完善《中国上市药品目录集》研究.pdf

1 Study of Improvement on the Approved Drug Catalog of China3 目录 DIRECTORY 前言：研究背景 Preface: Study Background 1. 前期研究成果综述 1. Summary of Previous Study Findings 2. 本课题的研究背景 2. Study Background of this Project 一、美国“桔皮书”制度及其评述 1.“Orange Book” System and Comments on it （一）桔皮书制度的来龙去脉 ( I ) The Origin and Development of Orange Book System （二）美国“桔皮书”制度的主要内容 ( II ) Main Content of the Orange Book System 1. 桔皮书的制定机构 1. Enacting Bodies of the Orange Book 2. 桔皮书的主要内容 2. Main Content of the Orange Book 3. 桔皮书的性质和功能 3. Nature and Functions of Orange Book （三）美国“桔皮书”制度实施情况及其完善 ( III ) Implementation and Evolution of the Orange Book System in the United States 1. “桔皮书”制度的完善 1. The Evolution of Orange Book System 6 6 9 14 14 20 20 21 29 31 314 33 38 42 42 44 49 49 49 51 54 61 2. 关于登记错误或不当的救济 2. Remedies for Erroneous or Improper Patent Registration （四）美国“桔皮书”制度的实施效果，影响及评价 等 ( IV ) Implementation and Influence of the U.S. Orange Book System, and Comments on it （五）其他国家和地区的相关制度 ( V ) Systems of Other Countries and Regions 1. 其他实施专利链接制度的国家 1. Other Countries with Patent Linkage 2. 未实施药品专利链接制度而有参比试剂或标准 试剂的国家和地区 2. Other Regions and Countries with RLDs or RS 二、中国上市药品目录集及其评述 2. The Approved Drug Catalog of China and Comments on it （一）中国上市药品目录集的出台背景 ( I ) Background of the Approved Drug Catalog of China 1. 出台背景 1. Background 2. 制定过程 2. Formulation Process （二）中国上市药品目录集的主要内容 ( II ) Main Content of the Approved Drug Catalog of China （三）实施情况及其效果 ( III ) Implementation of the Catalogue and the Results of it5 三、 中国上市药品目录集 与美国 “桔皮书” 之异同 3. Similarities and Differences between the Approved Drug Catalog of China and the Orange Book of the United States （1）起步阶段 (1) Early Stage （2）扩展阶段 (2) Expansion Stage （3）完善阶段 (3) Mature Stage 四、中国上市药品目录集之完善 4. Improvement on the Approved Drug Catalog of China 1. 明确中国上市药品目录集的功能和定位 1. Clarify the Functions and Roles of the Approved Drug Catalog of China 2. 立足中国国情，吸取国外经验教训 2. Based on Chinas Actual Situation, Draw on Experiences and Lessons from Foreign Countries 3. 厘清中国上市药品目录集存在的问题 3. Clarify Existing Problems of the Approved Drug Catalog of China 4. 完善中国上市药品目录集之建议 4. Suggestions for Improvement on the Approved Drug Catalog of China 结语：中国上市药品目录集示例及说明 Conclusion: Illustrations and Explanations on the Catalog 64 65 65 66 72 73 78 81 85 976 前言：研究背景 PREFACE: STUDY BACKGROUND 1. 前期研究成果综述 北京务实知识产权发展 中心 （以下简称 “务实中心” ） 于 2015 年 10 月 启 动“ 药 品 专利链接制度”研究相关工 作， 并 先 后 于 2016 年 12 月 25 日完成了建立药品上市 申报与专利保护衔接机制研 究报告（以下简称“一期 报 告 ”）， 于 2018 年 4 月 10 日完成了探索建立中国 药品专利链接制度研究报告 （以下简称“二期报告”）。 一期报告中，主要介绍 过其他国家和地区应对药品 注册过程中专利问题的相关 制度。考虑到研究的目的是 论证在中国建立药品上市申 报与专利保护衔接机制（即 1. Summary of Previous Study Findings Beijing Intellectual Property Institute (BIPI for short) started the study on pharma- ceutical patent linkage system in October 2015, and successively completed the Study Report on Establishing the Linkage Mech- anism between New Drug Application and Patent Protection (hereinafter referred to as Phase I Report) on December 25, 2016, and the Study Report on Exploring the Es- tablishment of Chinas Pharmaceutical Pat- ent Linkage System (hereinafter referred to as Phase II Report ) on April 10, 2018. The Phase I Report mainly introduces the counterpart systems of other countries and regions to deal with patent problems in the process of drug registration. Considering that the purpose of the study is to demon7 药品专利链接制度）的必要 性与可行性，报告的第一部 分重点介绍了以美国为代表 的药品专利链接制度 ，对 1984 年 Hatch-Waxman 法 案中与药品专利链接相关的 制度的出台背景、 制度规则、 实施情况及实施效果做了较 为详细、深入的研究。同时， 对于以欧盟、日本为代表的 侧重于创新药产业保护的数 据保护制度，以及报告中称 之为“第三种路径”的印度 的相关情况，也进行了研究 和评述。并对三种模式的效 果进行了比较研究。报告的 第二部分主要介绍了中国国 内医药产业的现状，并重点 关注了目前国内医药产业所 存在的问题。报告的第三部 分的梳理与药品管理和知识 产权保护相关的法律制度规 则基础上，尝试厘清现行医 药政策中存在问题。同时， 报告中指出，中国引入药品 专利链接制度具有必要性， 并且也具有可行性。在医药 制度改革之际，在药品法和 专利法修法之际，引入药品 专利链接制度，将有利于推 动我国医药产业的发展。报 告最后提出了相关的立法建 strate the necessity and feasibility of es- tablishing a linkage mechanism (i.e. phar- maceutical patent linkage system) between new drug application and patent protection in China, the first part of the report focuses on the pharmaceutical patent linkage sys- tem represented by the United States, and delves into the background for the promul- gation of provisions related to pharmaceu- tical patent linkage in the Hatch-Waxman Act of 1984, the provisions themselves and their implementation. In addition, the re- port also investigates and reviews the data protection system, typically in Europe and Japan, which favors the protection of inno- vative drug industry, as well as the model adopted by India, i.e. the Third Path, as the report puts it. The results of the three models are compared in the report. The second part of the report mainly introduces the current situation of the domestic phar- maceutical industry in China, and focuses on the problems existing therein. The third part of the report makes an attempt to clarify the problems in the current phar- maceutical policies after summarizing the legal systems related to drug administra- tion and intellectual property protection. At the same time, the report points out that it is both necessary and feasible for China to introduce the pharmaceutical patent linkage system. At the critical time for the8 议，并对引入药品专利 链接制度之后的实施效 果作出预期。 二期报告是在一 期报告基础上，在中共 中央办公厅、国务院办 公厅发布了关于深化 审评审批制度改革鼓励 药品医疗器械创新的意 见，明确要在中国探 索建立药品专利链接制 度的背景下完成的。如 果说一期报告还侧重 于论证是否应当引进药 品专利链接制度，二期 报告完成时，引进药品 专利链接制度的必要性 已经毋庸置疑，故研究 的侧重点放在如何在中 国构建药品专利链接制 度 ，换言之 ，如何实现 肇始于美国的药品专利 链接制度在中国的本土 化。二期报告首先探讨 了药品专利链接制度的 核心价值和制度基础， 即市场确定性是药品专 利链接制度的核心价值 所在，严格依法保护药 品创新是药品专利链接 制度有效实施的前提和 pharmaceutical system reform, and amendment of Pharmaceutical Administration Law and Patent Law, the introduction of pharmaceutical patent linkage system will be conducive to the develop- ment of Chinas pharmaceutical industry. At the end of the report, some legislative suggestions are put forward, and predictions are made on the implementation of pharmaceutical patent linkage system. The Phase II Report is worked out based on the Phase I Report and against the background of the Opinions on Deepening the Reform of the Review and Approval System to Encourage Innovation in Drugs and Medical Devices promulgated by the General Office of the CPC Central Committee and the General Office of the State Council, to confirm Chinas will to establish a pharmaceutical patent linkage system. It can be said that the Phase I Report still focuses on demonstrating whether the pharmaceutical patent linkage system should be adopted. However, by the time the Phase II Report is completed, all doubts about the neces- sity of adopting such a system have been cleared up, so the study focuses on how to build the sys- tem in China, in other words, how to realize the localization of the pharmaceutical patent linkage system which originated in the United States. The Phase II Report first discusses the core value and institutional basis of the pharmaceutical patent linkage system, and reveals that market certainty is the core value, and strict legal protection of9 基础。由于药品专利链接制 度涉及专利管理部门、药品 监管部门以及法院等相关机 构，报告的第二部分参照美 国 USPTO、FDA 及法院在药 品专利链接制度实施后的职 责情况，对中国实施药品专 利链接制度后各部门的职责 变化情况作出预期。报告随 后结合药品专利链接制度实 施的各个环节，探讨如何在 中国制度环境下实施药品专 利链接制度，包括：建立中 国的 “桔皮书” 制度， 建立 “拟 制侵权”制度，明确专利挑 战的程序规则，明确专利挑 战案件的管辖，以及专利挑 战案件中可能涉及的其他实 体及程序问题，如专利挑战 案件的法律责任，专利挑战 案件中相关技术的认定与查 明，专利无效结果的通知， 涉及多个仿制药申请人的案 件的处理，以及其他案件结 果的认可等。 2. 本课题的研究背景 药品专利链接制度肇始 于美国，其中，经治疗等 同性评价批准的药物（又 称“桔皮书”）收录了美国 drug innovation is the premise and basis for the effective implementation of such a sys- tem. As the pharmaceutical patent linkage system involves the patent administration department, drug regulatory agency, courts and other relevant authorities, the second part of the report anticipates the changes in the responsibilities of different authori- ties after the implementation of the system in China by reference to the responsibilities of USPTO, FDA and courts in the United States after the implementation of the pharmaceutical patent linkage system. The report then discusses all aspects of imple- mentation of the system in the context of Chinas institutional environment, including: establishing Chinas Orange Book system, building a artificial act of infringement system, clarifying the procedural rules and jurisdiction of patent challenges, as well as other entity or procedure issues that may be involved in patent challenge cases, such as legal liabilities in patent challenge cases, identification and ascertainment of related technologies in such cases, notification of patent invalidity, handling of cases involving multiple generic drug applicants, and rec- ognition of other outcomes of the cases, etc. 2. Study Background of this Proj- ect10 食品药品监管局（以下 简称“FDA”）根据联 邦食品 、药品 、化妆品 法案 （以下简称 “FD if the drug regulatory agency is mentioned when a proposal or suggestion is made, its name is “National Medical Products Administration” or NMPA.13 于中国尚未建立药品专利链 接制度，目录集的出台， 更主要的是为了满足“仿制 药一致性评价”的要求。在 两办已经发布相关意见 的基础上，在中国探索建立 药品专利链接制度的过程中， 目录集中所登载的内容 以及该目录集是否可以满 足中国药品专利链接制度的要求 值得进一步深入研究。 基于此 ，务实中心与 RDP AC 合作开展中国上市药 品目录集与美国“桔皮书”的 比较研究， 旨在为完善 目录集 ， 使其能在中国药品专利链接制度 的实施过程中有效发挥作用提供 意见与建议。 需要说明的是，由于专业 原因，务实中心主要是从药品专 利保护的角度开展研究，对于美 国桔皮书和目录集中所涉及 的药品领域的专业问题，由于学 识所限，不做赘述。 uation. On the basis of the Opinions issued by the Two Offices, and while the establish- ment of pharmaceutical patent linkage sys- tem is being explored in China, it is worth further study whether the Catalog and the content of it can meet the requirements of the system. For this purpose, the BIPI has cooperated with RDPAC to carry out a comparative study between the Catalog and the “Orange Book” of the United States, which aims to provide opinions and suggestions for im- proving the Catalog and bringing it into full play in the implementation of the Chinese pharmaceutical patent linkage system. It should be noted that due to professional reasons and limited knowledge, the BIPI carries out the study mainly from the per- spective of drug patent protection, and does not elaborate on the professional problems in the pharmaceutical field in- volved in the Orange Book of the United States and the Catalog.14 美国“桔皮书” 制度及其评述 （一）桔皮书制度 的来龙去脉 美国于1 9 0 6年通过了 食品和药品法案，该法 案并不要求药物在销售之前 在动物或者人身上进行安全 性检测，不要求药厂提供有 效证据。1912 年国会通过了 食品和药品法案的一条 修正案，规定：如果 FDA 认 为药厂存在虚假广告行为， 比如某药厂宣称它的某种药 能治某种肿瘤 ， F D A 不能靠 证明这个药有没有效来做决 定，而是要靠证明这个药确 实无效来做决定。这一情况 一直持续到 1937 年，美国发 生了著名的“磺胺酏事件”。 这是上世纪影响最大的药害 1 “ORANGE BOOK” SYSTEM AND COMMENTS ON IT ( I ) The Origin and Development of “Orange Book” System In 1906, the United States passed the Federal Food and Drug Act, which did not require prior testing of drugs for safety on human body or animals before they are sold, and did not require drug makers to prove the effectiveness of their drugs. In 1912, the Congress passed an amendment to the Federal Food and Drug Act, which stipulated that if the FDA believes that a drug maker is engaged in false advertising, for example, a drug maker claims that a drug can cure a certain tumor, the FDA cannot make a decision by proving whether the drug is effective or not, but by proving that the drug is indeed ineffective. The situation lasted until 1937, when the famous Elixir15 事件之一 。针对该事 件，美国国会于 1938 年 通 过 了 FD Section 505(j) (7) of the Federal Food, Drug, and Cosmetic Act (FD (3) drug products with approval under Section 505 of the FDCA administered by the Center for Biologics Evaluation and Research; and (4) a cumulative list of approved products that have never been marketed, are for exportation, are for military use, have been discontinued from marketing and we have not determined that they were withdrawn from sale for safety or effectiveness reasons, or have had their approvals withdrawn for other than safety or efficacy reasons subsequent to being discontinued from marketing. 20 This publication also includes indices of prescription and OTC22 所有确定的名称均与 21 CFR 299.4(e) 中规定的官 方药典名称或美国通用 药名 （USAN） 保持一致。 此外 ，附录 C 还提供了 一份统一术语列表。 增补版 包含 了处方药 、非处方药 、 停用药品目录及生物制 品评价与研究中心依照 FD + means that the product is a Reference Listed Drug (RLD), while ! means that the product is a Reference Standard (RS). 21 网页版桔皮书网址：accessdata.fda. gov/scripts/cder/ob/default.cfm 21 The website of the Orange Book: accessdata.fda.gov/ scripts/cder/ob/default.cfm25 美国桔皮书网页版公示形式示例 An example of the Web version Orange Book of the United States 市场状态 有效成分 药品名 申请号 剂型 给药 途径 规格 TE 编 码 参比 制剂 参考 标准 持有人 Mkt. Statu Active Ingredient Proprietary Name Appl No Dosage Form Route Strength TE Code RLD RS Applicant Holder RX ATORVASTATIN CALCIUM LIPITOR N020702 TABLET ORAL EQ 10MG BASE AB RLD PFIZER INC RX ATORVASTATIN CALCIUM LIPITOR N020702 TABLET ORAL EQ 10MG BASE AB RLD PFIZER INC RX ATORVASTATIN CALCIUM ATORVASTATIN CALCIUM A091226 TABLET ORAL EQ 10MG BASE AB MYLAN PHARMACEUTICALS INC 22 Section 505 (b) (1) of the Federal Food, Drug, and Cosmetic Act. 23 Section 314.53 (b) (1) of Title 21, the Code of Federal Regulations (CFR). 24 Section 314.53 (e) of Title 21, the Code of Federal Regulations (CFR). 就桔皮书所披露的专利 类型而言，根据相关规定， NDA 持有人须向 FDA 提交关 于下列内容的信息：“主张 申请人所提交申请的药品， 或主张使用该药品的一种方 法，或在一个未被所有者授 权的人从事该药品生产、使 用或销售的情况下可就该药 品合理主张专利侵权的专 利”。 22 此要求适用于“原料 药 （活性成分） 专利、 药品 （配 方和组成）专利以及使用方 法专利”。 23 FDA 将在桔皮书 中列出关于 NDA 持有人提交 的关于这些类型的专利的信 息。 24 而关于 “工艺专利 、 主张包装权利的专利、主张 代谢物权利的专利以及主张 22 联邦食品、 药品、 化妆品法案 第 505(b)(1) 条。 23 联 邦 法 规 汇 编 （C.F.R.） 第 21 篇 第 314.53(b)(1) 条。 24 联 邦 法 规 汇 编 （C.F.R.） 第 21 篇 第 314.53(e) 条。 In terms of the type of patent disclosed in the Orange Book, relevant regulations stipulate that, the NDA holder must submit to FDA information about the following: “patents that claim the drug that is the subject of the NDA, or a method of use for that drug, and with respect to which a claim of patent infringement could reasonably be asserted when a person who is not authorized by the owner is engaged in the production, use or sale of the drug.” 22 This requirement is applicable to “patents for Active Pharmaceutical Ingredients (APIs), drugs (formulations and compositions), and methods of use”. 23 FDA will list the information about these types of patents submitted by NDA holders in the Orange Book. 2426 25 联邦法规汇编（C.F.R.）第 21 篇 第 314.53(e) 条。 26 联邦法规汇编（C.F.R.）第 21 篇 第 314.53(e) 条。 27 联邦食品、药品、化妆品法案第 505(b)(2)(A) Whether the issue of a patent is delayed (and thus will not be taken as a basis to require applicants with pending ANDA or 505(b)(2) application to provide a certification or a statement) depends on the submission date of the patent information, instead of the date when the patent information is published in the Orange Book; whether 30-month stay of FDA approval is provided depends on whether the patent information has been submitted before ANDA or 505(b)(2) application is filed, instead of on when the patent information is published in the Orange Book. Although the law stipulates that NDA applicant should submit the patents (including patent application number and patent expiration date) related to the new drug application to FDA for their publication in the Orange Book, 30 based on the verdict of the Aaipharma Inc. V. Tomspon case, the 30 参见联邦法规汇编（C.F.R.）第 21 篇第 355(b)(1)(G