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July 25, 2023

Compliance with China’s Drug Marketing Authorization Holder Local Agent and Registration Agent Requirements 药品上市许可持有人境内代理人与注册代理人的合规要求

Advisory

In recent years, China’s current drug regulations and draft proposals have introduced a new requirement that foreign drug market authorization holders (MAHs) must designate a local agent in China. Therefore, multinational pharmaceutical companies operating in China should understand the qualifications of a local agent, appoint a local agent in a timely manner, and enter into written agreements to facilitate seamless business operations in China through close collaboration with the local agent.
近几年来,中国药品管理的现行法规以及征求意见稿,增加了一项新的要求,即境外的药品上市许可持有人(“境外持证商”)必须指定境外持证商境内代理人。因此,在中国开展业务的跨国制药公司,应充分了解境外持证商境内代理人的资格要求,及时指定境外持证商境内代理人,并与之签订书面合同,通过与境外持证商境内代理人的密切合作,确保在中国的业务顺利开展。

1. MAH, Local Agent, and Registration Agent | 证商,境内代理人,以及注册代理人

In 2015, China initiated a pilot program for the MAH system across several provinces and municipalities. In 2019, the MAH-centered regulatory framework was officially established in China following the amendment of the Drug Administration Law (DAL). Article 30 of the DAL defines an MAH as an enterprise, drug research and development institution, or any other entity that holds a drug registration certificate. An MAH is responsible for the entire lifecycle of drugs, including non-clinical research, clinical trials, manufacturing and distribution, post-marketing research, and adverse-reaction monitoring, reporting, and handling. An MAH may bear administrative, civil, and criminal liabilities for violation of the DAL and related regulations.
持证商制度试点自2015年在中国的多个省市开展,持证商为主线的监管理念也于2019通过《药品管理法》的修订正式确立。《药品管理法》第三十条规定,持证商是指取得药品注册证书的企业或者药品研制机构等。持证商负责药品的全生命周期的管理,对药品的非临床研究、临床试验、生产经营、上市后研究、不良反应监测及报告与处理等承担责任。对于违反《药品管理法》及相关规定的行为,境外持证商需承担行政责任、民事责任和刑事责任。

Article 38 of the DAL provides that a foreign MAH shall designate a domestic entity as its local agent to perform the MAH’s obligations and assume joint and several liabilities. The implementation details are outlined in two draft proposals issued by the National Medical Products Administration (NMPA) that have not yet come into effect: the Draft Interim Provisions on Local Agents of Foreign Drug Marketing Authorization Holder (the Draft Interim Provisions), issued on July 31, 2020, and the Draft Amendment to the Implementation Regulation of the Drug Administration Law (the Draft Regulation), issued on May 9, 2022.
根据《药品管理法》第三十八条,持证商为境外企业的,必须指定境内代理人履行境外持证商义务,并与境外持证商承担连带责任。具体的实施要求,体现在还未生效的两项征求意见稿中:国家药监局于2020年7月31日发布的《境外药品上市许可持有人境内代理人管理暂行规定(征求意见稿)》(《境内代理人征求意见稿》)和于2022年5月9日发布的《药品管理法实施条例(修订草案征求意见稿)》(《实施条例征求意见稿》)。

Prior to the 2019 DAL, foreign applicants for drug registration were already required to designate “registration agents” in China, a term likely to be confused with foreign MAHs’ “local agents.” The latest regulations on drug registration agents are in the Drug Registration Regulation revised in 2020, which stipulates that a foreign applicant for drug registration must designate a Chinese domestic entity as its registration agent to handle registration-related matters. The applicant bears full responsibility for the product. The registration agent does not assume joint and several liability with the applicant.
在《药品管理法》于2019年修订之前,境外的药品注册申请人,一直必须指定中国境内的注册代理人。注册代理人和境外持证商境内代理人的关系容易混淆。对于药品注册代理人的规定最新体现于2020年修订的《药品注册管理办法》,境外申请人在药品注册申请阶段应当指定注册代理人,以办理相关药品注册事项。申请人是申报产品的责任主体,注册代理人无需与之承担连带责任。

This article will focus on the similarities and differences between MAH local agents and registration agents in four aspects: qualifications and requirements, obligations and liabilities, procedures and timelines, and the MAH of cross-border licensed products.
对于境外持证商境内代理人和注册代理人的异同,我们将在本文中聚焦讨论以下四个方面:资质与要求、义务与责任、时间与流程,以及跨境许可引进药品的持证商。

2. Qualifications and Requirements | 资质与要求

(1) Local Agent | 境外持证商境内代理人

Article 38 of the DAL provides that an MAH local agent shall be a corporate entity established within China. Domestic branches of companies incorporated in China and representative offices of foreign companies located in China do not have legal personality and therefore cannot serve as local agents. In practice, multinational companies typically designate their wholly-owned or joint venture subsidiaries in China or their Chinese partner companies as their local agents.
根据《药品管理法》第三十八条,MAH境内代理人必须是在中国境内设立的企业法人。中国公司的境内分公司和外国公司在中国的代表机构不具有法人地位,不得担任境外持证商境内代理人。实践中,跨国企业通常指定其在中国境内的独资或合资的子公司,或者合作的中国公司,作为境外持证商境内代理人。

The Draft Regulation further stipulates that a local agent must possess certain capabilities in quality management and risk control. It must also establish a comprehensive pharmaceutical quality assurance system that includes management departments and professional technicians. While the Draft Regulation requires that an MAH shall have the capability of compensation for liability, it does not explicitly impose that requirement on the local agent. Given that the local agent should fulfill the MAH’s obligations, it is important that the MAH selects its local agent through a comprehensive evaluation in practice.
《实施条例征求意见稿》进一步规定,境外持证商境内代理人应当具备相应的质量管理能力和风险控制能力,建立药品全过程质量保证体系,配备相应管理部门和专业技术人员。虽然《实施条例征求意见稿》规定境外持证商需要具有赔偿能力,但未明确规定境外持证商境内代理人是否亦需要具备赔偿能力。由于境外持证商境内代理人将履行境外持证商的相应义务,在实践中,境外持证商需要在选择境外持证商境内代理人时对其进行全面评估,谨慎选择。

(2) Registration Agent | 注册代理人

Article 9 of the Drug Registration Regulation stipulates that a registration agent must be a corporate entity established in China. As with local agents, a foreign company’s subsidiary in China or its Chinese partner company can serve as the registration agent, while a domestic branch of a company incorporated in China or a representative office of a foreign company is unqualified. In addition, there are no established laws or regulations that define the competencies required for a registration agent in quality management, risk control, or liability compensation. In practice, the registration agent should be familiar with the laws, regulations, and technical requirements of drug registration. The MAH can evaluate and appoint the registration agent according to its own needs.
《药品注册管理办法》第九条规定,注册代理人需为中国境内设立的企业法人。与境外持证商境内代理人相似,注册代理人也可以为外国公司在华的子公司或中国合作公司,但不可以为中国公司的境内分公司或外国公司在中国的代表机构。此外,暂无法律法规对注册代理人的质量管控能力、风险防控能力和责任赔偿能力等进行规定。实践中,注册代理人应熟悉药品注册的法律、法规及技术要求,境外持证商可以根据自身需要评估和选择注册代理人。

3. Obligations and Liabilities | 义务和责任

(1) Local Agent | 境外持证商境内代理人

According to Article 38 of the DAL, the local agent shall assume the obligations of a foreign MAH. Following the establishment of the MAH system, some laws and regulations stipulated the responsibilities of local agents. For instance, Article 47 of the Administrative Measures on the Supervision of Drug Manufacturing provides that the local agent shall be responsible for drug market release and drug quality and coordinate with foreign inspections. Article 9 of the Administrative Measures for the Registration of Medical Representatives (for Trial Implementation) requires the local agent to be responsible for the registration and management of pharmaceutical representatives. Article 4 of the Administrative Provisions on Drug Annual Reporting establishes the requirement for the local agent to submit annual reports.
根据《药品管理法》第三十八条,持证商为境外企业的,境外持证商境内代理人需承担境外持证商的义务。MAH制度实施之后,陆续颁布的其他法律法规进一步规定了境外持证商境内代理人的义务。例如,《药品生产监督管理办法》第四十七条规定境外持证商境内代理人应履行药品上市放行责任及对药品质量负责等,并负责协调配合境外检查工作;《医药代表备案管理办法(试行)》第九条规定境外持证商境内代理人需要对医药代表的备案和管理负责;《药品年度报告管理规定》第四条中规定境外持证商境内代理人需要履行年度报告义务等。

However, there is controversy over how the obligations of local agents apply under laws and regulations that took effect before the 2019 DAL. For instance, the NMPA issued the Announcement on Direct Reporting of Adverse Reactions by Marketing Authorization Holders in 2018, requiring MAHs of imported drugs to designate representative offices within China or domestic corporate entities as agents to take charge of the monitoring, evaluation, and risk control over adverse reactions of imported drugs. It calls for future laws and regulations to clarify whether the agents responsible for the monitoring and evaluation of adverse reactions are MAH local agents or pharmacovigilance agents separately appointed.
但是,在早于2019年《药品管理法》之前生效的法律法规中,境外持证商境内代理人的义务如何适用仍存在争议。例如,2018年颁布的《国家药品监督管理局关于药品上市许可持有人直接报告不良反应事宜的公告》规定,进口药品持有人应当指定在我国境内设立的代表机构或者指定我国境内企业法人作为代理人,具体承担进口药品不良反应监测、评价、风险控制等工作。负责不良反应监测与评价的代理人的性质是否属于境外持证商境内代理人,还是属于境外持证商另行委托的药物警戒代理人,尚需要在今后的法律法规中进一步的明确。

The Draft Regulation does not specify the obligations of MAH local agents. Pursuant to the Draft Interim Provisions, local agents shall establish drug quality assurance systems; establish and maintain drug traceability systems and drug annual reporting systems; establish management systems of drug post-marketing changes; undertake drug post-marketing affairs, such as handling product recalls, quality complaints, and compensation; establish pharmacovigilance systems; submit reference materials; and accept random inspection. Local agents are also expected to collaborate with the Chinese regulatory authorities during government inspections, investigations, and enforcement on noncompliance identified at foreign MAHs’ manufacturing sites. However, the requirements for MAH local agents have not yet come into effect.
《实施条例征求意见稿》未对境外持证商境内代理人的义务进行具体的规定。根据《境内代理人征求意见稿》,境外持证商境内代理人需负责建立药品质量保证体系、建立并实施药品追溯制度、建立并实施药品年度报告制度、建立药品上市后的变更管理制度、承担药品上市后召回、质量投诉处理、质量赔偿等事务、负责建立药物警戒体系、提交标准物质并接受抽检工作以及负责与境外持有人联络,配合药品监督管理部门开展对境外持有人生产场地的检查、调查和违法违规行为查处。但是,这些对于境外持证商境内代理人义务的规定尚未生效。

For any violations, the MAH and its local agent shall assume joint and several liability, which typically includes administrative liability (such as a monetary penalty, revocation of licenses, or debarment for 10 years) and civil liability (such as cessation of infringement, compensation for losses, or continued performance).
对于未依照规定履行相关义务的违法违规行为,境外持证商境内代理人与境外持证商承担连带责任,常见的包括行政责任(如罚款、吊销许可证、十年内不受理其相应申请等)和民事责任(如停止侵害、赔偿损失、继续履行等)。

(2) Registration Agent | 注册代理人

A registration agent is responsible for handling drug registration matters. Currently, there are no specific laws or regulations governing the obligations and liabilities of a registration agent. In practice, a registration agent is generally responsible for submitting materials and communicating with regulatory authorities in China. The drug applicant remains the liable entity, and the registration agent bears no joint and several liability during the drug registration process.
注册代理人负责办理药品注册相关事项,目前暂无法律法规规定注册代理人的具体义务和责任。实践中,注册代理人一般负责向中国的监管机构提交资料和相关沟通工作。在药品的注册申报过程中,申请人仍为责任主体,注册申请人无需承担连带责任。

4. Procedures and Timelines | 流程与时间

(1) Local Agent | 境外持证商境内代理人

Current legislation and guidelines do not specify the procedures and timelines necessary for a foreign MAH to apply for the appointment of its local agent. The Draft Regulation proposes two schemes for designating local agents. In the first scheme, before the drug market authorization is approved, the foreign applicant shall designate a qualified Chinese domestic corporate entity as its local agent whose relevant information should be included in the drug registration certificate. In the second scheme, after the approval of the drug market authorization, the MAH shall designate a qualified Chinese domestic corporate entity as its local agent and register with the provincial medical products administration where it is located, and the drug can be marketed only after the registration is completed. If the first scheme is adopted, the application for local agents and drug marketing authorization should be carried out simultaneously. If the second scheme becomes effective, the application procedure for local agents will depend on the local regulations and practices of provincial authorities.
现行法律法规未规定境外持证商境内代理人的申请流程和时间。《实施条例征求意见稿》提出了两种指定境外持证商境内代理人的方案。方案一是在药品上市许可批准前,境外申请人应当指定符合条件的中国境内企业法人作为境内代理人,境内代理人相关信息在药品注册证书中载明。方案二为药品上市许可批准后,境外持证商应当指定符合条件的中国境内企业法人作为境内代理人,并向所在地省级药品监督管理部门登记。境外持证商境内代理人登记后,产品方可上市销售。若最终生效版本采用方案一,境外持证商境内代理人的申请与药品上市许可申请需同步进行。若方案二生效,则境外持证商境内代理人的申请流程和时间取决于各省局的地方性规定和实践。

(2) Registration Agent | 注册代理人

The Draft Regulation does not specify the application procedure for registration agents. According to the current requirements, the applicants for clinical trials and marketing authorization shall submit the registration agents’ information as part of the application. In other words, a foreign applicant for clinical trials or market authorization in China shall designate its registration agent before the investigational new drug or new drug application is submitted.
《实施条例征求意见稿》未规定注册代理人的申请流程。根据现行的申请资料要求,临床试验的申请人在申请临床试验时、上市许可申请人在申请上市许可时,应提交注册代理人的信息,即在临床试验或上市许可申请前,境外的临床试验的申请人和上市许可申请人应指定好其在中国的注册代理人。

5. MAH of Cross-Border Licensed Products | 跨境许可引进药品的境外持证商

In recent years, an increasing number of drugs have been introduced into the Chinese market through cross-border licensing. For drugs manufactured outside China, Chinese regulatory authorities require the MAH in China to be consistent with that in the foreign market. The MAH of cross-border licensed drugs is typically the foreign licensor or the foreign affiliate of the Chinese licensee and meets the requirement using one of two approaches:

近年来,越来越多的药品通过跨境许可引进的方式在中国上市。对于境外生产的药品,中国的监管机构要求境外市场的持证商与中国的持证商保持一致为满足此项要求,许可引进药品的持证商通常由境外许可方或者中国引进方的境外关联方担任,具体有以下两种方式:

Approach 1: The foreign licensor acts as the MAH in China with the Chinese licensee acting as its local agent.
方式一:由境外许可方担任中国的持证商,中国引进方担任境外持证商的境内代理人。

Approach 2: The foreign affiliate of the Chinese licensee acts as the MAH in China. Specifically, the Chinese licensee obtains the marketing authorization of the drug in a third country or region outside mainland China (e.g., Hong Kong, Taiwan, Singapore, or EU member states) through its existing or newly established affiliate therein, and the affiliate acts as the MAH in China.
方式二:由中国引进方的境外关联方担任中国的持证商。具体而言,中国引进方通过其在中国大陆以外的第三方国家或地区的、已有或新设的关联方(例如,香港、台湾、新加坡或欧盟成员国等),取得药品在该第三方国家或地区的上市许可,并由该关联方担任中国的境外持证商。

The first approach, where the foreign licensor acts as the MAH in China, is adopted in the vast majority of cross-border drug licensing transactions. The benefits are the process is fairly straightforward and facilitates the expedited launch of products in China. However, since the MAH shall be responsible for the safety, efficacy, and quality controllability of the product of which the foreign licensor is not the actual operator, the licensor is often unwilling to act as the MAH in China. In this case, we suggest the licensor adopt appropriate risk-prevention measures. For example, it should include sufficient representations and warranties in the agreement; require the licensee to compensate for any losses incurred due to its failure to fulfill the obligations of local agents; and require the licensee to obtain prior review and approval from the licensor before its submission of files to regulatory authorities to ensure compliance with relevant Chinese laws and regulations, such as the DAL and the Regulation on the Administration of Human Genetic Resources.
绝大部分的药品跨境许可交易采取第一种方式,即由境外许可方担任中国的境外持证商,其好处是流程相对简便,有利于推动药品尽快在中国上市。但是,考虑到MAH需为产品的安全性、有效性和质量可控性负责,且境外许可方不是产品在中国的实际运营人,许可方往往没有意愿担任中国的境外持证商。在此种情况下,我们建议许可方采取适当的风险防范措施,例如,在协议中约定充分的陈述与保证条款、要求引进方因未履行境外持证商境内代理人义务而导致许可方遭受损失时予以赔偿、要求引进方在向监管机构提交文件前由许可方事先审阅和批准,确保符合包括《药品管理法》、《人类遗传资源管理条例》等相关中国法律法规的要求。

A small number of cross-border licensing transactions adopt the second approach, where the foreign affiliate of the Chinese licensee first obtains the drug marketing authorization in a country or region outside mainland China and then acts as the MAH in China. This approach exempts the licensor from the obligations and liabilities of an MAH in China, reducing its regulatory risks. However, the licensor has to give up the marketing authorization in a third country or region or transfer it to the licensee. For the licensee, the time, cost, and uncertainty may increase because it has to obtain the drug market authorization in a third country or region. Moreover, it also has to bear the cost of maintaining the operation of the foreign affiliate to meet the drug marketing requirements in the third country or region.
少数跨境许可引进交易采取第二种方式,即由中国引进方的境外关联方先在中国大陆以外国家或地区取得相关药品的上市许可,并由该关联方担任中国的境外持证商。此种方式下,许可方无需承担中国境外持证商的义务和责任,降低了许可方的监管风险,但是,许可方需要放弃境外某个第三方国家或地区的上市许可或将其转让给引进方。引进方则需要取得该境外第三方国家或地区的药品上市许可,增加了时间成本和不确定性;并且,为满足第三方国家或地区的药品上市监管要求,引进方需承担维护境外关联方的运营成本。

After weighing the pros and cons of the two approaches, the stakeholders involved in cross-border licensing transactions may opt for the more suitable option to serve as the MAH in China, balancing timelines, cost, and complexity.
跨境许可引进的双方需了解上述两种方式的优缺点,综合考虑时间、成本、难度等因素,选择合适的一方担任中国的境外持证商。

6. Conclusion | 结语

The MAH local agent and registration agent play important roles within China’s unique regulatory landscape. The Draft Regulation introduces new qualification criteria for MAH local agents as well as timeframes and processes for their appointment. Pharmaceutical companies are advised to monitor future developments regarding the Draft Regulation and adapt their collaboration strategies with local agents accordingly to ensure timely compliance once the amended Implementation Regulation of the Drug Administration Law comes into force.
境外持证商境内代理人和注册代理人是中国药品监管体系下独特的制度。《实施条例征求意见稿》对境外持证商境内代理人的资质要求、指定的时间和流程等提出了新规。医药企业应持续关注《实施条例征求意见稿》的后续进展,调整与境外持证商境内代理人的合作策略,以期在《药品管理法实施条例》正式修订后及时做出应对。

© Arnold & Porter Kaye Scholer LLP 2023 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.