦理委员会的批准，CTA审查和批准过程大约需要12到14周。向SAHPRA提交的主要文件包括研究者手册、临床试验方案和知情同意书。 其他重要文件包括研究者接受过良好临床实践培训的证明、开展试验的详细保险信息。SAHPRA在其2019年7月的指导文件中详细说明了如何申请药品注册，包括解释了不同的审查类型和快速审批途径。申请必须事先获得其他国家（如美国、欧盟、英国、澳大利亚或日本）监管机构的批准，才有资格获得其中一种快速审批途径。 ▏金砖国家的上市许可 金砖国家的上市许可申请可与美国、欧洲和日本的申请同时提交，并使用在这些主要市场进行的临床试验所收集的数据。申请表、一般信息和管理文件（application form, general information and administrative documents）是金砖国家的一般要求。印度、中国和南非也要求提交CTD摘要。在欧洲经济与货币联盟（EEU），使用与ICH CTD格式类似的电子eCTD格式。 02 亚太地区 亚太地区（APAC）是目前全球临床开发中发展最迅速的医药市场之一。亚太地区的语言、宗教、文化、经济以及监管要求多种多样。虽然该地区较小的国家有自己特定的规则和法规，但澳大利亚和日本等其他国家的药品注册程序与美国相当。 ▏亚太地区的临床试验申请与审批 不同国家的CTA流程各不相同，但有一些要素是相似的。一般来说，CTA的必备要素包括申请表、临床试验方案、研究者手册、研究者证书（日本、韩国和泰国除外）、知情同意书、病例报告表（韩国和泰国除外）、药物化学、生产和控制信息以及非临床研究和任何临床研究的数据。在许多国家（如日本、韩国和印度尼西亚），还需要提供一份声明，说明临床试验在科学上是合理的。监管机构对CTA进行评估的时间从几天到几个月不等，视国家而定。 在澳大利亚，人类研究伦理委员会（HREC）负责监督、审查和批准临床试验。临床试验提交 HREC批准后，治疗用品管理局（TGA）会向监管部门发出试验通知。在澳大利亚，研究未经批准的医药产品的临床试验可根据两种不同的计划进行：临床试验通知（Clinical Trial Notification，CTN计划和CTA计划。最常见的审批程序是CTN系统。这两种制度的不同之处在于，CTN是向澳大利亚药品管理局发出通知，而CTA则是由澳大利亚药品管理局进行评估。除非向TGA通报CTN试验，否则不得开始临床试验。与拟议试验有关的所有材料，包括试验方案，都直接提交给HREC，由HREC进行科学和伦理审查。CTA计划涉及TGA在试验开始前对相关但有限的科学数据（可能是临床前数据或早期临床数据）进行审查。在澳大利亚进行临床试验，要求申办者在国内派驻/代表。 在日本，临床试验的审批程序是按顺序进行的，申请首先由PDMA批准，然后由机构审查委员会 (IRB) 批准。日本有自己的良好临床实践标准，该标准与ICH制定的标准相一致。在提交 CTN之前，日本PMDA将进行检查，以确保所有适用标准都得到遵守，无论是科学标准、数据收集标准、分析标准、患者安全标准还是伦理标准。按照CTD药物申请的格式，大约需要 1-4 周的时间由 IRB 进行审查和批准。一旦获得IRB批准，即可开始临床试验。 韩国遵循与ICH指南相一致的韩国良好临床实践指南。IRB和独立伦理委员会（IEC）大多是地方性的，但也有少数医院集团通过中央IRB/IEC开展工作。IND申请可与IRB/IEC（ independent ethics committee（IEC)）程序同时进行。 在新西兰，监管机构Medsafe和健康与残疾伦理委员会 (HDEC) 要求申办者提交临床试验申请。在临床试验期间，申办者还需遵守持续的监管报告要求。 在新加坡，对未注册和已注册的本地药品进行临床研究必须申请临床试验证书（CTC）。申办者必须是在本地注册的公司组织，必须在线向卫生服务管理局提交CTC申请。该申请可与提交IRB和特定领域审查委员会（DSRB）的申请同时提交。 各研究机构可接受或拒绝联合机构审查委员会（JIRB）或中央机构审查委员会（CIRB）的决定，然后可由各自的机构审查委员会取而代之。 ▏亚太地区的上市许可 亚太地区的所有国家都要求在获得上市许可前提交NDA。NDA必须包括足够的数据，以支持新药品的疗效、安全性和质量。 在日本，如果需要，PMDA可能会安排一次面对面的会议。审查结束后，专家会将审查结果连同符合良好医疗规范的证据提交给厚生劳动省（MHLW）。经与药事和食品卫生委员会（PAFSC）协商，药品管理局为该局审查的药品颁发批准证书。 在较小的亚太地区国家，一般不要求进行本地临床试验，通常接受来自海外临床研究的数据。大多数国家要求提供原产国的药品证书（Certificate of Pharmaceutical Product，CPP）。亚太地区监管机构通常还需要额外的地区性文件，包括完整分析方法的细节、分析方法验证报告和其他原始数据。东南亚国家联盟（ASEAN）内的国家，包括新加坡、泰国和越南等，由于地处湿热或热带气候（即IV区），也有特定的药品稳定性要求。大多数国家都采用了东盟CTD，该CTD与ICH CTD相似，但作了局部修改。 03 中东和北非（MENA）地区 从东部的伊朗到西部的突尼斯和摩洛哥，中东和北非地区的临床试验监管多种多样。不过，该地区最近一直在努力协调监管要求，例如使数据展示保持一致，并确保为CTA卷宗提供类似的信息。 ▏中东和北非地区的临床试验申请与审批 中东和北非地区的临床试验申请由相关国家的伦理委员会审查，并以书面形式确认批准或拒绝。有些国家（如科威特）有一个中央伦理委员会，由其发表单一意见，但中东和北非地区的大多数国家都有地方伦理委员会。在大多数国家，负责监管的机构并不独立于卫生部。阿尔及利亚、巴林、约旦和沙特阿拉伯是例外。ICH良好临床实践指南以及当地法规都得到了遵守，而且大多数国家都有一个按顺序提交的流程。 这意味着只有在伦理委员会同意后，CTA才能获得主管监管机构的批准。黎巴嫩是唯一一个在开始临床试验之前不需要伦理委员会批准的国家。临床试验文件必须根据当地要求进行调整，各国要求不尽相同，但通常需要以下文件：CTA封面信、方案、知情同意书、IRB/伦理委员会批准证明、研究者手册副本、良好医疗实践证书和“研究药物分析证书”副本、拟议标签信息、病例报告表、临床试验协议副本以及临床 试验保险证明。CTA批准的时间因国家和拟议的临床试验类型而异。例如，在阿拉伯联合酋长国，审查可能需要45到90天。 ▏中东和北非地区的上市授权 中东和北非地区各国在获得上市许可方面存在很大差异。不过也有一些相似之处，几乎所有国家都使用CTD格式，尽管许多国家还不能提交电子CTD。值得注意的是，相关的研究用药产品必须在原产国获得有效的上市许可。 中东和北非国家属于III和IVa气候带（III为高原山地气候,IV为温带沙漠气候），因此必须提交特定的药物稳定性数据。 在大多数中东和北非国家，必须由当地代理进行沟通并向卫生当局提交。 海湾合作委员会成员国的药品注册由海湾药品注册中央委员会（GCC-DR）负责。海湾药品注册中央委员会是一个多国合作机构，巴林、阿曼、沙特阿拉伯、科威特、阿拉伯联合酋长国和卡塔尔都参与其中。自1999年以来，所有海湾国家和也门都可以通过单一的中央程序获得医药产品的销售许可。 申办者向GCC-DR提交上市许可档案，GCC-DR必须批准申请，医药产品才能在海湾国家上市。除海湾合作委员会-监管局集中授权的药品外，在其他国家获得销售授权的申请人不得向海湾国家的地方卫生当局提交任何申请。监管程序的统一加快了药品审批速度，使患者更容易获得药品，也使外国公司更容易进入中东和北非市场。 — 结论 — 当今世界需要利用全球临床试验来覆盖更广泛的人群，以支持安全、有效和可负担得起的药品的审批。这对于开发治疗罕见疾病的产品、阻止传染病的蔓延以及减轻非传染性疾病的影响至关重要。虽然在统一药品监管方面取得了很大进展，但仍有许多工作要做。在此之前，监管专业人员需要了解世界各地主管当局所要求的途径和流程。 监管趋同可以采取多种不同形式，从非正式努力到相互承认协议（from informal efforts to mutual recognition agreements (MRAs)）。这些举措通常侧重于提高透明度、协调机构间的互动、改善信息共享和集体决策（enhancing transparency, aligning interactions between agencies, and improving information- sharing and collective decision-making.） 参考文献：（上下滑动查看更多） All references verified 30 March 2023. 1. 21 CFR Part 312, Investigational New Drug Application. Current as of 21 March 2023. Accessed 25 March 2023. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312 2. Food and Drug Administration. Investigational New Drug Application (IND). Current as of 20 July 2022. Accessed 25 March 2023. https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application 3. Food and Drug Administration. Emergency Use Authorization for Vaccines to Prevent COVID-19. Current as of March 2022. Accessed 25 March 2023. https://www.fda.gov/regulatory-information/ search-fda-guidance-documents/emergency-use-authorization-vaccines-prevent-covid-19 4. European Medicines Agency. ICH guideline M4 (R4) on common technical document (CTD) for the registration of pharmaceuticals for human use - organisation of CTD (19 March 2021 EMA/CPMP/ICH/2887/1999). Current as of 19 March 2021. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-m4-r4-common-technical-document-ctd-registration-pharmaceuticals-human-use_en.pdf 5. Food and Drug Administration. IND Application Procedures:Clinical Hold. Current as of 10 September 2015. Accessed 25 March2023. https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-application-procedures-clinical-hold 6. Food and Drug Administration. IND Application Reporting: Annual Reports. Current as of 23 December 2015. https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-application-reporting-annual-reports 7. US Food and Drug Administration. New Drug Application (NDA). Current as of 21 January 2022. Accessed 25 March 2023. https://www.fda.gov/drugs/types-applications/new-drug-application-nda 8. 21 CFR 314 Applications for FDA Approval to Market a New Drug. Current as of 1 April 2019. Accessed 19 January 2023. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314 9. Food and Drug Administration. PDUFA VII: Fiscal Years 2023 – 2027. Accessed 19 January 2023. https://www.fda.gov/ industry/prescription-drug-user-fee-amendments/pdufa-vii-fiscal-years-2023-2027. 10. European Commission. EudraLex – volume 10 – clinical trials guidelines. Accessed 29 March 2023. https://health.ec.europa.eu/ medicinal-products/eudralex/eudralex-volume-10_en 11. Bly S, Khera A. Understanding the new EU Clinical Trial Regulation: seven things sponsors should know. European Pharmaceutical Review. Current as of 28 January 2023. Accessed 12 January 2023.https://www.europeanpharmaceuticalreview.com/article/168043/understanding-the-new-eu-clinical-trial-regulation-seven-things-sponsors-should-know/ 12. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Current as of 5 December 2022. Accessed 4 January 2023. http://data.europa.eu/eli/reg/2014/536 13. European Medicines Agency. FAQs How to evaluate a clinical trial application: assessment and decision. CTIS training programme– module 08, version 1.5. Current as of May 2022. Accessed 29 March 2023. https://www.ema.europa.eu/en/documents/other/faqs-how-evaluate-initial-clinical-trial-application-assessment- decision-ctis-training-programme_en.pdf 14. European Medicines Agency. Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials. Current as of 20 September 2017. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-chemical-pharmaceutical-quality- documentation-concerning-investigational_en.pdf 15. World Health Organisation. Number of clinical trials by year, country, WHO region and income group (1999-2021). Current as of February 2022. Accessed 6 January 2023. https://www-who-int.libproxy1.nus.edu.sg/observatories/global-observatory-on-health-research-and-development/monitoring/number-of-clinical-trials-by-year-country-whoregion 英文原文 （上下滑动查看更多） The differences in regulatory requirements across regulatory authorities is an impediment to speedy drug development. To address this concern, the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) have undertaken several steps to seek convergence on the regulatory requirements to minimize the impact on drug development programs. While it would be ideal to have completely harmonized requirements across all regulatory authorities, it is important to recognize that this is probably not a realistic expectation, considering the different regulatory and legal frameworks under which the agencies operate. This chapter takes a look at the various submission types and data requirements during clinical investigation and marketing approval stages, pointing out the similarities and differences between the various marketing regions of the world. Drug Application Types in the US Two important submission types for new drug development in the US are the investigational new drug application (IND) and the New Drug Application (NDA). While clinical investigations of a new molecule must be conducted under an investigational new drug (IND) Application to assess its safety and efficacy, the marketing approval is obtained through an NDA submission process. Investigational New Drug Application Submitting an IND to the FDA is a key milestone in developing a new drug for the US market. Before any clinical trials can start, Form FDA-1571 must be completed and submitted to the FDA.1 Indeed, US Federal law requires that a drug be the subject of an approved marketing application such as an IND before it is transported or distributed across state lines. Thus, filing an IND application enables a sponsor to ship an experimental drug between the states, which is important when conducting multi-center studies. According to the FDA, the primary objectives of the IND review process are, “in all phases of the investigation, to assure the safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety”.1 Investigational New Drug Application Submitting an IND to the FDA is a key milestone in developing a new drug for the US market. Before any clinical trials can start, Form FDA-1571 must be completed and submitted to the FDA.1 Indeed, US Federal law requires that a drug be the subject of an approved marketing application such as an IND before it is transported or distributed across state lines.Thus, filing an IND application enables a sponsor to ship an experimental drug between the states, which is important when conducting multi-center studies. According to the FDA, the primary objectives of the IND review process are, “in all phases of the investigation, to assure the safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety”. Types and categories of IND The FDA recognizes three types of INDs – Investigator INDs, Emergency Use INDs, and Treatment INDs – and two categories of INDs – Commercial INDs and Research INDs.2 Looking first at the different types, an Investigator IND is one that is submitted by a physician or group of physicians who are looking to study the effects of a drug, approved or unapproved, in a specific patient population or for a new indication.2 An Emergency Use IND may be granted when there is not enough time for the usual IND submission process. This may be where there is an urgent need that is in the public health interest or a patient needs to be treated urgently as there are no other options.2 A recent example of an Emergency Use IND being granted is the authorization for vaccines to prevent COVID-19 in line with stipulations set out in 21 CFR Section 312.1,3 Finally, the purpose of a Treatment IND is to make an unapproved drug available for the treatment of serious or immediately life-threatening condition. This type of IND is submitted before an NDA or biologic license application (BLA).2 As for the different categories, Commercial INDs are those which are submitted by companies to gain permission to market a new medication whereas researchers submit Research INDs.2 Content and submission The content and submission of the IND follows the common technical structure (CTD) developed by the International Council for Harmonisation on Technical Requirements for Pharmaceuticals for Human Use ICH. Details that must be included in an IND application are:1 •Information on the investigational drug’s pharmacology and toxicology, based on nonclinical testing (see Chapter 6). This includes information on its mechanism of action and likely efficacy in specific indications; •The manufacturer and manufacturing process, including such details as the drug’s composition and stability, and the manufacturing controls to be used; •Clinical protocols to be used: a first-in-human protocol is commonly a single ascending dose design; •Investigator information, including names and qualifications of the professionals (generally physicians) who will supervise the administration of the investigational drug; •Investigator’s Brochure, giving information on the investigational drug so that a clinical trial can be conducted safely. Beginning clinical trials Before any clinical trials can begin, the sponsor must wait 30 calendar days after the IND has been submitted.2 This allows the FDA time to review the application and evaluate whether there is enough data to permit the investigational drug’s safe administration to humans. It also enables the FDA to gauge whether trial subjects’ rights are guaranteed to be protected. INDs are not approved; instead, they become effective 30 days after they are received by the FDA. That is unless the FDA finds any reason to place the proposed trial on full or partial clinical hold.5 When an application is put on hold, it means that there are significant safety concerns regarding the use of the investigational.5 A complete clinical hold is when all clinical work requested under the IND is delayed or suspended, whereas a partial clinical hold is when only part of the clinical work is delayed or suspended. A hold may also mean that the investigational drug should not be given to study subjects, or that no new participants can be recruited if the study is on-going.5 The sponsor should provide a ‘complete response’ to the issue(s) raised by the FDA in writing.5 The FDA will then review sponsor’s response and determine whether the issues raised have been adequately addressed to enable the IND application to be re-opened.5 If the response is considered adequate, the sponsor can then conduct human clinical trials based on the protocol detailed within the IND.1,5 Amendments and reports When a drug is undergoing development, the IND needs to be updated regularly.6 Annual reports need to be submitted to the FDA and should serve as the focus for reporting the status of studies being conducted under the IND and inform the general investigational plan for the coming year. Subsequent amendments to the IND that contain new or revised protocols s hould build logically on previous submissions and should be supported by additional information, including the results of animal toxicology studies or other human studies as appropriate. New Drug Application The NDA is the formal means by which drug sponsors request that the FDA approves a new pharmaceutical drug for sale and marketing in the US.7 An NDA must contain all information regarding an investigational drug, including nonclinical and clinical trial results and details of its manufacturing, so that the FDA can evaluate the drug’s safety, efficacy and quality as a pharmaceutical product. Reports on all studies, data, and analysis must be included by the sponsor and the sponsor must provide details on: •Proposed labeling •Safety updates •Drug misuse potential •Patent information •Any data from studies that may have been conducted outside of the US •Institutional review board compliance information •Directions for use The NDA consists of a cover letter and a completed Form FDA-356h with other supportive documentations.7 21 CFR § 314.50 describes the content and format of an NDA; for a new chemical entity, this states that the NDA “generally contains an application form, an index, a summary, five or six technical sections, case report tabulations of patient data, case report forms, drug samples, and labelling”. The NDA should also include the data obtained during nonclinical and clinical trials that were included in the preceding IND. (See Table 15-1) After it has been submitted, the sponsor can expect to wait up to 60 days for the FDA to perform its preliminary evaluation of the NDA and determine whether it is “sufficiently complete to permit a substantive examination”.8 If the FDA deems that the NDA is not sufficiently complete, the application will be rejected, with a ‘Refuse to File’ letter being sent to the sponsor. This letter will specify which requirements of the NDA that the application did not meet. However, if the FDA issues a ‘Complete Response Letter’ this means that the NDA cannot be granted for substantive reasons. If the application is accepted for filing, the FDA decides whether the NDA requires a standard or accelerated review. This decision will be communicated to the sponsor within 74 days and the review of application will be performed based on performance goal dates listed in the Prescription Drug User Fee Act (PDUFA) VII.9 Conducting Clinical Trials in the EU The assessment of an investigational drug for the conduct of clinical trials and obtaining marketing authorization in the EU is carried out by EMA’s Committee for Medicinal Products for Human Use (CHMP). Sponsors need to adhere to legislation as set out in volume 10 of the EudraLex10 and submit a Clinical Trial Application (CTA). CTA submission in EU is equivalent to an IND submission in the US. The Investigational Medicinal Product Dossier (IMPD) is one of the essential documents of a CTA. EU legislation for Clinical Trials Legislation concerning the conduct of clinical trials in the EU has recently changed. The EU Clinical Trial Regulation 536/2014 (EU-CTR) came into effect on 31 January 2022 and replaced the EU Clinical Trial Directive (EU-CTD) 2001/20/EC. There is 3-year switchover period between the legislation which is scheduled to end in January 2025 (Table 15-2).11 Changes mandated by EU-CTR 536/2014 have resulted in revisions and updates to volume 10 of the EudraLex, with specific documents relating to its use and other relating to the older EUCTD 2001/20/EC.10 Sponsors should therefore take care when consulting this volume to ensure that they are referring to the relevant documentation. Clinical Trial Application and Approval According to EU-CTD 2001/20/EC, clinical trials are authorized at the national level in the EU, that is by the competent authority of the member state in which the clinical trial will be conducted. Thus before initiating clinical studies in humans, a sponsor of an investigational medicinal product (IMP) needs to file a clinical trial application (CTA) and obtain approval from the competent authority of their member state. Guidance on what to include in the submission packaged is given in EU Regulation 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use.12 In the EU, CTA documentation is divided into two parts (see Table 15-3): •Part I contains documents to be submitted to the regulatory authority (some of which will also need to be reviewed by the ethics committee); •Part II only contains the documentation to be sent to the ethics committee. According to the EMA13 Part I of an initial CTA assessment starts 1 day after the submission of the validation decision, This may be up to 10 days after the sponsor has submitted the CTA application. The entire Part I assessment can take anywhere between 45 to 76 days, depending on whether the EMA requests any further information. Investigational Medicinal Product Dossier An Investigational Medicinal Product Dossier (IMPD) is submitted as part of the CTA dossier and should include the most up-to-date information relevant to the clinical trial available at time. 12,14 The IMP dossier is divided in two sections – one on the quality of the IMP and one on its safety and efficacy.14 The quality part contains information on the active medicinal product and, if applicable, on the placebo and/or the reference product. The safety and efficacy part contains data from all non-clinical and clinical studies with a risk-benefit evaluation. Non-clinical and clinical sections are frequently cross-referenced to data in the trial’s investigator brochure. Data Requirements in the Rest of the World Europe and North America continue to dominate the clinical trials sector, with more than 70% of active commercial clinical trial sites listed in the World Health Organisation’s International Clinical Trials Registry Platform (ICTRP) up to 2021 being in these regions.15 However, due to increased globalization, clinical trials are now being conducted in a broader range of countries, particularly in emerging markets. An overview of the clinical trial and marketing authorization application in countries other than in the EU and North America is now provided, with tabular comparisons for Brazil, Russia, India, China, South Africa (BRICS), Asia-Pacific (APAC), and Middle East/North Africa (MENA) regions given in Table 15-4 and Table 15-5. Brazil, Russia, India, China, South Africa Brazil, Russia, India, China and South Africa are considered to have developing economies and are referred to collectively as BRICS countries. The pharmaceutical market in these countries has grown rapidly over the last two decades and significant changes have occurred in the regulation of clinical trials and drug registration. Clinical Trial Application and Approval in BRICS Countries Clinical trials conducted in more than one country or region under a single protocol are gaining popularity. This is because they enable data from one country or region to help gain approval in another country or region. This in turn helps with the successful and timely development and registration of medicines globally. There can be challenges for conducting multi-regional clinical trials in some BRICS countries. In Russia, for example, all clinical studies for new medicines must be conducted locally, with exception given for orphan drugs.16 Local clinical trials were also mandated in China until relatively recently, however, reforms have meant that it is now possible to conduct global phase I trials in the country.17-19 To enable overseas data to be used for clinical trial registration in China, sponsors must be able to show that the data are reliable, authentic and traceable. The trial must follow good clinical practice guidance set out by ICH20 with the safety, rights and well-being of the subjects protected as laid down in the Declaration of Helsinki. Data on the safety and efficacy of the investigational drug must be provided in the target indication and the sponsor must ensure that there are no ethnic sensitivities that might influence these. Finally, the sponsor must ensure that the data meet all the requirements for drug registration in China.20 While local clinical trials are not required in Brazil, India and South Africa, a European-based sponsor cannot initiate a multi-regional clinical trial in one of these countries until the European Commission has reviewed and approved the CTA. Regulatory authority and ethics committee review may, however, be conducted in BRICS21 and EU22 countries in parallel. To be able to conduct a clinical trial in China or India, the sponsor must have an in-country presence or representation.23 Pharmaceutical stability studies need to be performed in each country in accordance to their stability zone, which for Brazil is Zone IVb, for Russia is Zone I, for India and South Africa it is Zone IV, and for China is Zone II.24 Requirements in Brazil In Brazil, the regulatory authority in charge of clinical trial application (CTA) review and approval is the Agência Nacional de Vigilância Sanitária; (ANVISA).25 To gain approval to conduct a clinical trial the sponsor must submit a Drug Clinical Development Dossier (DDCM). The Institutional ethics committee review and approve all CTAs. The DCCM should include the following documents:25 •CTA form •Proof of Sanitary Surveillance Inspection Fee payment (or proof of exemption) •Protocol for Clinical Trial •Proof the trial is registered in the WHO’s ICTRP or other recognized database •Drug development plan, •Investigator brochure •Summary of available safety information •Description of the investigational drug and placebo •Labelling of investigational drug •Summary of non-clinical and any previous clinical studies •Certified copy of the clinical agreement between the sponsor and Clinical Research Organization ANVISA has 90 days to review the CTA and if the agency does not respond within this timeframe, clinical development can begin provided that all ethical approvals have been obtained.  ANVISA has released guidance on the fast-track review of drugs in Brazil based on submission of information that is already approved by an ICH member country or by the Medicines an Healthcare products Regulatory Agency (MHRA) in the UK. Requirements in Russia Russia is the part of the Eurasian Economic Union (EEU) which includes of four other member states: Belarus, Kazakhstan, Kyrgyzstan, and Armenia. The CTA dossier required for Russian approval resembles the EU dossier in that it must include an application letter, proof of payment of state duty, copy of the trial protocol, investigator’s brochure, details of the investigator(s) credentials, informed consent form, Certificate of Analysis and good manufacturing practice certificates. However, the law does not specify a format for reports on non-clinical and clinical studies. Nevertheless, the content is similar to the European IMPD and should include information about the composition of the investigational product, preclinical data and any clinical data, toxicology reports, and any efficacy data (both non-clinical and clinical). The approximate approval timeline is between 2 to 4 months. Requirements in India The national regulatory authority in India is the Central Drugs Standard Control Organization (CDSCO) which is headed up by the Drugs Controller General of India (DCGI) or Central Licensing Authority.27 According to the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases NIAID ClinRegs website:27 “CDSCO is responsible for approving new drugs, conducting clinical trials, establishing drug standards, overseeing the quality of imported drugs, providing expert advice, and coordinating the state licensing authorities who regulate the manufacture, sale, and distribution of drugs. CDSCO has 90 calendar days to decide about global clinical trial applications (i.e., for drugs developed outside of India) and 30 days for local trials. All clinical trials must be approved by the Institutional Ethics Committee also, and that approval takes 30 days. The need for a local trial may be waivered if the trial if for a drug already approved outside of India (e.g. in the US or Canada, the UK, EU, Australia, or Japan).27 Requirements in in China The regulatory authority responsible for national drug registration and CTAs in China is the National Medical Products Administration (NMPA).20 More specifically it is the NMPA’s Center for Drug Evaluation (CDE) that evaluates clinical trial requests and marketing authorization applications. In general, a clinical trial application will be considered approved after 60 working days if the applicant does not receive a rejection or an inquiry for clarification from the NMPA. After accepting the application, approval of CTAs with a new drug originating from outside China can take anywhere between 3-6 months to be approved, depending on whether it is already approved in another country or fulfils an urgent unmet medical need. Requirements in South Africa The South African Health Products Regulatory Authority (SAHPRA) is responsible for clinical trial oversight, approval, and inspections in South Africa.28. Approval from the SAHPRA and a registered ethics committee must be given before a clinical trial can begin, with the CTA review and approval process taking approximately 12 to 14 weeks. Key documents to submit to SAHPRA are the investigators brochure, the clinical trial protocol, and the informed consent form. Other important documentation is proof of good clinical practice training for the investigators, insurance details for the conduct of the trial. SAHPRA sets out details of how to apply for drug registration in its July 2019 guideline document.29 This includes explanation of the different review types and pathways for expedited approval. 29 To qualify for one of the expedited review pathways, an application must have received prior approval from a regulatory authority in another countries, such as the US, EU, the UK, Australia, or Japan.29 Marketing Authorization in BRICS Countries Applications for marketing authorization in BRICS countries can be submitted at the same time as in those in the US, Europe, and Japan, using data collected from the clinical trials conducted in these major markets. The application form, general information and administrative documents are general requirements in BRICS countries. CTD summaries are also required in India, China and South Africa.30 In the EEU an electronic eCTD format is used that is similar to the ICH CTD format.31 Asia-Pacific Region The APAC region is currently one of the most rapidly growing pharmaceutical markets for global clinical development. It is a diverse region with a variety of languages, religions, cultures, and economics, as well as regulatory requirements. While smaller countries within the region have their own specific rules and regulations, others, such as Australia and Japan, have drug registration procedures that are comparable to those in the US. Clinical Trial Application and Approval in the APAC Region The CTA process varies from one country to another, but there are elements of the process that are similar. Mandatory components of the CTA, in general, are an application form, clinical trial protocol, investigator’s brochure, investigator’s credentials (except in Japan, South Korea, and Thailand), informed consent form, case report form (except in South Korea and Thailand), information on the drug’s chemistry, manufacturing and controls, and data from non-clinical and any clinical studies. In many countries (i.e., Japan, South Korea, and Indonesia), a statement is also needed on why the clinical trial is scientifically justified. The duration of CTA assessment by the responsible regulatory body ranges from a few days to months, depending on the country. •In Australia, the Human Research Ethics Committee (HREC) is responsible for monitoring, reviewing, and approving clinical trials. After the submission of a clinical trial to HREC for approval, the Therapeutic Goods Administration (TGA) gives the regulatory notification of the trial. Clinical trials investigating unapproved medicinal products may be carried out in Australia under two different schemes: the Clinical Trial Notification (CTN) scheme and the CTA scheme. Most common process for approval is CTN system. The two schemes differ in that the CTN is a notification to TGA while the CTA is an evaluation process by TGA. A clinical trial must not start unless the CTN trial is notified to the TGA. All materials relating to the proposed trial,  including the trial protocol, are submitted directly to HREC, which provides scientific and ethical review. The CTA scheme involves the TGA’s review of relevant, but limited, scientific data (which may be preclinical or early clinical data) prior to the start of a trial. In-country sponsor presence/representation is required for conducting clinical trials in Australia.32,33 •In Japan, the approval process for clinical trials is sequential, with the application being first approved by the PDMA then by an institutional review board (IRB).34 Japan has its own good clinical practice standard that is harmonized with that produced by the ICH. Before a CTN can be submitted, Japan’s PMDA will check to make sure all the applicable standards are being adhered to, be that scientific, data gathering, analytical, patient safety, or ethical. The CTD drug application format is followed, with around 1-4 weeks for review and approval but the IRB. Once approval from the IRB is received, clinical trials can begin. •South Korea follows Korean Good Clinical Practice guidelines, which are harmonized with ICH guidance. The IRB and independent ethics committee (IEC) are mostly local., although a few hospital groups work via a central IRB/IEC,. An IND application may be processed in parallel with the IRB/IEC procedure.35 •In New-Zealand the regulatory body Medsafe and the Health and Disability Ethics Committees (HDECs) require that the sponsor submit an application to conduct a clinical trial. During the and to comply with ongoing regulatory reporting requirements.35 •In Singapore, a Clinical Trial Certificate (CTC) must be requested to conduct clinical studies on both unregistered and registered local pharmaceutical products. The sponsor must be an organization with local corporate registration has to submit the CTC application to the Health Services Authority online. This application may be submitted in parallel with those for the IRB and Domain Specific Review Board (DSRB).35 •Local and central ethics systems are used in Taiwan, with the latter used in multi-site trials.35 The decision of a Joint Institutional Review Board (JIRB) or Centralized Institutional Review Board (CIRB) may be accepted or rejected by the individual research institutes, who may then replace it with their own.35 Marketing Authorization in the APAC Region All countries in the APAC region require an NDA to be submitted before marketing authorization can be grated. The NDA must include sufficient data to support the efficacy, safety, and quality of a new pharmaceutical product. In Japan, the PMDA may schedule a face-to-face meeting if required. After review, the experts submit the results along with evidence of adherence to good medical practice to the Ministry of Health and Labor Welfare (MHLW). Upon consultation with the Pharmaceutical Affairs and Food Sanitation Council (PAFSC), the MHLW may approve the NDA. The PMDA delivers the approval certification for the drugs reviewed by the bureau. In the smaller APAC countries, local clinical trials are generally not required and data from overseas clinical studies are usually accepted. Most countries require a Certificate of Pharmaceutical Product (CPP) from the country of origin. APAC regulatory authorities also generally need additional regional documentation, including details of the full analytical methods, analytical method validation reports, and other raw data). Countries within the Association of South East Asian Nations (ASEAN), which includes Singapore, Thailand, and Vietnam, among others, also have specific pharmaceutical stability requirements as they are in hot and humid or tropical climates (i.e., zone IV). The majority of countries have adopted the ASEAN CTD which is similar to the ICH CTD, with local modifications.36,37 Middle East and Northern Africa (MENA) Region From Iran in the east to Tunisia and Morocco in the west the regulation of clinical trials in the MENA region is diverse. There have been recent efforts to harmonize regulatory requirements in the region, however, such as making data presentation consistent and ensuring that similar information is provided for the CTA dossier. Clinical Trial Application and Approval in MENA Region Clinical trial applications in the MENA region are reviewed by the relevant country’s ethical committee(s), with confirmation of approval or rejection provided in writing. While some countries, such as Kuwait, have a central ethical committee that issues a single opinion, the majority of countries in the MENA region have local ethical committees. In most countries, the responsible regulatory authority is not independent from the ministry of health; the exceptions are in Algeria, Bahrain, Jordan, and Saudi Arabia. ICH good clinical practice guidelines, as well as local regulations, are followed, and in most countries, there is a sequential submission process. This means that the CTA can only be approved by the responsible regulatory authority after the ethical committee has given the go-ahead. Lebanon is the only country that does not require ethics committee approval before starting a clinical trial.38 Clinical trial documentation must be adapted to local requirements, which vary from country to country, but the following documents are generally required: CTA letter, protocol, informed consent form, evidence of IRB/ethical committee approval, a copy of the investigator brochure, a copy of the good medical practice certificate and the ‘Certificate of Analysis of Study Drug’, proposed labeling information, case report forms, a copy of the clinical trial agreement, and evidence of clinical trial insurance. The timing of CTA approval varies by country and the type of clinical trial being proposed. In the United Arab Emirates, for example, the review may take anything from 45 to 90 days. Marketing Authorization in the MENA Region There are significant differences between countries in the MENA region in terms of obtaining marketing authorizations. 40,41 There are some similarities, however, with almost all countries using the CTD format, although submission of an eCTD is not possible in many countries yet. Of note, the investigational medicinal product in question must have a valid marketing authorization in the country of origin. MENA countries are categorized in climatic zones III and IVa; therefore specific pharmaceutical stability data must be submitted.  In most MENA countries, a local agent is required for communication and submission to the health authorities. Registration of pharmaceutical products in the member states of GCC is enabled by Gulf Central Committee for Drug Registration (GCC-DR). The GCC-DR is a multinational partnership with the participation of Bahrain, Oman, Saudi Arabia, Kuwait, United Arab Emirates, and Qatar. Since 1999, all Gulf States and Yemen have been able to obtain a marketing license for a medicinal product through a single central procedure. The sponsor submits the dossier for marketing authorization to the GCC-DR, which must approve the applications before the medicinal product can be marketed in Gulf countries. With the exception of drug that has been centrally authorized by the GCC-DR, a sponsor who is a marketing authorization holder in another country is not permitted to submit any application to the local health authorities of a Gulf country. The unification of regulatory processes has expedited the approval of medicines for access to patients and has made it easier for foreign companies to enter the MENA market.  Conclusion Today’s world requires the use of global clinical trials to reach a wider swath of the population to support the approval of safe, effective, and affordable medicines. This is crucial to developing products to address rare diseases, to stem the spread of communicable diseases, and to mitigate the impact of non-communicable diseases. While much progress has been made in harmonizing pharmaceutical regulation, must work still must be done. Until then, regulatory professionals will need to understand the pathways and processes required by competent authorities around the world. Regulatory convergence can take many different forms, from informal efforts to mutual recognition agreements (MRAs). These initiatives typically concentrate on enhancing transparency,aligning interactions between agencies, and improving information-sharing and collective decision-making. 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！ 长按关注本公众号  粉丝群/投稿/授权/广告等 请联系公众号助手 觉得本文好看，请点这里↓