ⅠIntroduction前言
This guidance describes the Agency’s current thinking on factors to consider when demonstrating that a proposed therapeutic protein product (hereinafter proposed product or proposed biosimilar product) is highly similar to a reference product licensed under section 351(a) of the Public Health Service Act (PHS Act) for the purpose of submitting a marketing application under section 351(k) of the PHS Act. Specifically, this guidance is intended to provide recommendations to sponsors on the scientific and technical information for the chemistry, manufacturing, and controls (CMC) section of a marketing application for a proposed product submitted under section 351(k) of the PHS Act.
The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) amends the PHS Act and other statutes to create an abbreviated licensure pathway in section 351(k) of the PHS Act for biological products shown to be biosimilar to or interchangeable with an FDA-licensed biological reference product (see sections 7001 through 7003 of the Patient Protection and Affordable Care Act (Affordable Care Act) (Public Law 111-148). The BPCI Act also amended the definition of biological products to include “protein (except any chemically synthesized polypeptide).” A 351(k) application for a proposed biosimilar product must include information demonstrating biosimilarity, based on data derived from, among other things, “analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components.”
Although the 351(k) pathway applies generally to biological products, this guidance focuses on therapeutic protein products and provides an overview of analytical factors to consider in demonstrating biosimilarity between a proposed product and the reference product.
本指南是为了指导申请人对拟申请的治疗性蛋白制品（后文称“拟申请产品”）根据《公共健康服务法（PHS法案）》351（K）部分要求提交上市许可申请时，如何证明其与参比制剂的生物相似性。《生物制品价格竞争和创新法案2009》（BPCI Act）修订了PHS法案和其他相关规定，为拟申请生物制品在PHS Act 351（K）要求下证明与已获批参比制剂的生物相似性或可替代性提供了一个简化申请路径（详见《患者保护和可支付医疗法案》7001-7003部分）。虽然351（K）路径普遍适用于生物制品，本指南重点关注治疗性蛋白制品，并概括了这些制品在生物相似性论证过程中的注意事项。本指南中描述的科学原则也可用于其他类型的生物类似药。
This guidance is one in a series of guidances that FDA is developing to implement the BPCI Act. These guidances address a broad range of issues, including:
• Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product
• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009
• Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants
• Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
本指南是FDA为了实施BPCI Act所发布的指南之一，这些指南涉及多方面的问题，主要包括：
•治疗蛋白制品与参比制剂生物相似性论证中的质量考量；
•与参比制剂生物相似性论证中的科学考量；
•生物类似药：关于实施BPCI Act（2009）的问与答；
•FDA与生物类似药申请企业或申请人之间的正式会议；
•证明与参比制剂具有生物相似性的临床药理学数据。
In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
一般而言，FDA指南文件并非强制执行。除非引用特定监管或立法机构的要求，本指南的内容只是作为建议，指南中的“应该”是指的建议，而非必须。
ⅡScope范围
This guidance gives an overview of FDA’s approach to determining biosimilarity and discusses important scientific considerations in demonstrating biosimilarity, including:
• A stepwise approach to demonstrating biosimilarity, which can include a comparison of the proposed product and the reference product with respect to structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity, and clinical safety and effectiveness
• The totality-of-the-evidence approach that FDA will use to review applications for biosimilar products, consistent with a longstanding Agency approach to evaluation of scientific evidence
• General scientific principles in conducting comparative structural analyses, functional assays, animal testing, human PK and PD studies, clinical immunogenicity assessments, and comparative clinical studies (including clinical study design issues).
本指南总结了FDA对于论证生物相似性的研究，并讨论了生物相似性论证过程中的重要科学问题，包括：
•论证生物相似性的阶梯式方法，包括试验药物和参比制剂在结构、功能、动物毒理、人体药代动力学（PK）、药效学（PD）、临床免疫学和临床安全性及有效性方面的比较。
•FDA采用“整体证据”法来审批生物类似药的申请，这与FDA长期以来评价科学证据的方法是一致的（详见相关工业指南原则）。
•在进行结构比较分析、功能测定、动物试验、人体PK/PD研究、临床免疫学评价和临床比较研究（包括临床研究设计）过程中的一般科学原则。
Additional topics discussed include the following:
• Considerations of the complexities of therapeutic protein products when designing a biosimilar development program, including manufacturing process considerations
• Use of data derived from studies comparing a proposed product with a non-U.S.- licensed comparator product
• Postmarketing safety monitoring considerations
此外，本指南还讨论了以下主题：
•设计治疗性蛋白质品类似药研发方案时关于该产品复杂性的考虑，包括生产工艺复杂性考虑；
•如何使用拟申请产品和非FDA批准的参比制剂的对比数据；
•上市后安全性监测。
This guidance applies to applications submitted under section 351(k) of the PHS Act. However, some scientific principles described in this guidance may be informative for the development of certain biological products under section 505(b)(2) of the FD&C Act.Section 505(b)(2) of the FD&C Act and section 351(k) of the PHS Act are two separate statutory schemes. This guidance is not intended to describe any relationship between the standards for approval under these schemes.
本指南适用于依据PHS Act351（K）提交的申请。但是，本指南中的一些科学原则也适用FD&C Act 505(b)(2)中某些生物制品的开发。FD&C Act505(b)(2)与PHS Act 351(K)是相互独立的阶段，本指南不对两者审批标准的关系进行说明。
ⅢBackground背景
The BPCI Act was enacted as part of the Affordable Care Act on March 23, 2010. The BPCI Act creates an abbreviated licensure pathway for biological products demonstrated to be biosimilar to or interchangeable with a reference product. Section 351(k) of the PHS Act (42 U.S.C. 262(k)), added by the BPCI Act, sets forth the requirements for an application for a proposed biosimilar product and an application or a supplement for a proposed interchangeable product. Section 351(i) of the PHS Act defines biosimilarity to mean “that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”The BPCI Act also amended the definition of biological product to include “protein (except any chemically synthesized polypeptide).”
BPCI Act是2010年3月23日颁布的《可支付医疗法案》的一部分。BPCI Act为那些已证明与参比制剂具有生物相似性或可替代性的生物制品提供了简化申请路径。PHS Act中351(K)(42u.s.c.262(K)部分补充了BPCI Act对生物类似药申请的相关规定。PHS Act的351(i)定义“生物相似性”为：“一种生物制品和参比制剂高度相似，尽管非活性成分存在微小差异”，且“两者在安全性、纯度和产品效价（有效性）上不存在临床意义上的差异”。此外，BPCI Act还修定了生物制品的定义，包括蛋白制品，但不包括化学合成多肽。
Under section 351(k) of the PHS Act, a proposed biological product that is demonstrated to be biosimilar to a reference product can rely on certain existing scientific knowledge about the safety, purity, and potency of the reference product to support licensure. FDA will license a proposed biological product submitted under section 351(k) of the PHS Act if FDA “determines that the information submitted in the application is sufficient to show that the biological product is biosimilar to the reference product” and the 351(k) applicant (or other appropriate person) consents to an inspection of the facility that is the subject of the application (i.e., a facility in which the proposed biological product is manufactured, processed, packed, or held).
PHS Act351(K)规定，类似药可使用参比制剂原有的安全性、纯度和有效性数据来进行生物相似性的论证，作为许可申请的支撑。若FDA认为“申请提交的信息足以表明该类似药与参比制剂生物相似”，且申请人同意对生产、加工、包装或持有该类似药的工厂进行检查，则FDA将批准其申请。
An application submitted under section 351(k) of the PHS Act must contain, among other things, information demonstrating that “the biological product is biosimilar to a reference product” based upon data derived from:
• Analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components;
• Animal studies (including the assessment of toxicity); and
• A clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product.
PHS Act351(K)要求提交的申请除其他事项外，必须包括证明生物制品和参比制剂生物相似的信息，这些数据可来源于：
•论证尽管非活性成分存在微小差异，但该类似药和参比制剂高度相似的分析试验研究；
•动物试验（包括毒理学评价）；
•一个或多个临床试验（包括免疫学和PK/PD研究），以证明其在一个或多个条件下（参比制剂获批适应症下或生物制品申请使用的条件）的安全性、纯度和效价。
The Agency has the discretion to determine that an element described above is unnecessary in a 351(k) application. FDA advises sponsors intending to develop biosimilar products to meet with FDA to present their product development plans and establish a schedule of milestones that will serve as landmarks for future discussions with the Agency. FDA anticipates that early discussions with FDA about product development plans and about approaches to providing adequate scientific justifications will facilitate biosimilar development.
FDA有权认为351(K)申请书中的某些内容是不必要的，因此FDA建议拟开发生物类似药的申请人，应向FDA说明产品开发计划，并定期与FDA讨论。FDA认为，提前和FDA讨论产品研发计划和科学依据有助于生物类似药的发展。
ⅣComplexities of protein products 蛋白制品的复杂性
A sponsor should consider the complexities of protein products and related scientific issues when designing a development program to support a demonstration of biosimilarity.
申请人应考虑蛋白制品的复杂性以及在设计开发计划论证生物相似性时的科学问题。
A．Nature of Protein Products and Relates Scientific Considerations
蛋白产品的性质及相关科学考虑
Unlike small molecule drugs, whose structure can usually be completely defined and entirely reproduced, proteins are typically more complex and are unlikely to be shown to be structurally identical to a reference product. Many potential differences in protein structure can arise. Because even minor structural differences (including certain changes in glycosylation patterns) can significantly affect a protein’s safety and/or effectiveness, it is important to evaluate these differences.
和结构能完全确定和完整复制的小分子药物不同，蛋白质结构复杂得多，且结构上不大可能和参比制剂完全一致。蛋白质结构中会出现很多潜在的差异。因为极小的结构差异（包括某些糖基结构的改变）都可以极大影响一个蛋白质的安全性和有效性，因此对差异的评估十分重要。
In general, proteins can differ in at least three ways:
(1) primary amino acid sequence;
(2) modification to amino acids, such as sugar moieties (glycosylation) or other side chains; and
(3) higher order structure (protein folding and protein-protein interactions).
一般而言，蛋白质的差异主要有以下几类：
（1）主要氨基酸序列；
（2）氨基酸的修饰，如糖基或侧链；
（3）高级序列结构（蛋白折叠和相互作用）。
Modifications to amino acids may lead to heterogeneity and can be difficult to control. Protein modifications and higher order structure can be affected by formulation and environmental conditions, including light, temperature, moisture, packaging materials, container closure systems, and delivery device materials. Additionally, process- as well as product-related impurities may increase the likelihood and/or the severity of an immune response to a protein product, and certain excipients may limit the ability to characterize the protein product.
氨基酸的修饰可能导致异质性且很难控制。蛋白质的修饰及其高级序列结构会受到处方及环境条件的影响，如光、温度、湿度、包装材料、容器密闭系统和运输设备材料。另外，工艺及产品有关物质可增加蛋白制品免疫应答的可能性和严重性，且某些辅料也可能限制蛋白制品的表征。
Advances in analytical sciences enable some protein products to be extensively characterized with respect to their physicochemical and biological properties, such as higher order structures and functional characteristics. These analytical methodologies have increasingly improved the ability to identify and characterize not only the drug substance of a protein product but also excipients and product- and process-related impurities.
分析科学的进步使得蛋白制品的物理化学和生物学特性得到广泛表征，比如高级序列结构和功能特性。这些分析方法学不仅提高了一种蛋白制品的物质的鉴定和表征能力，同时也提高其辅料以及工艺有关物质的鉴定和表征能力。
Despite such significant improvements in analytical techniques, however, current analytical methodology may not be able to detect all relevant structural and functional differences between two protein products. In addition, there may be incomplete understanding of the relationship between a product’s structural attributes and its clinical performance. Thus, as set forth in the PHS Act, data derived from analytical studies, animal studies, and a clinical study or studies are required to demonstrate biosimilarity unless FDA determines an element unnecessary.
尽管分析科学有了巨大的进步，然而目前的分析方法还不能完全检测到两个蛋白质之间结构和功能上的所有差异；并且，目前一种蛋白质制品的结构特性与临床行为之间的关系还未有透彻的理解。因此，如PHS Act规定，证明生物相似性要求提供分析研究、动物研究、临床研究的数据，除非FDA认为某一项不是必须的。
B．Manufactring Process Considerations 生产工艺的考虑
Different manufacturing processes may alter a protein product in a way that could affect the safety or effectiveness of the product. For example, differences in biological systems used to manufacture a protein product may cause different posttranslational modifications, which in turn may affect the safety and/or effectiveness of the product. Thus, when the manufacturing process for a marketed protein product is changed, the application holder must assess the effects of the change and demonstrate—through appropriate analytical testing, functional assays, and/or in some cases animal and/or clinical studies—that the change does not have an adverse effect on the identity, strength, quality, purity, or potency of the product as they relate to the safety or effectiveness of the product. The International Conference on Harmonisation (ICH) guidance for industry Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process (ICH Q5E) describes scientific principles in the comparability assessment for manufacturing changes.
不同的生产过程可能会一定程度上改变蛋白制品，从而影响其安全性或有效性。例如，蛋白制品在生产时使用不同的生物系统可能会引起不同的翻译后修饰，从而影响产品的安全性和/或有效性。因此，若已上市蛋白制品的生产过程发生变化，申请人必须评价这种改变带来的影响，并通过分析试验、功能测试、动物或临床试验（若必要）等适用的方法说明这些改变对产品的一致性、强度、质量、纯度和效价没有不良影响。ICH Q5E指南（《生物技术产品/生物制品在工艺变更时的可比性》）描述了生产工艺变更时可比性评估的科学原则。
Demonstrating that a proposed product is biosimilar to a reference product typically will be more complex than assessing the comparability of a product before and after manufacturing changes made by the same manufacturer. This is because a manufacturer that modifies its own manufacturing process has extensive knowledge and information about the product and the existing process, including established controls and acceptance parameters. By contrast, the manufacturer of a proposed product is likely to have a different manufacturing process (e.g., different cell line, raw materials, equipment, processes, process controls, and acceptance criteria) from that of the reference product and no direct knowledge of the manufacturing process for the reference product. Therefore, even though some of the scientific principles described in ICH Q5E may also apply in the demonstration of biosimilarity, in general, FDA anticipates that more data and information will be needed to establish biosimilarity than would be needed to establish that a manufacturer’s post-manufacturing change product is comparable to the pre-manufacturing change product.
论证生物类似药和参比制剂的生物相似性，相比评估同一制造商生产工艺变更前后的可比性要复杂得多。因为同一制造商对自己产品和生产工艺（包括控制和可接受参数）的信息十分了解，相比之下，类似药生产商的生产工艺（如细胞线、原材料、设备、工艺、工艺控制和可接受标准）与参比制剂的不同，而且没有参比制剂生产工艺的相关信息。因此，尽管ICH Q5E中提供了关于生物相似性论证科学原则，但相比工艺变更可比性论证仍需要更多的信息。
ⅤU.S.-Licensed ReferenceProduct and other Comparators
美国批准的参比制剂和其他对照药
To obtain licensure of a proposed product under section 351(k) of the PHS Act, a sponsor must demonstrate that the proposed product is biosimilar to a single reference product that previously has been licensed by FDA. In general, a sponsor needs to provide information to demonstrate biosimilarity based on data directly comparing the proposed product with the reference product. As a scientific matter, analytical studies and at least one clinical PK study and, if appropriate, at least one PD study, intended to support a demonstration of biosimilarity for purposes of section 351(k) of the PHS Act must include an adequate comparison of the proposed biosimilar product directly with the U.S.-licensed reference product unless it can be scientifically justified that such a study is not needed. However, a sponsor may seek to use data derived from animal or clinical studies comparing a proposed product with a non-U.S.-licensed comparator product to address, in part, the requirements under section 351(k)(2)(A) of the PHS Act. In such a case, the sponsor should provide adequate data or information to scientifically justify the relevance of these comparative data to an assessment of biosimilarity and establish an acceptable bridge to the U.S.- licensed reference product.17 Sponsors are encouraged to discuss with FDA during the development program their plans to provide an adequate scientific justification and bridge to the U.S.-licensed reference product. A final decision about the adequacy of such justification and bridge will be made by FDA during review of the 351(k) application.
为获得PHS Act351(k)项下的生物制品许可证，申请人必须证实生物类似药和一个已经获得FDA 批准的产品的生物相似性。通常情况下，申请人需要提供两者生物相似性的直接对比数据。包括通过分析研究、至少一个临床药代动力学研究和药效学研究等充分的对比研究，除非通过科学论证某一项研究可免。然而，某些情况下，申请人可以通过与非美国批准的参比制剂的动物或临床研究对比来论证PHS Act 351(k)(2)(A)的部分要求。这种情况下，申请人必须提供足够的数据信息来论证这些可比性数据与生物相似性评价的相关性，并且和美国获批产品建立适当桥接。FDA鼓励申请者在项目开发的过程中主动沟通讨论，最终，FDA将在351(K)申请审评时会对信息是否充足做出决定。
