中美欧开展同情用药管理制度及其合规关注要点

2024-02-15

抗体药物偶联物临床研究申请上市

为打造全球ADC/RDC未来产业高地，成都医学城拟于2024年4月18日-19日举办首届未来XDC新药大会！大会以“共创偶联药物产业未来”为主题，由同写意策划，安排一场主论坛和九场主题论坛，邀请“政、产、学、研、金、媒”各领域专家，通过“成果发布、主题演讲、热点对话、表彰颁奖、展览展示”五位一体的多元化的组织形式，迸发更多XDC产业新科技、新业态、新模式，构建XDC产业全新生态，触摸医药产业未来脉动。同情用药制度在促进国内外临床急需用药患者尽快获得试验用药，以及在合法的基础上加快临床试验用药物安全性数据的收集方面发挥了重大作用。由于在同情用药制度下用作治疗的药物尚未正式被批准上市，治疗的结果具有不确定性。因此，为了保护患者的合法权益，各国有必要对药企和临床试验机构采取严格的监管措施，以使其充分履行用药安全责任。同情用药作为一种较为关键的医疗手段，受到了美国和欧盟等多个国家和地区的广泛关注，并建立了较为完善的同情用药制度，为我国同情用药制度的发展和完善带来一些启发。本文将分别对同情用药在中国、美国和欧盟的法律法规和监管要求进行总结，并结合同情用药开展的实践案例为拟开展同情用药的医药企业厘清合规关注点，以减少可能存在的同情用药违规法律风险以及更好地保障国内外同情用药患者的生命健康等权益。1中国对同情用药的监管01同情用药相关法律法规我国2019年修订的《药品管理法》第23条首次在法律层面提出并确立了同情用药制度，并称为“拓展性临床试验”，但前述第23条仅为原则性规定，并未对同情用药制度执行层面的实施细则进行明确。2017年12月发布的《拓展性同情使用临床试验用药物管理办法(征求意见稿)》(“《同情用药管理意见稿》”)对拓展性临床试验的目标人群、适用情形、申请人和申请程序等做出了较为详细的规定，但目前[1]该办法尚未正式颁布实施。在国家层面的法律框架下，2023年3月1日起施行的《深圳经济特区细胞和基因产业促进条例》作为地方性法规对细胞和基因药物拓展性临床试验的适用条件、审查主体、风险提示、退出与终止等方面进行了具体规定，为同情用药的发展起到了一定引领作用。从国家和地方层面对同情用药相关法律法规部分总结如下：02开展同情用药的监管要点1、同情用药的适用条件在现行有效的《药品管理法》的基础上，我国的同情用药制度仅有框架且尚不完善。但《药品管理法实施条例（修订草案征求意见稿）》和《同情用药管理意见稿》作为探索确立同情用药制度的过程性文件，具有参考指导意义。在前述征求意见稿文件框架项下，开展同情用药的适用条件包括但不限于以下几点：值得注意的是，在同情用药方面，深圳规定了更为审慎的要求。《深圳经济特区细胞和基因产业促进条例》要求拟开展细胞和基因药物拓展性临床试验的药物注册申请人已经完成支持新药品上市注册的临床试验阶段并向国家药品监督管理部门提交上市许可申请（“NDA”），体现出对同情用药安全更加审慎的态度。2、同情用药的审批程序根据现行有效的《药品管理法（2019修订）》第23条，同情用药需“经审查”，但未明确申请主体、审查主体和审查程序。参照《药品管理法实施条例（修订草案征求意见稿）》和《同情用药管理意见稿》的要求，主要涉及如下两方面的关注要点：（1）申请主体针对申请主体，根据《同情用药管理意见稿》的规定，申请主体为注册申请人，一般情况下，药品的注册申请人为医药企业。该点要求与《医疗器械拓展性临床试验管理规定（试行）》的要求有所区别，患者、申办者或者研究者可提出开展医疗器械拓展性临床试验。（2）审查主体和审查程序针对审查主体和审查程序，《同情用药管理意见稿》与《药品管理法实施条例（修订草案征求意见稿）》的规定也有所不同。《同情用药管理意见稿》第5条要求注册申请人向国家药监局药品审评中心申请并获得批准，还要求注册申请人应在“药物临床试验登记与信息公示平台”登记拓展性同情使用临床试验用药物的相关信息，收集相关安全性数据。而《药品管理法实施条例（修订草案征求意见稿）》仅要求经过伦理委员会审查同意，上述两者均未生效。实践中已有医药企业在“药物临床试验登记与信息公示平台”登记同情用药情况，2020年7月23日，罗氏在药物临床试验登记与信息公示平台官网登记一项《阿替利珠单抗（Atezolizumab）一线治疗三阴性乳腺癌患者拓展性同情使用方案》，该研究参加机构为重庆医科大学附属第一医院，计划在国内招募50例患者，目的是将阿替利珠单抗在中国大陆获批适应症上市前能将其提供给急需的患者，使得三阴性乳腺癌患者能尽早获得有效治疗手段，并基于法规要求收集药物安全性数据。[2]此外，从北京协和医院一位阵发性睡眠性血红蛋白尿症（PNH）患者同情用药的实践案例来看，同情用药的开展除了经过北京协和医院伦理委员会的伦理审查，国家药监局也按照《药品管理法（2019修订）》规定在合法合规的前提下全力推进临床试验的审批流程，开启了同情用药制度在我国的破冰之路。[3]3、同情用药的管理根据《同情用药管理意见稿》对同情用药的定义，同情用药是临床试验的一种形式，因此在开展过程中需参考《药物临床试验质量管理规范》（“GCP”）。参考《医疗器械拓展性临床试验管理规定（试行）》，医药企业、研究者、临床试验机构和伦理委员会应参照GCP的要求承担各自的责任，针对同情用药建立相应的临床试验质量管理体系。4、同情用药的费用针对费用问题，鉴于GCP中明确规定了研究者在临床试验过程中，不得向受试者收取试验用药所需的费用，同时结合《同情用药管理意见稿》第13条的规定，原则上不允许医药企业在药品同情用药期间向患者收取临床试验用药物费。03违规开展同情用药的法律后果由于开展同情用药是在临床试验之外使用未经上市审批的药品，药品使用单位可能被认定为使用假药劣药，被按照销售假药、零售劣药的规定处以罚款；情节严重的，法定代表人、主要负责人、直接负责的主管人员和其他责任人员（“相关责任人员”）有医疗卫生人员执业证书的，还应吊销执业证书。违规开展同情用药也可能被认定为未经批准开展药物临床试验，从而被处50-500万元罚款；情节严重的，吊销药品批准证明文件、药品生产许可证、药品经营许可证，对相关责任人员处2-20万元罚款，十年直至终身禁止从事药品生产经营活动。[4]此外，由于同情用药是涉及以人为研究参与者的科技活动，需经过伦理审查，未按照规定获得伦理审查批准擅自开展同情用药的，将被有管辖权的机构依据法律、行政法规和相关规定给予处罚或处理；造成财产损失或其他损害的，依法承担民事责任；构成犯罪的，依法追究刑事责任。[5]2美国对同情用药的监管01同情用药相关法律法规美国的同情用药制度起源于20世纪70年代，1987年美国食品药品管理局（“FDA”）在《美国联邦法规》正式确立了同情用药制度，对适用标准及提交申请的条件等做出了明确规定；1997年的《食品药品管理现代化法案》明确了同情用药的三种情形；2016年美国国会通过的《21世纪治愈法案》对医药企业的公开义务进行了详细的规定，并进一步细化了同情用药的实施细则，总体已建立起较为完善的同情用药制度。实践中，2023年9月22日，美国马里兰大学医学中心表示继开创全球先例后，他们通过同情用药制度完成全球第二例将转基因猪心脏移植给患者的手术[6]；以及根据《新英格兰医学杂志》（NEJM）2020年6月11日的报道，在53名因重症Covid-19住院的患者中，有36人（68%）接受了同情性使用静脉注射吉利德科学（Gilead Sci.）公司研制的瑞德西韦（Remdesivir）的治疗，临床症状有所改善，衡量疗效还需要持续进行瑞德西韦治疗的随机安慰剂对照试验。[7]但针对允许进行同情用药的瑞德西韦（Remdesivir），FDA于2021年2月4日警示HCP不要在同情用药情形之外使用该药物，并指出该药物未经FDA批准，也未经FDA评估其安全性、有效性或质量[8]。02开展同情用药的监管要点1、同情用药的申请条件根据CFR第312.300节，“同情用药”是指“患者患有危重症疾病，处于危及生命或在几个月内发生死亡的合理可能性的疾病阶段，在当前没有可比性或者令人满意的替代疗法来诊断、监测、治疗该病症且不在临床试验组别中，患者可以申请IND治疗”。根据CFR.312的规定，申请同情用药需满足以下标准：（1）患者患有危及生命的疾病或状况；（2）已经穷尽现有已上市药品等来诊疗前述疾病；（3）患者无法入组临床试验；（4）IND已获得一定的安全性、有效性数据，经评估患者使用该IND的潜在获益大于疾病本身所带来的风险；以及（5）同情用药的使用不影响该IND的研发及临床试验。2、同情用药的基本类型参考FDA的同情用药问答指南[9]，根据FDA现行规定，同情用药可以划分为3种基本类型：（1）用于单个患者的同情用药，包括紧急使用（21 CFR 312.310）；（2）用于中等人群的同情用药，通常小于治疗型IND或治疗方案的典型规模--治疗方案由现有IND的申办者作为现有IND的方案提交（21 CFR 312.315）；（3）治疗型IND或治疗方案，常用于招募大量患者为其提供更广泛的治疗（21 CFR 312.320）。3、同情用药的审批程序根据21 CFR 312.305(b)，所有类型的同情用药都需经过FDA审批，不同类型同情用药所需的FDA审批时间如下：以单个患者IND的程序为例，根据21 CFR 312.310以及21 CFR part 56，单个患者IND治疗申请首先需由患者委托主治医生联系医药企业以确保其愿意提供药物，获得医药企业的授权书（LOA），该授权书授权FDA查阅该企业提交的IND申请信息；之后由医生或医药企业的临床研究负责人向伦理委员会（Institutional Review Board，“IRB”）提交IND治疗申请；IRB批准后方可继续向FDA的药品审评与研究中心（CDER）或生物制品审评与研究中心（CBER）申请IND治疗。FDA在同情用药审批上实行严格把关、高批准率的原则。在进行风险收益评估时， FDA必须确定病情严重或立即危及生命，没有类似或令人满意的替代疗法，而且准入不会干扰关键临床试验，其中：(1)对于治疗型IND的同情用药申请，FDA要求必须找到足够的安全性和有效性证据，通常包括临床试验III期的数据，但也可能包括已完成的临床试验II期中令人信服的数据；(2)而对于单个患者IND的申请，则只需医师判断IND治疗风险低于疾病本身即可。[10]4、同情用药的管理（1）充分的知情同意为确保患者被告知他/她将接受一种试验性产品的治疗，以及该产品的安全性和有效性可能存在不确定性，FDA要求患者充分知情同意。（2）IRB审查除了在没有足够时间进行预期IRB审查的紧急使用的情况下，研究者在开展同情用药治疗患者时，有责任在开始使用研究药物治疗前通过符合条件的IRB审查。（3）同情用药的政策公开值得注意的是，《21世纪治愈法案》SEC. 3032要求开发研究药物（包括生物制品）的公司应将其有关评估和响应同情用药请求的政策公开，包括公开联系方式、请求的程序、评估和回应单个患者要求获得临床试验药物的请求的标准，以及在公共网站上发布同情用药的实施计划以及促进病危或急需治疗的患者参加同情用药项目。在里根-尤德尔基金会的扩展访问导航器外部链接免责声明上发布此信息，包括描述其研究药物政策的公司自己的网页的链接，可用于满足此要求。当公司开发多种研究药物时，可以为其每种研究药物制定不同的同情用药政策，并按上述名称单独发布这些政策。[11]（4）同情用药的费用根据21CFR312.8中对于同情用药收费的规定，同情用药的医药企业必须在开始对IND治疗收费前完成一定工作并获得FDA的书面授权。根据21CFR312.8(d)(1)，FDA规定医药企业只能收回在同情用药中为受试者提供药物的直接成本，包括按FDA已批准临床试验所需数量生产药物的成本，或从其他来源获得药物的成本，以及运送和储存药品等所产生的费用。03违规开展同情用药的法律后果如医疗专业人员或组织使用存在潜在安全风险、缺乏有效性证据的未经批准的药物，它们可能会受到FDA的执法行动，这些行动可能通常涉及以下一项或多项措施：请求自愿遵从；在《联邦纪事》公告中发布行动通告；发布无标题信函；发布警告信；或启动查封、禁令或其他程序。[12]根据《21世纪治愈法案》的信息封锁条款[13]，医疗信息技术开发者不得采取任何构成信息封锁的行动。对于医疗服务提供者，“信息封锁”的法律适用标准是指他们是否知道该做法不合理，是否可能干扰电子健康信息的访问、交换或使用[14]。若医药企业没有履行同情用药政策公开的义务，可能会认定为构成信息封锁，而被美国卫生与公共服务部的审计长调查，转交给相应机构，根据适用的联邦法律接受适当的抑制措施[15]。3欧盟对同情用药的监管01同情用药相关法律法规2020年4月3日，欧洲药品管理局（“EMA”）建议吉利德 GILD的瑞德西韦（Remdesivir）应用于治疗COVID-19的同情用药项目中，并向欧盟成员国提供了关于在其国家实施瑞德西韦扩大可及方案的建议，除了扩大可及方案之外，吉利德还以个例为基础，继续为儿童和孕妇提供瑞德西韦的同情用药。截至2020年4月4日，已有1700多名患者通过这些方案获得治疗。[16]EMA的人用药委员会（Committee for Medicinal Products for Human Use，CHMP）于2007年7月发布了关于同情用药的官方指南《医疗产品同情用药指南》。虽然EMA在推进同情用药方面做了许多工作，但由于其法规和指南非约束性的特点，使得每个成员国仍需严格按照各国相应的法律程序来引入和实施同情用药。欧盟针对同情用药的具体监管相关法律法规如下[17]：02开展同情用药的监管要点1、同情用药的申请条件根据《医疗产品同情用药指南》第3条的规定，同情用药需要满足以下条件：（1）申请主体应为患有慢性或严重疾病以及患有危及生命疾病的患者，且使用已经批准上市的药品不能获得令人满意的治疗；（2）同情用药的对象是群组患者（group of patients），此处的群组患者是指多个患者，与集体使用（collective use）相对应；（3）同情用药的客体必须是根据EC/726/2004第6条提交上市批准申请的药物或正在进行临床试验的药物。2、同情用药的审批程序患者为了参与同情使用项目，首先需要向医生申请。通常，患者使用未批准药物的首要途径是通过参与临床试验。医生首先建议患者了解本国是否有可参与的合适的临床试验。如情况允许，医生应向患者所在国监管机构申请，并为患者寻求最合适的同情使用项目。在欧盟成员国，同情使用申请一般由医生向各成员国监管机构提出，经批准后允许同情使用，同时通知EMA。成员国监管机构保留同情使用项目中用药患者的登记册，并建立患者或医生药物不良事件报告系统。EMA的人用药品委员会（CHMP）仅对成员国提供建议，包括同情使用的条件、患者对象和分发使用药物等。EMA在官方网站上发布已被CHMP认可的同情使用的药物目录，该目录还包括CHMP的建议，如适用的患者以及如何使用药物。[18]3、同情用药的费用根据《医疗产品同情用药指南》第8条的规定，如同一公司提交了同一药品上市许可申请，则针对同情使用药品的意见应付的费用应从向EMA支付的费用中扣除。被EMA授予中小企业（SME）地位的公司有资格享受90%的科学服务费减免，其中包括对同情使用药品的意见。03违规开展同情用药的法律后果根据（EC）No 726/2004第84条，在不损害《关于欧洲共同体特权与豁免的议定书》的前提下，每个成员国应确定适用于违反EC/726/2004或根据EC/726/2004制定的法规的处罚，并采取一切必要措施进行实施，这些处罚应是有效的、成比例的，并具有威慑作用。因此，在不同欧盟成员国违规开展同情用药的，可能会受到不同的处罚措施。4中美欧开展同情用药合规关注要点01在中国开展同情用药合规关注要点首先，医药企业应结合治疗所用的药物类型和接受治疗的患者的情况，同时，以审慎的态度判断和评估是否符合同情用药的开展条件，如药物类型为开展细胞和基因药物拓展性临床试验的药物，应该核查药物是否到NDA阶段。确保仅在开展临床试验的机构开展同情用药，且该机构具备开展同情用药的相应资质和能力以及配备有使用经验和资质的医师。其次，开展同情用药前应通过临床试验机构伦理审查委员会的伦理审查，确保受试者了解其将接受试验用药品的治疗，明确告知受试者同情用药所用的药品尚未获得境内上市许可，在安全性和有效性方面可能存在的风险，且有权随时退出试验等内容，对应留存好知情同意的过程记录和相关文件。此外，应参考GCP的要求承担起药品质量安全和风险控制的责任，建立针对同情用药的质量管理体系，不得向患者收取同情用药费用。从次，虽然现行有效的法律法规中并未明确要求同情用药需经主管部门审批，但从涉及同情用药的征求意见稿和地方层面法规的监管趋势来看，我们倾向于建议，医药企业在开展同情用药之前应和国家药监部门进行沟通，以明确（1）是否需要取得国家药监局药审中心的批准，以及（2）是否需要在“药物临床试验登记与信息公示平台”进行登记。同时，在申请开展同情用药以及实施同情用药期间与药监部门、市监部门等机构保持良好交流，寻求必要的技术和法律指导。再次，在开展同情用药过程中，如发生不良事件、严重不良事件、药物质量问题等用药安全问题，医药企业应及时调整同情用药方案、暂停或者终止同情用药，协助患者进行良好的治疗，并向药监部门报告。最后，鉴于我国对同情用药制度体系的建设仍在探索阶段，我们倾向于建议拟在我国开展同情用药的医药企业密切关注和跟进国家和地方层面相关法规制度文件的颁布和更新及监管实践情况等。02在美国或欧盟开展同情用药合规关注要点首先，在收到患者同情用药的请求后，医药企业应判断当前情形是否满足美国或欧盟对同情用药设定的准入标准；其次，在开展同情用药前应取得伦理委员会的批准，并获得患者的充分知情同意，并关注上述开展知情同意的合规要点；从次，根据不同的同情用药类型，由医师或研究者向相应的监管机关提出申请并获得批准；最后，医药企业在美国开展同情用药的，还应将如何评估和回应单个患者要求获得临床试验药物的请求公开，并在公共网站上发布同情用药的实施计划等。— 结语 — 同情用药制度为一些特殊疾病患者带来生存的希望以及对健康的美好期待，实践中，国内外社会对同情用药的迫切需求客观存在，但因药物非合法完成注册上市的药品，同时也伴随着用药的各项风险。我国对同情用药制度的建立起步较晚，在实施落地方面仍在探索阶段，医药企业在开展同情用药时应关注药品质量安全和风险控制的义务，也有待我国监管部门吸取欧美等发达国家或地区的监管经验，对医药企业同情用药的适用条件、申请主体、申请程序、审查主体、审查内容、审查要点、质量管理体系、各方的责任承担等作出进一步实践指引。作为深耕于生命科学和医药健康领域的专业律师团队，笔者期待本文对中美欧开展同情用药管理制度及其合规关注要点的分析总结，能让医药企业更好了解同情用药的现行监管内容，在合法合规的基础上造福更多药物急需患者。最后，也欢迎各位读者就相关法律合规问题，随时和我们沟通联系。英文版（上下滑动查看更多）Management Systems and Compliance Concerns of Compassionate Use of Drugs in China, the United States, and the European UnionI.IntroductionThe compassionate use of drugs has played a significant role in facilitating prompt access to investigational drugs for patients in need of urgent clinical treatment, both domestically and internationally. It also accelerates the collection of safety data for investigational drugs on a legal basis. Since drugs used for treatment under compassionate use have not been formally approved for marketing, the outcomes of treatment carry uncertainties. Therefore, to protect the patients’ legitimate rights and interests, it is necessary for countries to take strict supervision measures for pharmaceutical companies and clinical trial institutions to fulfill their responsibilities for medication safety fully. Compassionate use of drugs, as a critical medical intervention, has garnered widespread attention in countries and regions such as the United States and the European Union. Comprehensive compassionate use of drugs systems has been established, providing insights for the development and improvement of such systems in China.This article will summarize the laws, regulations and regulatory requirements for compassionate use of drugs in China, the United States, and the European Union. It will also incorporate practical cases of compassionate use to help pharmaceutical companies intending to engage in compassionate use clarify compliance concerns. This aims to minimize potential violations of compassionate use of drugs systems, ensuring better protection of the life, health, and other rights of compassionate use patients domestically and internationally.II.Regulation of compassionate use of drugs in Chinai.Laws and regulations related to compassionate use of drugsArticle 23 of Drug Administration Law revised in 2019 proposed and established the compassionate use of drugs systems for the first time at the legal level, which is known as “expanded clinical trials (拓展性临床试验)”. However, the article 23 aforementioned served as only provided general principles, and did not clarify the implementation details of the compassionate use of drugs systems at the executive level. While the Measures for the Administration of Expanded Compassionate Use of Drugs for Clinical Trials (Revised Draft for Comment) (“Compassionate Use of Drugs Administration Draft”)released in December 2017 made more detailed provisions on the target population, applicable conditions, applicants and application procedures for expanded clinical trials, etc., this measure has not been officially promulgated and implemented[1]. Under the legal framework at the national level, the Regulations on Promotion of Cell and Gene Industry in Shenzhen Special Economic Zone, which came into effect on March 1, 2023, as a local regulation, provides specific provisions on the applicable conditions, review entities, risk warnings, withdrawal and termination of expanded clinical trials of cellular and gene drugs, which have played a leading role in the development of compassionate use of drugs. The following is a partial summary of the laws and regulations related to compassionate use of drugs from the national and local levels:ii.Regulatory points for the implementation of compassionate use of drugs1.Applicable conditions for compassionate use of drugsOn the basis of the existing effective Drug Administration Law, the system of compassionate use of drugs in China is only a framework. However, the Implementing Regulations of the Drug Administration Law (Revised Draft for Comment) and the Compassionate Use of Drugs Administration Draft serve as procedural documents to explore the establishment of the system of compassionate use of drugs, providing reference and guidance. Under the framework of the Implementing Regulations of the Drug Administration Law(Revised Draft for Comment) and the Compassionate Use of Drugs Administration Draft, the applicable conditions for compassionate use of drugs include but are not limited to the following points:Notably, Shenzhen has stipulated more prudent requirements for compassionate use. The Regulations on Promotion of Cell and Gene Industry in Shenzhen Special Economic Zone require that applicants for drug registration who intend to conduct expanded clinical trials of cell and gene drugs have completed the phase of clinical trials in support of the marketing registration of the new drug and submitted an application for marketing authorization (“NDA”) to the National Medical Products Administration, reflecting a more prudent approach to compassionate use safety.2.Approval procedure of compassionate use of drugsAccording to the existing effective Article 23 of Drug Administration Law(Revised in 2019), compassionate use of drugs requires to be “upon review”. However, the applicant, reviewing entity, and review procedures are not explicitly specified. According to the requirements of the Implementing Regulations of the Drug Administration Law(Revised Draft for Comment)and the Compassionate Use of Drugs Administration Draft, the following two concerns are mainly involved:(1)ApplicantRegarding the applicant, according to the Compassionate Use of Drugs Administration Draft, the applying entity is the registered applicant. Under normal circumstances, the registered applicant for drugs might be a pharmaceutical company. Different from Regulations on the Management of Expanded Clinical Trials for Medical Devices(Trial), patients, sponsors, or researchers may propose the conduct of expanded clinical trials for medical devices.(2)Reviewing entity and review procedureRegarding the reviewing entity and review procedure, there are differences between the provisions of the Compassionate Use of Drugs Administration Draft and the Implementing Regulations of the Drug Administration Law (Revised Draft for Comment). Article 5 of the Compassionate Use of Drugs Administration Draft requires the registration applicant to apply for and obtain approval from the National Medical Products Administration Center for Drug Evaluation. It also mandates that the registration applicant should register relevant information on the “Registration and Information Publicity Platform of Clinical Trials for Drugs” for expanded compassionate use clinical trials and collect safety data. On the other hand, the Implementing Regulations of the Drug Administration Law (Revised Draft for Comment) only requires approval after ethical committee review, and neither of these has been officially effective.In practice, there have been pharmaceutical companies registering compassionate use cases on the “Registration and Information Publicity Platform of Clinical Trials for Drugs”. On July 23, 2020, Roche registered an Expanded Access Program for Atezolizumab as first-line treatment for patients with triple-negative breast cancer. The participating institution for this study is the First Affiliated Hospital of Chongqing Medical University, with plans to recruit 50 patients domestically. The purpose of this program is to provide Atezolizumab to patients in urgent need before its approved indication is available in mainland China. This allows patients with triple-negative breast cancer to access effective treatment as early as possible and collect safety data in accordance with regulatory requirements.[2]In addition, from the practical case of compassionate use of drugs for a patient with paroxysmal sleep hemoglobinuria (PNH) at Peking Union Medical College Hospital (PUMC), the compassionate use of drugs was carried out in addition to ethical review by the Ethics Committee of PUMC, and National Medical Products Administration also pushed forward the approval process of the clinical trial with full force under the premise of legal compliance in accordance with the provisions of the Drug Administration Law (Revised 2019). This signifies a breakthrough step in the implementation of the compassionate use of drugs system in China.[3]3.The management of compassionate use of drugsIn accordance with the definition of compassionate use of drugs provided in the Compassionate Use of Drugs Administration Draft, it is considered a form of clinical trial. Therefore, during the implementation, reference should be made to the Good Clinical Practice for Drug Trials (GCP). Drawing on the Regulations on the Management of Expanded Clinical Trials for Medical Devices(Trial), pharmaceutical companies, researchers, clinical trial institutions, and ethics committees are expected to assume their respective responsibilities in accordance with GCP requirements. This involves establishing an appropriate quality management system for clinical trials specifically tailored to compassionate use of drugs.4.Fees of compassionate use of drugsRegarding the issue of fees, considering that GCP clearly stipulates that researchers shall not charge subjects for the investigational drugs during the clinical trial process, and in conjunction with the provisions of Article 13 of the Compassionate Use of Drugs Administration Draft, it is generally not allowed for pharmaceutical companies to charge patients for investigational drug expenses during compassionate use of drugs.iii.Legal consequences of non-compliance with compassionate use of drugsDue to the fact that compassionate use involves the use of unapproved drugs outside of clinical trials, a drug user may be deemed as using counterfeit or inferior drugs. According to the regulations on the sale of counterfeit drugs or retailing inferior drugs, fines may be imposed. If the circumstances are serious, the certificate of practice for medical and health personnel, if any, of its legal representative, main principal, directly responsible executive or any other responsible personnel (“relevant responsible personnel”) shall further be revoked. Illegitimate conduct in compassionate use may also be considered as conducting drug clinical trials without approval, resulting in fines ranging from CNY500,000 to CNY5 million. if the circumstances are serious, its relevant drug approval documents, Drug Manufacturing Certificate and Drug Distribution Certificate shall be revoked, and relevant responsible personnel shall be imposed a fine of not less than CNY20,000 but not more than CNY200,000 and be prohibited from engaging in drug production and distribution activities for ten years or even for life.[4]Furthermore, since compassionate use involves technological activities with humans as research participants, it is subject to ethical review. Undertaking compassionate use without obtaining proper ethical review approval, as stipulated, may lead to penalties or actions taken by the relevant competent authorities based on laws, administrative regulations, and relevant provisions. If it results in financial losses or other damages, civil liability must be borne in accordance with the law. If it constitutes a crime, criminal responsibility will be pursued in accordance with the law.[5]III.Regulation of compassionate use of drugs in the United Statesi.Laws and regulations related to compassionate use of drugsThe compassionate use system in the United States originated in the 1970s, and in 1987, the U.S. Food and Drug Administration (FDA) formally established the compassionate use system in the Code of Federal Regulations. The regulations provided clear specifications on applicable standards and conditions for submitting applications. The Food and Drug Administration Modernization Act of 1997 further defined three categories for compassionate use. In 2016, the U.S. Congress passed the 21st Century Cures Act, which detailed the disclosure obligations of pharmaceutical companies and further refined the implementation details of compassionate use. Overall, the United States has established a relatively comprehensive compassionate use system.In practice, on September 22, 2023, the University of Maryland Medical Center in the United States announced that, following the pioneering precedent, they completed the second global case of transplanting a genetically modified pig heart to a patient through the compassionate use system.[6] Additionally, according to a report in the New England Journal of Medicine (NEJM) on June 11, 2020, among 53 hospitalized patients with severe Covid-19, 36 individuals (68%) received compassionate use of intravenous injection of Remdesivir, a drug developed by Gilead Sciences with clinical symptoms improved but assessing efficacy requires continued randomized placebo-controlled trials of Remdesivir treatment.[7] However, concerning Remdesivir allowed for compassionate use, the FDA issued an alert on February 4, 2021, advising healthcare professionals not to use the drug outside of compassionate use. The FDA noted that the drug had not been approved by the FDA, and its safety, efficacy, or quality had not been evaluated by the FDA.[8]ii.Regulatory points for the implementation of compassionate use of drugs1.The eligibility criteria for compassionate use of drugsIn accordance with CFR Section 312.300, “compassionate use” refers to a situation where a patient has a serious or life-threatening disease or condition or is in a stage where there is a reasonable likelihood of death within a few months, there is no comparable or satisfactory alternative therapy for diagnosing, monitoring, or treating the disease, and the patient is not in a clinical trial group. The patient can apply for Investigational New Drug (IND) treatment. According to CFR Section 312, the criteria for applying for compassionate use are as follows:(1)Patient has a serious or immediately life-threatening disease or condition；(2)There is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition；(3)Patient enrollment in a clinical trial is not possible；(4)the IND has already obtained certain safety and efficacy data, and after evaluation, it is determined that potential patient benefit justifies the potential risks of treatment; and(5)The use of compassionate use does not impact the development and clinical trials of the IND.2.Basic categories of compassionate useReferring to the FDA’s Compassionate Use Q&A Guidance[9], under FDA’s current regulations, there are three categories of compassionate use:(1)Compassionate use for individual patients, including for emergency use (21 CFR 312.310);(2)Compassionate use for intermediate-size patient populations, generally smaller than those typical of a treatment IND or treatment protocol — a treatment protocol is submitted as a protocol to an existing IND by the sponsor of the existing IND (21 CFR 312.315); (3)Compassionate use for widespread treatment use through a treatment IND or treatment protocol, designed for use in larger patient populations (21 CFR 312.320).3.Approval procedure of compassionate use of drugsUnder 21 CFR 312.305(b), all categories of compassionate use are subject to FDA approval, and the time required for FDA approval of different categories of compassionate use is listed below:In the case of a single-patient IND procedure, based on 21 CFR 312.310 and 21 CFR Part 56, the process for a single-patient IND treatment application begins with the patient's treating physician contacting a pharmaceutical company to ensure their willingness to provide the investigational drug. The physician obtains a Letter of Authorization (LOA) from the pharmaceutical company, granting the FDA access to the information submitted in the company's IND application. Subsequently, either the physician or the clinical research lead from the pharmaceutical company submits the IND treatment application to the Institutional Review Board (IRB). Upon approval by the IRB, the application can then proceed to the Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) of FDA for IND treatment approval.The FDA adheres to a strict review process and a principle of high approval rates in compassionate use approvals. In conducting a risk-benefit assessment, the FDA must determine that the condition is serious or immediately life-threatening, that there is no comparable or satisfactory alternative therapy, and that access will not interfere with a pivotal clinical trial, where (1) for treatment IND compassionate use applications, the FDA requires that sufficient evidence of safety and effectiveness must be found, which typically includes data from Phase III clinical trials, but may also include compelling data from completed Phase II clinical trials; and (2) for single-patient IND applications, on the other hand, only a physician's judgment that the experimental drug does not pose a greater risk than the disease itself is required. [10]4.The management of compassionate use of drugs(1)Adequate informed consent.To ensure that the patient is informed that he/she will be treated with an investigational product and that there may be uncertainty about the safety and effectiveness of the product, the FDA requires patients to provide fully informed consent.(2)IRB review. Except for emergency compassionate use when there is not sufficient time to secure prospective IRB review, an investigator treating a patient with an investigational drug under compassionate use is responsible for obtaining IRB review and approval before treatment with the investigational drug may begin. (3)Disclosure of compassionate use policy. Notably, the 21st Century Cures Act requires that a company developing investigational drugs (including biologics) shall make its policy regarding evaluating and responding to requests for expanded access public and readily available, including disclosure of contact information, procedures for making requests, criteria for evaluating and responding to individual patient requests for access to drugs in clinical trials, and posting on a public Web site the implementation plan for compassionate use of drugs as well as facilitating the participation in compassionate use programs for patients who are terminally ill or in urgent need of care. Posting this information on the Reagan-Udall Foundation’s Expanded Access Navigator External Link Disclaimer, including links to a company’s own web page describing its policy for the investigational drug, can be used to satisfy this requirement. When a company is developing multiple investigational drugs, they may establish different expanded access policies for each of their investigational drugs and post these individually by name as outlined above.[11](4)Fees of compassionate use. Under the provisions of 21CFR312.8 for charging for compassionate use, pharmaceutical companies engaged in compassionate use must complete specific tasks and obtain written authorization from the FDA before initiating charges for IND treatment. As per 21 CFR 312.8(d)(1), the FDA stipulates that pharmaceutical companies are only permitted to recover the direct costs incurred in providing the drug to the subjects in compassionate use. These direct costs include the expenses related to manufacturing the drug in quantities necessary for the FDA-approved clinical trial, acquiring the drug from other sources, as well as costs associated with transportation and storage of the drug.iii.Legal consequences of non-compliance with compassionate use of drugsIf healthcare professionals or organizations use unapproved drugs that pose potential safety risks or lack evidence of effectiveness, they may be subject to FDA enforcement actions. These actions typically involve one or more of the following: requesting voluntary compliance; providing notice of action in a Federal Register notice; issuing an untitled letter; issuing a Warning Letter; or initiating a seizure, injunction, or other proceeding.[12]In accordance with information blocking provisions under the 21st Century Cures Act[13], a health IT developer must not take any action that constitutes information blocking. For healthcare providers, the law applies the standard of whether they know that the practice is unreasonable and is likely to interfere with the access, exchange, or use of electronic health information (EHI)[14]. If a pharmaceutical company fails to fulfill its obligation to disclose its compassionate use drug policy, it may constitute information blocking. In such cases, it could be investigated by the Inspector General of the Department of Health and Human Services in the United States and be determined to have committed information blocking, it may be referred to the appropriate agency to be subject to appropriate disincentives under applicable federal laws[15]. IV.Regulation of compassionate use of drugs in the European Unioni.Laws and regulations related to compassionate use of drugsOn April 3, 2020, the European Medicines Agency (EMA) recommended the compassionate use of Gilead's Remdesivir for the treatment of COVID-19. EMA provided guidance to European Union member states on implementing compassionate use programs for Remdesivir within their countries. In addition to the compassionate use programs, Gilead continued to provide compassionate use of Remdesivir on an individual basis for children and pregnant women. As of April 4, 2020, more than 1,700 patients had received treatment through these programs.[16]The EMA's Committee for Medicinal Products for Human Use (CHMP) released the official guideline “Guideline on Compassionate Use of Medicinal Products” in July 2007. While EMA has made significant efforts in advancing compassionate use, the non-binding nature of their regulations and guidelines means that each member state must adhere strictly to its respective legal procedures for introducing and implementing compassionate use. The specific regulatory laws and regulations in the European Union regarding compassionate use are as follows[17]:ii.Regulatory points for the implementation of compassionate use of drugs1.The eligibility criteria for compassionate use of drugsAccording to Article 3 of the Guideline on Compassionate Use of Medical Products, compassionate use of drugs is subject to the following conditions:(1)The applicant must be a patient suffering from chronic or severe diseases, including life-threatening conditions who cannot be satisfactorily treated with a drug already approved for marketing; (2)Compassionate use is applicable to a group of patients, where a group refers to multiple patients, as opposed to collective use; (3)The object of compassionate use must be a medicinal product for which an application for marketing authorization has been submitted in accordance with Article 6 of EC/726/2004 or a medicinal product which is undergoing clinical trials.2.Approval procedure of compassionate use of drugsTo enter a compassionate use programme, patients must speak to their doctor. In general, medicines that have not been authorised are first made available to patients through clinical trials, and the doctor will first advise the patient on whether there is a suitable clinical trial in their country than they can enter. If appropriate, the doctor can speak to the authority that is responsible for compassionate use programmes in their country and find out whether a suitable compassionate use programme is available. In European Union member states, compassionate use applications are typically submitted by doctors to the regulatory authorities of each member state. Once approved, compassionate use is permitted, and EMA is also notified. The national authority keeps a register of the patients treated with the medicine within the compassionate use programme, and systems are in place to record any side effects reported by the patients or their doctors. The EMA’s Committee for Medicinal Products for Human Use (CHMP) can provide recommendations to all EU Member States on conditions for compassionate use, target patients and how to distribute and use the drugs for compassionate use. The European Medicines Agency publishes on its website a list of opinions on the compassionate use of medicines that the CHMP has adopted. This registry also includes information on the CHMP’s recommendations, such as the patients in whom the medicine can be used, and how it should be used.[18]3.Fees of compassionate useAccording to Article 8 of the Guideline on Compassionate Use of Medicinal Products, if the same company submits the same drug for a marketing authorization application, the fees related to the opinion on compassionate use of the drug should be deducted from the fees paid to EMA. Companies granted Small and Medium-sized Enterprise (SME) status by EMA are eligible for a 90% reduction in scientific service fees, including fees related to the opinion on compassionate use of drugs.iii.Legal consequences of non-compliance with compassionate use of drugsPursuant to Article 84 of(EC) No 726/2004, without prejudice to the Protocol on the Privileges and Immunities of the European Communities, each Member State shall determine the penalties to be applied for infringement of the provisions of EC/726/2004 or the regulations adopted pursuant to it and shall take all measures necessary for their implementation. The penalties shall be effective, proportionate and dissuasive. Therefore, if compassionate use of drugs is conducted in violation of regulations in different EU member states, various penalties may be imposed.V.Compliance concerns with compassionate use of drugs in China, the United States and the European Unioni.Compliance concerns with compassionate use of drugs in ChinaFirst of all, pharmaceutical companies should take into account the type of drug used for treatment and the condition of patients receiving treatment, and at the same time, judging and evaluating in a prudent manner whether they are in compliance with the conditions for compassionate use. For drugs involved in expanding clinical trials of cell and gene therapies, it should be verified whether the drug has reached the NDA stage. Ensure that compassionate use of drugs is conducted only in institutions conducting clinical trials, with the institution possessing the appropriate qualifications and capabilities to carry out compassionate use and is staffed with physicians who have experience and qualifications in the practice of compassionate use.Secondly, before initiating compassionate use, ethical review by the institutional review board should be conducted to ensure that subjects understand the treatment with the investigational drug. Subjects should be clearly informed that the drug used for compassionate use has not yet obtained domestic marketing approval, potential risks in terms of safety and efficacy, and the right to withdraw from the trial at any time. The process records and relevant documents of the informed consent should be retained. Additionally, adhere to GCP requirements for drug quality, safety, and risk control responsibilities. Establish a quality management system specifically for compassionate use, and refrain from charging patients for compassionate use of drugs.Thirdly, although existing effective laws and regulations do not explicitly require approval from regulatory authorities for compassionate use, considering the regulatory trends in drafts for comment and local regulations related to compassionate use, it is advisable for pharmaceutical companies to communicate with the National Medical Products Administration to clarify whether approval from the NMPA's Center for Drug Evaluation is required and whether registration on the “Registration and Information Publicity Platform of Clinical Trials for Drugs” is necessary. At the same time, during the application for and implementation of compassionate use, pharmaceutical companies shall maintain good communication with regulatory authorities for Medical Products and Market Regulation, etc., seeking necessary technical and legal guidance.Fourthly, during the compassionate use, if adverse events, serious adverse events, or drug quality issues occur, pharmaceutical companies should promptly adjust the compassionate use protocol, suspend, or terminate compassionate use, assist patients in receiving appropriate treatment and report to regulatory authorities.Lastly, given that the establishment of the compassionate use system in China is still in the exploratory stage, we tend to suggest that pharmaceutical companies intending to conduct compassionate use in China should pay close attention to follow up on the promulgation and updating of relevant regulatory documents at the national and local levels, as well as regulatory practices.ii.Compliance concerns with compassionate use of drugs in the United States and the European UnionFirstly, upon receiving a request for compassionate use of drugs from a patient, pharmaceutical companies should assess whether the current situation meets the admission criteria set by the United States or the European Union for compassionate use;Secondly, prior to initiating compassionate use, approval from the Institutional Review Board (IRB) and the patient's informed consent should be obtained with attention to the compliance concerns for conducting informed consent as described above;Thirdly, depending on the category of compassionate use, applications should be submitted by physicians or researchers to the respective regulatory authorities and obtain approval;Finally, for pharmaceutical companies conducting compassionate use in the United States, they should also publicly disclose how they evaluate and respond to individual patient requests for access to investigational drugs, and should publish the implementation plan for compassionate use on a public website, among other details.VI.ConclusionThe compassionate use system brings hope for survival and positive expectations for health to patients with special diseases. In practice, there is an objective and urgent demand for compassionate use of drugs in both domestic and international societies. However, as these drugs have not yet legally completed the registration for market approval, they come with various risks associated with their use. China's establishment of the compassionate use system started relatively late, and the implementation is still in the exploration stage. Pharmaceutical companies engaging in compassionate use should pay attention to their obligation regarding the quality and safety of drugs and risk control. Additionally, regulatory authorities in China need to learn from the regulatory experiences of developed countries or regions such as the European Union and the United States. Further guidelines are required for pharmaceutical companies on the applicable conditions, applicants, application procedures, reviewing entities, reviewing criteria, reviewing focus areas, quality management systems, and responsibilities of all parties involved in compassionate use.As a professional legal team deeply involved in the life sciences and healthcare areas, we hope that this analysis and summary of the compassionate use management systems and compliance concerns in China, the United States, and the Europe Union can help pharmaceutical companies better understand the current regulatory landscape for compassionate use. This understanding, coupled with compliance with legal requirements, can benefit more patients in need of urgent medication. Finally, we welcome readers to communicate with us at any time regarding related legal and compliance issues.本文作者简介刘婷婷刘婷婷律师是上海市锦天城律师事务所资深律师，现为中国生物医药产业链创新与转化联盟（CBIITA联盟）商务拓展专委会副主委、威科先行医药行业智合规专家委员会成员等。刘律师被知名法律评级机构LEGALBAND评为2023年度中国律界俊杰三十强，刘律师还被国际权威法律评级机构《The Legal 500》评为2024年中国大陆生命科学与大健康领域重点推荐律师。刘婷婷律师自执业以来精耕于生命科学和医药健康领域，主要为跨国药械企业（包括但不限于阿斯利康、雅培、西门子医疗、默沙东、勃林格殷格翰、罗氏、百济神州、爱施健、美纳里尼、石药集团、天境生物、京新药业、凯因科技、邦耀生物、鞍石生物等）、医疗机构（包括但不限于国内首家外资三甲综合性医院和顶级公立三甲医院）、医疗（生）集团、互联网医疗健康企业、保险公司以及专投医疗药械项目的专业基金公司等企业机构提供境内外投融资并购、跨境药械技术交易和合作、监管合规、争议解决及公司日常等法律服务，包括协助国内外多家知名药企开展多个跨境License in/out技术交易和合作开发项目等。刘婷婷律师在上海律协、威科先行、LexisNexis、LEB、E药经理人等专业法律和医药行业平台发表医药健康领域法律实务总结文章和报告近百篇，包括但不限于：《医药企业技术交易实务系列文章（合辑）》（中英文版本，2023年，联合E药经理人发布）；《医疗机构新设并购及合规管理实务手册》（2023年，联合威科先行法律数据库发布）；《医药行业行政处罚风险提示与防范解析报告》(2020年，联合威科先行法律数据库发布)；《医疗AI法律及监管报告》行业发展与现状和医疗AI产品责任章节（2019年，联合腾讯健康发布，国内首份医疗AI法律研究报告）等。联系电话：15216738527（同微信）联系邮箱：tinaliu@allbrightlaw.com黄冠鸿黄冠鸿律师是上海市锦天城律师事务所资深律师、国际公认反洗钱师（CAMS）。黄冠鸿律师自执业以来，专注在金融监管、风险与内控管理、生命大健康等领域的法律服务。在医疗药械常法、合规融资交易业务领域，黄律师曾服务的客户包括但不限于罗氏诊断、美纳里尼、石药集团、京新药业、凯因科技、嘉和美康、健新原力、鞍石生物、邦耀生物、祥耀生物、思勤医疗、勤浩医药、逻晟生物、帝奇医药、子瞻生物、纽安津生物、迈诺威医药、霖鼎光学、森世海亚集团、阳光医疗集团、哈特瑞姆心脏医疗集团、上海联影集团等医疗药械企业，为他们提供的法律服务范围涵盖企业日常事务、研发及临床、运营和数据合规、境内外投资、股权融资、及跨境BD交易等方面的法律服务。黄冠鸿律师毕业于华东政法大学，同时获得法学学士、经济学（金融方向）学士学位。联系电话：18817836896（同微信）联系邮箱：hgh@allbrightlaw.com周汝歆周汝歆是上海市锦天城律师事务所律师助理。周汝歆毕业于华东政法大学, 获得法学学士学位, 并于美国乔治城大学法学院获得法学硕士学位和证券与金融法证书。具有中国法律职业资格。周汝歆主要就生命科学与医疗健康、网络安全与数据合规、反垄断、反腐败及公司合规的日常事务提供法律服务。赵依红赵依红是上海市锦天城律师事务所实习生。赵依红目前在华东政法大学已获得文学(英语专业)学士学位与攻读法学第二学士学位。专注于生命科学和医药健康领域的法律服务。参考文章：（上下滑动查看更多）1.截至2024年1月20日。2.参见https://xueqiu.com/8965749698/155015480。3.参见https://ims.pumch.cn/detail/26052.html。4.《药品管理法(2019修订)》第118，125条。5.《科技伦理审查办法(试行)》第47条。6.参见https://content-static.cctvnews.cctv.com/snow-book/index.html?item_id=6279027731641022429&toc_style_id=feeds_default&share_to=qq&track_id=bc584e4f-f09f-4742-859a-07346b4e5265。7.参见https://www-nejm-org.libproxy1.nus.edu.sg/doi/full/10.1056/NEJMoa2007016。8.参见https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-professionals-and-compounders-potential-risks-associated-compounding。9.参见https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expanded-access-investigational-drugs-treatment-use-questions-and-answers。10.参见Darrow J J, Sarpatwari A, Avorn J, et al. Practical, legal, and ethical issues in expanded access to investigational drugs [J]. N Engl J Med, 2015, 372(3): 279-286。11.参见 https://www.fda.gov/news-events/expanded-access/expanded-access-information-industry#IndustryRole。12.参见FDA药品评价与研究中心发布(CDER)的《已上市未经批准药物——合规政策指南》第II节B。13.参见45 CFR Part 170.401。14.参见42 U.S.C. 300jj–52(a)(1)。15.参见42 U.S.C. 300jj–52(b)(2)(B)。16.参见https://stories.gilead.com//articles/an-update-on-covid-19-from-our-chairman-and-ceo。17.《同情用药的国内外发展现状与思考》，高杨，梅丹，李大魁，张波，胡扬，左玮，赵蕾蕾，张鹏霄，王少红，中国医学科学院北京协和医学院北京协和医院药剂科，临床药物治疗杂志第18卷第7期。18.参见欧盟药品管理局于2010年1月21日发布的《欧盟药品同情使用问答》。更多优质内容，欢迎关注↓↓↓