FDA：与参比制剂生物相似性论证中的科学方面考量

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FDA：与参比制剂生物相似性论证中的科学方面考量
来源：FDA


Ⅰ Introduction 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。

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Ⅱ Scope 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。

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Ⅲ Background 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。

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Ⅳ Complexities 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。

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Ⅴ U.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。

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Ⅵ APPROACHES TO DEVELOPING AND ASSESSING EVIDENCE TO
DEMONSTRATE BIOSIMILARITY 论证生物相似性的方法




FDA recommends that sponsors use a stepwise approach to develop the evidence needed to demonstrate biosimilarity. FDA intends to consider the totality of the evidence provided by a sponsor when the Agency evaluates the sponsor’s demonstration of biosimilarity, consistent with a longstanding Agency approach to evaluating scientific evidence.


FDA 建议申请人采用阶梯式方法来收集证据论证生物相似性。FDA 将整体衡量申请者证明生物相似性的所有证据，这和一直以来用以评价科学证据的方法一致。






A.Using a Stepwise Approach to Demonstrate Biosimilarity 阶梯式方法论证生物相似性






The purpose of a biosimilar development program is to support a demonstration of biosimilarity between a proposed product and a reference product, including an assessment of the effects of any observed differences between the products, but not to independently establish the safety and effectiveness of the proposed product. FDA recommends that sponsors use a stepwise approach to developing the data and information needed to support a demonstration of biosimilarity. At each step, the sponsor should evaluate the extent to which there is residual uncertainty about the biosimilarity of the proposed product and identify next steps to try to address that uncertainty. Where possible, studies conducted should be designed to maximize their contribution to demonstrating biosimilarity. For example, a clinical immunogenicity study may also provide other useful information about the safety profile of the proposed product.


生物相似性研究的目的是论证一个类似药与参比制剂的生物相似性，包括评估两者之间任何可见差异产生的影响，而不是独立地建立该类似药的安全性和有效性。FDA 建议采用阶梯式方法来建立数据和信息，在实施每一步研究时，申请人应评估还有哪些不确定性因素，并确定进一步论证相似性的后续研究。可能的话，试验设计应最大可能地发挥其论证生物相似性的作用。例如，临床免疫性研究也可能提供类似药安全性方面的有用信息。






The stepwise approach should start with extensive structural and functional characterization of both the proposed product and the reference product, which serves as the foundation of a biosimilar development program (sections VII.A and VII.B). The more comprehensive and robust the comparative structural and functional characterization—the extent to which these studies are able to identify (qualitatively or quantitatively) differences in relevant product attributes between the proposed product and the reference product (including the drug substance, excipients, and impurities)—the more useful such characterization will be in determining what additional studies may be needed. For example, rigorous structural and functional comparisons that show minimal or no difference between the proposed product and the reference product will strengthen the scientific justification for a selective and targeted approach to animal and/or clinical testing to support a demonstration of biosimilarity. It may be useful to further quantify the similarity or differences between the two products using a meaningful fingerprint-like analyses algorithm that covers a large number of additional product attributes and their combinations with high sensitivity using orthogonal methods. Such a strategy may further reduce the possibility of undetected structural differences between the products and lead to a more selective and targeted approach to animal and/or clinical testing. A sufficient understanding of the mechanism of action (MOA) of the drug substance and clinical relevance of any observed structural differences, clinical knowledge of the reference product and its class that indicates low overall safety risks, and the availability of a relevant PD measure(s) may provide further scientific justification for a selective and targeted approach to animal and/or clinical studies.


这种阶梯式方法应基于对类似药和参比制剂全面的结构和功能表征信息，这也是相似性研究的基础( VII.A 和VII.B)。这些结构和功能特性的比较越全面彻底，包括药物成分、辅料和杂质是定量或定性比较研究，对确定下一步具体研究越有利。例如，如果有严格的结构和功能比较表明类似药和参比制剂没有或者仅有很小的差异，越能说明为什么采用一个选择性和目标性的动物或临床试验来证明相似性。也可以利用指纹图谱分析方法（利用正交法能覆盖到大部分产品性质及之间的关系），进一步对这相似性或差异进行定量分析。这种方法能进一步降低检测不到产品间差异存在的可能性，从而使下一步动物或临床试验的选择更有目的性。为了证明选择该试验的合理性，还要对活性成分作用机制、结构差异导致的临床反应、参比制剂的临床信息及其产品类别表明的低风险性、动物或临床相关PD研究方法及数据等进行全面的了解。






The sponsor should then consider the role of animal data in assessing toxicity and, in some cases, in providing additional support for demonstrating biosimilarity and in contributing to the immunogenicity assessment (section VII.C). The sponsor should then conduct comparative human PK and PD studies (if there is a relevant PD measure(s)) (section VII.D.1) and compare the clinical immunogenicity of the two products in an appropriate study population (section VII.D.2). If there is residual uncertainty about biosimilarity after conducting structural analyses, functional assays, animal testing, human PK and PD studies, and the clinical immunogenicity assessment, the sponsor should then consider what additional clinical data may be needed to adequately address that uncertainty (section VII.D.3). FDA encourages sponsors to consult extensively with the Agency after completion of comparative structural and functional analyses (before finalizing the clinical program) and throughout development as needed.


申请人要考虑动物试验数据在毒理学研究和某些情况下证明生物相似性的和免疫原性研究当中的重要性（详见VII.C部分），然后在合适的试验人群中进行类似药和参比制剂的人体PK/PD的可比性研究(VII.D.1部分)和临床免疫性的比较研究( VII.D.2部分)。若在结构分析、功能测定、动物试验、人体PK/PD试验后还不能完全确定其生物相似性，则需提供更充分的临床安全数据(VII.D.3部分)。FDA 建议，结构和功能比较分析完成之后（临床试验完成前）或研究过程如有需要，申请者应当和审批机构进行广泛的沟通讨论。






FDA recognizes that some of the aforementioned investigations could be performed in parallel; however, the Agency recommends that sponsors use a stepwise approach to better address residual uncertainty about biosimilarity that might remain at each step and incorporate FDA’s advice provided after FDA review of data and information collected at certain milestones.


FDA要求上述提到的部分研究应当进行平行试验，但是审批机构也建议申请人采用阶梯式方法可以更好的证明每一步生物相似性研究当中的可能存在的不确定性因素；也建议在FDA收到关键的数据信息后，申请人应当和FDA沟通讨论。


B.Using a Totality-of-the-Evidence Approach to Assess a Demonstration of Biosimilarity 采用证据整体法评价生物相似性论证过程


In evaluating a sponsor’s demonstration of biosimilarity, FDA will consider the totality of the data and information submitted in the application, including structural and functional characterization, nonclinical evaluation, human PK and PD data, clinical immunogenicity data, and comparative clinical study(ies) data. FDA intends to use a risk-based approach to evaluate all available data and information submitted in support of the biosimilarity of the proposed product.


评价生物相似性论证时，FDA会全面考察申请人提交的所有的数据信息：包括结构功能特性、非临床研究、人体PK/PD数据、临床免疫性数据和临床研究比较数据。FDA倾向于采用一种基于风险的方法来评估生物相似性论证过程中所有可获得的数据。






Thus, a sponsor may be able to demonstrate biosimilarity even though there are formulation or minor structural differences, provided that the sponsor provides sufficient data and information demonstrating that the differences are not clinically meaningful and the proposed product otherwise meets the statutory criteria for biosimilarity. For example, differences in certain posttranslational modifications or differences in certain excipients (e.g., human serum albumin) might not preclude a finding of biosimilarity if data and information provided by the sponsor show that the proposed 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 products in terms of safety, purity, and potency. Clinically meaningful differences could include a difference in the expected range of safety, purity, or potency of the proposed product and the reference product. By contrast, slight differences in rates of occurrence of certain adverse events between the two products ordinarily would not be considered clinically meaningful differences.


因此，尽管存在处方或者微小的结构差异，只要能够提供有效的数据信息说明这些差异没有临床意义且该类似药符合生物相似性的法规要求，申请人仍然可以证明其生物相似性。例如，如果申请人提供的数据信息可以证明类似药和参比制剂高度相似，且非活性成分差异无论是在安全性、纯度和有效性方面均没有临床有意义差异，那么某些翻译后修饰或某些特定辅料（如人血清蛋白）的不同可能就不会对其生物相似性结果产生影响。有临床意义的差异包括类似药和参比制剂在可控范围内安全性、纯度和效力的差异。相比之下，某些不良反应发生率方面的微小差异通常被认为无临床有意义差异。

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Ⅶ DEMONSTRATING BIOSIMILARITY生物相似性的论证




This section discusses scientific considerations in the stepwise approach to developing data and information needed to support a demonstration of biosimilarity. To demonstrate biosimilarity, a sponsor must provide sufficient data and information to show that the proposed product and the reference product are highly similar notwithstanding minor differences in clinically inactive components and that there are no clinically meaningful differences between the two products in terms of safety, purity, and potency. The type and amount of analyses and testing that will be sufficient to demonstrate biosimilarity will be determined on a product-specific basis.


本部分主要讨论采用阶梯式方法收集生物相似性的数据信息时应注意的科学问题。为了论证生物相似性，申请者必须提供有效的数据信息来说明尽管临床非活性成分存在微小差异，类似药和参比制剂仍然高度相似，且两种产品间的安全性、纯度和效能无临床有意义差别。应根据每个产品的特性，分别采用不同的分析试验类型和数量充分证明其生物相似性。






A.Structural Analyses结构分析






    The PHS Act requires that a 351(k) application 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, unless FDA determines that an element is unnecessary in a 351(k) application. FDA expects that first, a sponsor will extensively characterize the proposed product and the reference product with state-of-the-art technology, because extensive characterization of both products serves as the foundation for a demonstration of biosimilarity. It is expected that the expression construct for a proposed product will encode the same primary amino acid sequence as its reference product. However, minor modifications such as N- or Cterminal truncations that are not expected to change the product performance may be justified and should be explained by the sponsor. Additionally, sponsors should consider all relevant characteristics of the protein product (e.g., the primary, secondary, tertiary, and quaternary structure; posttranslational modifications; and biological activities) to demonstrate that the proposed product is highly similar to the reference product notwithstanding minor differences in clinically inactive components. The more comprehensive and robust the comparative structural and functional characterization is, the stronger the scientific justification for a selective and targeted approach to animal and/or clinical testing.


除非FDA认为不需要，PHS Act要求 351(k) 申请提交的证明生物相似性性的信息，除了其他必需事项外，还应包括能够证明即使临床非活性成分存在微小差异，类似药和参比制剂仍然高度相似的分析试验研究。首先，FDA 希望申请者采用最先进的技术对类似药和参比制剂进行广泛研究，因为这些研究结果是论证生物相似性的基础。通常情况下，FDA 希望类似药和参比制剂的氨基酸序列表达构造相同，但是，像N-或C-端断裂等不会影响安全有效性的微小差异，申请者只要给出科学合理性的解释即可。另外，申请人还必须考虑到蛋白制品所有相关性质（包括一、二、三、四级结构、翻译后修饰、生物活性），以证明即使在临床非活性成分存在微小差异的情况下，其与参比制剂仍具有高度生物相似性。对结构功能比较得越全面，动物和/或临床试验的选择和针对性越科学合理。






Sponsors should use appropriate analytical methodologies with adequate sensitivity and specificity for structural characterization of the proteins. Generally, such tests include the following comparisons of the proposed product and the reference product:


• Primary structures, such as amino acid sequence


• Higher order structures, including secondary, tertiary, and quaternary structure (including aggregation)


• Enzymatic posttranslational modifications, such as glycosylation and phosphorylation


• Other potential variations, such as protein deamidation and oxidation


• Intentional chemical modifications, such as PEGylation sites and characteristics


申请人需要使用灵敏度高、专属性强的分析方法分析蛋白质的结构特性。一般而言，分析实验通常需要比较以下几个方面：


（1）一级结构，如氨基酸序列；


（2）高级结构，包括二级、三级和四级结构（包括聚合）；


（3）酶转录后的修饰，如糖基化和磷酸化；


（4）其他可能的变化，如蛋白脱酰基化反应和氧化反应；


（5）意向化学修饰，如聚乙二醇化结合位点及其特征。






    Sponsors should conduct extensive structural characterization of both the proposed product and the reference product in multiple representative lots to understand the lot-to-lot variability of both products in the manufacturing processes. Lots used for the analyses should support the biosimilarity of both the clinical material used in the clinical study(ies) intended to support a demonstration of biosimilarity, and the to-be-marketed proposed product, to the reference product. Characterization of lots manufactured during process development for the proposed product may also be useful. Sponsors should justify the selection of the representative lots, including the number of lots.


申请人应该对类似药和参比制剂多个有代表性批次进行广泛的结构确认，以了解生产过程中不同批次间的变化。用于进行生物相似性分析的批次应能够代表临床试验、待上市的产品和参比制剂。类似药产品工艺开发期间批次的性质也是有用信息，申请者应能够说明批次及批数选择的合理性。


In addition, FDA recommends that sponsors analyze the finished dosage form of multiple lots of the proposed product and the reference product, assessing excipients and any formulation effect on purity, product- and process-related impurities, and stability. Differences in formulation between the proposed product and the reference product are among the factors that may affect the extent and nature of subsequent animal or clinical testing. A sponsor considering manufacturing changes after completing the initial analytical similarity assessment or after completing clinical testing intended to support a 351(k) application should perform an additional analytical similarity assessment with lots manufactured by the new process and the reference product and establish comparability of the proposed product manufactured by the old and new manufacturing processes. The nature and extent of the changes may determine the extent of the analytical similarity and comparability studies and any necessary additional studies.


此外，FDA 建议申请人分析多个批次的成品来评价辅料和处方对纯度、产品和工艺相关杂质和稳定性的影响。类似药和参比制剂处方不同可能是后续动物或临床试验的影响因素之一。在完成初始相似性评估或临床试验后，申请人为支持其351（K）申请考虑到生产工艺变化，应对新工艺和参比制剂生产的批次进行额外的相似性分析评估，并对由新旧生产工艺生产的产品进行相似性分析。生产工艺的变化可能决定相似性分析的程度，是否需要对比及其他附加试验。


If the reference product or the proposed product cannot be adequately characterized with stateof-the-art technology, the application for the proposed product may not be appropriate for submission under section 351(k) of the PHS Act; and the sponsor should consult FDA for guidance on the appropriate submission pathway.


如果利用最先进的技术仍不能全面描述类似药和参比制剂的特征，则PHS Act351(k) 可能不适用于该产品的申请，申请人应咨询FDA，请FDA指导PHS Act 351(k)是否适用于这种蛋白产品的申请。






B.Functional Assays功能性实验






    The pharmacologic activity of protein products should be evaluated by in vitro and/or in vivo functional assays. In vitro assays may include, but are not limited to, biological assays, binding assays, and enzyme kinetics. In vivo assays may include the use of animal models of disease (e.g., models that exhibit a disease state or symptom) to evaluate functional effects on pharmacodynamic markers or efficacy measures. A functional evaluation comparing a proposed product to the reference product using these types of assays is also an important part of the foundation that supports a demonstration of biosimilarity and may be used to scientifically justify a selective and targeted approach to animal and/or clinical testing.


蛋白产品的药理学活性应当通过体内和/或体外功能性实验评估。体外分析包括但不仅限于生物分析、结合分析和酶动力学。体内分析包括应用动物病理模型（例如表现出疾病状态或病症的模型）来评价对药效学标志物或疗效测定的影响。功能性试验不仅是论证生物相似性的基础，还可用于合理和有针对性的选择动物和/或临床试验。






Sponsors can use functional assays to provide additional evidence that the biologic activity and potency of the proposed product are highly similar to those of the reference product and/or to support a conclusion that there are no clinically meaningful differences between the proposed product and the reference product. Such assays also may be used to provide additional evidence that the MOA of the two products is the same to the extent the MOA of the reference product is known. Functional assays can be used to provide additional data to support results from structural analyses, investigate the consequences of observed structural differences, and explore structure-activity relationships. These assays are expected to be comparative so they can provide evidence of similarity or reveal differences in the performance of the proposed product compared to the reference product, especially differences resulting from variations in structure that cannot be detected using current analytical methods. FDA also recommends that sponsors discuss limitations of the assays they used when interpreting results in their submissions to FDA. Such discussions would be useful for the evaluation of analytical data and may guide whether additional analytical testing would be necessary to support a demonstration of biosimilarity.


申请人可以利用功能性实验进一步说明类似药的生物活性和效力与参比制剂高度相似，证明两者没有临床有意义差异；亦可用于证明两者作用机制相同。功能性试验也可以用于结构分析的结果分析，研究结构差异的影响和结构-活性之间关系。功能性试验应该是比较性的，从而能够证明类似药和参比制剂之间的相似性或揭示其差异，尤其是在现有分析方法不能检测到结构变化导致的结果差异的情况下。此外，FDA 建议申请人在提交的结果中应当讨论功能性实验的限制条件。此类讨论将有助于评估分析数据，并可以用来判断是否需要进行额外的分析测试以支持其生物相似性。






Functional assays can also provide information that complements the animal and clinical data in assessing the potential clinical effects of minor differences in structure between the proposed product and the reference product. For example, cell-based bioactivity assays may be used to detect the potential for inducing cytokine release syndrome in vivo. The available information about these assays, including sensitivity, specificity, and extent of validation, can affect the amount and type of additional animal or clinical data that may be needed to establish biosimilarity. As is the case for the structural evaluation, sponsors should justify the selection of the representative lots, including the number of lots.


功能性实验也可以为用于评价类似药和参比制剂存在微小结构差异时可能会有的临床反应的动物、临床试验提供补充数据。例如，基于细胞的生物活性测定实验可用于检测诱发体内细胞因子释放综合能力的潜能。这些功能性实验分析信息，包括灵敏性、特异性和有效范围，均能够影响下一步所需的动物或临床数据的数量和类型。对于结构评价，申请人应选择有代表性的批次和批次数量。






C.Animal Data动物试验数据






The PHS Act also requires that a 351(k) application include information demonstrating biosimilarity based on data derived from animal studies (including the assessment of toxicity), unless FDA determines that such studies are not necessary in a 351(k) application. Results from animal studies may be used to support the safety evaluation of the proposed product and more generally to support the demonstration of biosimilarity between the proposed product and the reference product.


除非FDA认为不需要，PHS Act要求351(k)申请还应包括动物试验数据（包括毒性评价）。动物试验数据不仅可以用于类似药的安全性评价，更常用于支持类似药和参比制剂之间的生物相似性评价。


1.Animal Toxicity Studies动物毒理学研究


    As a scientific matter, animal toxicity data are considered useful when, based on the results of extensive structural and functional characterization, uncertainties remain about the safety of the proposed product that need to be addressed before initiation of clinical studies in humans (assuming results from animal studies can meaningfully address the remaining uncertainties).


在产品结果和功能特性结果研究、临床试验之前某些需要确证的不确定性安全问题中，动物毒理学数据十分重要(假定动物试验研究结果对这些不确定性产生有益效果)。


The scope and extent of any animal toxicity studies will depend on information about the reference product, information about the proposed product, and the extent of known similarities or differences between the two. As described further in section IX, FDA encourages sponsors to initiate early discussions with the Agency with regard to their biosimilar development plans, including identifying appropriate scientific justifications for not conducting an animal toxicity study or for the scope and extent of such a study.


动物毒理学研究的内容需要根据已知的参比制剂信息、类似药的信息、以及两者相似和差异的程度决定。正如IX部分所述，FDA建议申请人提前和审批机构就生物类似药研究计划进行讨论，讨论不进行动物毒理学研究的原因，或者确定动物毒理学研究的内容。






If comparative structural and functional data using the proposed product provide strong support for analytical similarity to a reference product, then limited animal toxicity data may be sufficient to support initial clinical use of the proposed product. Such a study may be non-sacrificial and include endpoints that measure in-life parameters, PD, and PK (with an assessment of immunogenicity).


若所申请产品的比较结构和功能数据与参比制剂相比有较高相似性，则特定的动物毒性数据可能足以支持所产品的初始临床研究。此类研究是无死亡的，且包括测量寿命参数，PD和PK研究（具有免疫原性评估）。


If the structural and functional data are limited in scope or there are concerns about the proposed product quality, a general toxicology study may be needed that includes full animal pathology, histopathology, PD, PK, and immunogenicity assessments. When animal toxicology studies are conducted, it will be useful to perform a comparative study with the proposed product and the reference product (i.e., comparative bridging toxicology studies). The selection of dose, regimen, duration, and test species for these studies should provide a meaningful toxicological comparison between the two products. It is important to understand the limitations of such animal studies (e.g., small sample size, intra-species variations) when interpreting results comparing the proposed product and the reference product. For a detailed discussion on the design of animal toxicology studies relevant to biological products, see the ICH guidance for industry S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (ICH S6(R1)).


若结构和功能数据的范围有限，或怀疑产品质量，则需要进行一般毒理学研究，包括完整的动物病理学、组织病理学、 PD、PK和免疫原性评估。当进行动物毒理学研究时，将类似药和参比制剂进行比较研究是很有必要的（例如交叉毒理学比较研究）。剂量、给药途径、给药频率和测试对象的选择应使两种产品之间的毒理学比较有意义。当对类似药和参比制剂之间的结果进行对比分析时，了解动物研究的限制是十分重要的，例如小样本量、种内变异等。关于生物制品动物毒理学研究设计的讨论，详见ICH工业指导原则：《S6（R1）对生物技术来源药物的临床前安全性评价指南》。






Safety data derived from animal toxicity studies generally are not expected if clinical data (e.g., from studies or marketing experience outside the United States) using the proposed product are available (with the same proposed route of administration and formulation) that provide sufficient evidence for its safe use, unless animal toxicity studies are otherwise needed to address a specific product quality concern.


除非特殊制品需要额外的毒理研究，若生物类似药的临床数据（如来自美国境外的研究或市场销售数据）是可用的（相同的给药途径和剂型），且为其安全性提供了足够的支持，则通常不要求进行动物毒理实验。






Animal toxicity studies are generally not useful if there is no animal species that can provide pharmacologically relevant data for the product (i.e., no species in which the biologic activity of the product mimics the human response). For a detailed discussion about demonstrating species relevance, see the criteria described in ICH S6(R1). However, there may be some instances when animal data from a pharmacologically nonresponsive species (including rodents) may be useful to support clinical studies with a proposed product that has not been previously tested in human subjects, for example, comparative PK and systemic tolerability studies. If animal toxicity studies are not warranted based on an acceptable scientific justification, additional comparative in vitro testing (using human cells or tissues when appropriate) is encouraged. Data derived using human cells can provide important comparative information between the proposed product and the reference product regarding potential clinical effects (section VII.B), particularly in situations where there are no animal species available for safety testing.


若没有合适的动物能为生物类似药提供药理学相关数据（如在某种产品的生物活性反应中没有物种可以模拟人类的反应），则该动物毒理实验是无用的。关于物种相关性的详细讨论参见ICH S6（R1）。然而，在某些情况下，药理学非应答物种的动物（包括啮齿类）实验数据也可用于未进行临床试验的生物类似药的研究中，例如，比较性PK试验或全身耐受性研究。若动物毒理研究不够科学充分，需要进行额外的体外（适当的人细胞或组织）比较研究。在临床效用（第VII.B节）方面，人细胞试验数据可以提供生物类似药和参比制剂对比的重要信息，尤其是在没有安全性研究、没有合适动物物种的情况下。




In general, nonclinical safety pharmacology, reproductive and developmental toxicity, and carcinogenicity studies are not warranted when the proposed product and the reference product have been demonstrated to be highly similar through extensive structural and functional characterization and animal toxicity studies (if such studies were conducted).


通常情况下，若通过结构功能分析和动物毒理学研究已证实类似药和参比制剂高度相似，就不必再进行非临床安全性研究、生殖发育毒性研究、和致癌性研究。




2. Inclusion of Animal PK and PD Measures动物PK/PD研究




Under certain circumstances, a single-dose study in animals comparing the proposed product and the reference product using PK and PD measures may contribute to the totality of evidence that supports a demonstration of biosimilarity. Specifically, sponsors can use results from animal studies to support the degree of similarity based on the PK and PD profiles of the proposed product and the reference product. PK and PD measures also can be incorporated into a single animal toxicity study, where appropriate. Animal PK and PD assessment will not negate the need for human PK and PD studies.


某些情况下，类似药和参比制剂采用PK/PD方法进行动物单一剂量研究有助于论证生物相似性。特别指出，申请人可以依据动物PK/PD 研究结果论证两药相似的程度。如适用，PK/PD试验也可用于单次动物毒性研究。动物PK/PD研究并不意味着无需进行人体PK/PD研究。




3. Interpreting Animal Immunogenicity Results动物免疫学研究




Animal immunogenicity assessments are conducted to assist in the interpretation of the animal study results and generally do not predict potential immune responses to protein products in humans. However, when differences in manufacturing (e.g., impurities or excipients) between the proposed product and the reference product may result in differences in immunogenicity, measurement of anti-therapeutic protein antibody responses in animals may provide useful information. Additionally, differences observed in animal immunogenicity assessments may reflect potential structural or functional differences between the two products not captured by other analytical methods.


动物免疫学研究可以用来帮助解释动物研究的结果，但并不能预测蛋白制品在人体内的免疫反应。但是，若类似药和参比制剂生产工艺不同（包括杂质或辅料）导致免疫原性反应不同，测试动物的抗体反应可能会能提供某些有用信息。此外，在动物免疫原性研究观察到的差异可能反应出没有被其他分析方法检测到的类似药和参比制剂潜在的结构或功能差异。

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Ⅶ DEMONSTRATING BIOSIMILARITY生物相似性的论证




This section discusses scientific considerations in the stepwise approach to developing data and information needed to support a demonstration of biosimilarity. To demonstrate biosimilarity, a sponsor must provide sufficient data and information to show that the proposed product and the reference product are highly similar notwithstanding minor differences in clinically inactive components and that there are no clinically meaningful differences between the two products in terms of safety, purity, and potency. The type and amount of analyses and testing that will be sufficient to demonstrate biosimilarity will be determined on a product-specific basis.


本部分主要讨论采用阶梯式方法收集生物相似性的数据信息时应注意的科学问题。为了论证生物相似性，申请者必须提供有效的数据信息来说明尽管临床非活性成分存在微小差异，类似药和参比制剂仍然高度相似，且两种产品间的安全性、纯度和效能无临床有意义差别。应根据每个产品的特性，分别采用不同的分析试验的类型和数量充分证明其生物相似性。






A.Structural Analyses结构分析




The PHS Act requires that a 351(k) application 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, unless FDA determines that an element is unnecessary in a 351(k) application. FDA expects that first, a sponsor will extensively characterize the proposed product and the reference product with state-of-the-art technology, because extensive characterization of both products serves as the foundation for a demonstration of biosimilarity. It is expected that the expression construct for a proposed product will encode the same primary amino acid sequence as its reference product. However, minor modifications such as N- or Cterminal truncations that are not expected to change the product performance may be justified and should be explained by the sponsor. Additionally, sponsors should consider all relevant characteristics of the protein product (e.g., the primary, secondary, tertiary, and quaternary structure; posttranslational modifications; and biological activities) to demonstrate that the proposed product is highly similar to the reference product notwithstanding minor differences in clinically inactive components. The more comprehensive and robust the comparative structural and functional characterization is, the stronger the scientific justification for a selective and targeted approach to animal and/or clinical testing.


PHS Act要求 351(k) 申请提交的证明生物相似性性的信息，除了其他必需信息外，还应包括能够证明即使临床非活性成分存在微小差异，类似药和参比制剂仍然高度相似的分析试验数据，除非FDA认为某一数据在351（k）申请中不是必要的。 FDA 希望申请者首先采用最先进的技术对类似药和参比制剂进行广泛研究，因为这些研究结果是论证生物相似性的基础。FDA 期望类似药和参比制剂的氨基酸序列表达构造相同。然而，如N-或C-端断裂等微小差异，申请者可通过科学论证其不会影响安全有效性。另外，申请人还必须考虑到蛋白制品所有相关性质（包括一、二、三、四级结构、翻译后修饰、生物活性），以证明即使在临床非活性成分存在微小差异的情况下，其与参比制剂仍具有高度生物相似性。对结构功能比较得越全面，越有利于动物和/或临床试验的选择和针对性的科学论证。






Sponsors should use appropriate analytical methodologies with adequate sensitivity and specificity for structural characterization of the proteins. Generally, such tests include the following comparisons of the proposed product and the reference product:


申请人应使用灵敏度高、专属性强的分析方法分析蛋白质的结构特性。一般而言，这些分析试验通常包括以下几个方面的可比性：


（1）Primary structures, such as amino acid sequence 一级结构，如氨基酸序列；


（2）Higher order structures, including secondary, tertiary, and quaternary structure (including aggregation) 高级结构，包括二级、三级和四级结构（包括聚合体）；


（3）Enzymatic posttranslational modifications, such as glycosylation and phosphorylation 酶转录后的修饰，如糖基化和磷酸化；


（4）Other potential variations, such as protein deamidation and oxidation 其他可能的变化，如蛋白脱酰基化反应和氧化反应；


（5）Intentional chemical modifications, such as PEGylation sites and characteristics 有意的化学修饰，如聚乙二醇化结合位点及其特征。






Sponsors should conduct extensive structural characterization of both the proposed product and the reference product in multiple representative lots to understand the lot-to-lot variability of both products in the manufacturing processes. Lots used for the analyses should support the biosimilarity of both the clinical material used in the clinical study(ies) intended to support a demonstration of biosimilarity, and the to-be-marketed proposed product, to the reference product. Characterization of lots manufactured during process development for the proposed product may also be useful. Sponsors should justify the selection of the representative lots, including the number of lots.


申请人应该对类似药和参比制剂多个有代表性批次进行广泛的结构表征，以了解生产过程中的批次间差异。这些批次的检测结果应能够支持生物相似性临床试验批次和待上市的产品与参比制剂的生物相似性。类似药产品工艺开发的批次也可用于上述表征分析，申请者应论证批次及批数选择的合理性。






In addition, FDA recommends that sponsors analyze the finished dosage form of multiple lots of the proposed product and the reference product, assessing excipients and any formulation effect on purity, product- and process-related impurities, and stability. Differences in formulation between the proposed product and the reference product are among the factors that may affect the extent and nature of subsequent animal or clinical testing. A sponsor considering manufacturing changes after completing the initial analytical similarity assessment or after completing clinical testing intended to support a 351(k) application should perform an additional analytical similarity assessment with lots manufactured by the new process and the reference product and establish comparability of the proposed product manufactured by the old and new manufacturing processes. The nature and extent of the changes may determine the extent of the analytical similarity and comparability studies and any necessary additional studies.


此外，FDA 建议申请人分析多批类似药和参比制剂成品来评价辅料和处方对纯度、产品和工艺有关杂质和稳定性的影响。类似药和参比制剂处方不同可能是后续动物或临床试验的影响因素之一。申请人在完成初始相似性评估或用于351（K）申请临床试验后，若要改变生产工艺，应对新工艺生产批次与参比制剂生产进行额外的相似性分析评估，并对由新旧生产工艺生产的产品进行相似性分析。生产工艺的变化可能决定相似性分析的程度，是否需要对比及其他附加试验。






If the reference product or the proposed product cannot be adequately characterized with state-of-the-art technology, the application for the proposed product may not be appropriate for submission under section 351(k) of the PHS Act; and the sponsor should consult FDA for guidance on the appropriate submission pathway.


如果利用最先进的技术仍不能全面描述类似药和参比制剂的特征，则PHS Act351(k) 可能不适用于该产品的申请，申请人应咨询FDA，请FDA指导PHS Act 351(k)是否适用于这种蛋白产品的申请。

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B.Functional Assays功能性实验




The pharmacologic activity of protein products should be evaluated by in vitro and/or in vivo functional assays. In vitro assays may include, but are not limited to, biological assays, binding assays, and enzyme kinetics. In vivo assays may include the use of animal models of disease (e.g., models that exhibit a disease state or symptom) to evaluate functional effects on pharmacodynamic markers or efficacy measures. A functional evaluation comparing a proposed product to the reference product using these types of assays is also an important part of the foundation that supports a demonstration of biosimilarity and may be used to scientifically justify a selective and targeted approach to animal and/or clinical testing.


蛋白产品的药理学活性应当通过体内和/或体外功能性实验评估。体外分析包括但不仅限于生物分析、结合分析和酶动力学。体内分析包括应用动物病理模型（例如表现出疾病状态或病症的模型）来评价对药效学标志物或有效测量值的影响。这些功能性试验不仅是论证生物相似性的重要基础，还可作为选择针对性的动物和/或临床试验的科学论证。






Sponsors can use functional assays to provide additional evidence that the biologic activity and potency of the proposed product are highly similar to those of the reference product and/or to support a conclusion that there are no clinically meaningful differences between the proposed product and the reference product. Such assays also may be used to provide additional evidence that the MOA of the two products is the same to the extent the MOA of the reference product is known. Functional assays can be used to provide additional data to support results from structural analyses, investigate the consequences of observed structural differences, and explore structure-activity relationships. These assays are expected to be comparative so they can provide evidence of similarity or reveal differences in the performance of the proposed product compared to the reference product, especially differences resulting from variations in structure that cannot be detected using current analytical methods. FDA also recommends that sponsors discuss limitations of the assays they used when interpreting results in their submissions to FDA. Such discussions would be useful for the evaluation of analytical data and may guide whether additional analytical testing would be necessary to support a demonstration of biosimilarity.


申请人可以利用功能性实验进一步说明类似药的生物活性和效力与参比制剂高度相似以及/或证明两者没有临床有意义差异；亦可用于证明两者作用机制相同。功能性试验可用于支持结构分析的结果，研究结构差异的影响和结构-活性之间关系。这些试验是可比性试验，因此能够证明类似药和参比制剂之间的相似性或揭示其差异，尤其是现有分析方法不能检测到的结构变化导致的结果差异。此外，FDA 建议申请人在提交资料中阐述试验结果时对这些试验的局限性进行讨论，这将有助于评估分析数据，据此判断是否需要进行额外的分析测试以支持其生物相似性。






Functional assays can also provide information that complements the animal and clinical data in assessing the potential clinical effects of minor differences in structure between the proposed product and the reference product. For example, cell-based bioactivity assays may be used to detect the potential for inducing cytokine release syndrome in vivo. The available information about these assays, including sensitivity, specificity, and extent of validation, can affect the amount and type of additional animal or clinical data that may be needed to establish biosimilarity. As is the case for the structural evaluation, sponsors should justify the selection of the representative lots, including the number of lots.


功能性实验也可以为用于评价类似药和参比制剂存在微小结构差异时可能引起的临床反应的动物、临床试验提供补充数据。例如，基于细胞的生物活性测定实验可用于检测体内诱发细胞因子释放的潜能。这些功能性试验所得信息，包括灵敏性、特异性和有效范围，均能够影响下一步所需的动物或临床数据的数量和类型。对于结构评价试验，申请人论证代表性批次和批次数量的选择。

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C.Animal Data动物试验数据




The PHS Act also requires that a 351(k) application include information demonstrating biosimilarity based on data derived from animal studies (including the assessment of toxicity), unless FDA determines that such studies are not necessary in a 351(k) application. Results from animal studies may be used to support the safety evaluation of the proposed product and more generally to support the demonstration of biosimilarity between the proposed product and the reference product.


PHS Act要求351(k)申请应包括动物试验数据（包括毒性评价）用于证明生物相似性，除非FDA认为不需要。动物试验数据不仅可以用于类似药的安全性评价，更常用于支持类似药和参比制剂之间的生物相似性评价。






1. Animal Toxicity Studies动物毒理学研究


As a scientific matter, animal toxicity data are considered useful when, based on the results of extensive structural and functional characterization, uncertainties remain about the safety of the proposed product that need to be addressed before initiation of clinical studies in humans (assuming results from animal studies can meaningfully address the remaining uncertainties).


在结构和功能特性研究后，对于类似药的安全性仍有不确定性时，在人体临床试验之前，开展动物毒理学研究是很有用的(假定动物试验研究结果对证实这些不确定性有意义)。






The scope and extent of any animal toxicity studies will depend on information about the reference product, information about the proposed product, and the extent of known similarities or differences between the two. As described further in section IX, FDA encourages sponsors to initiate early discussions with the Agency with regard to their biosimilar development plans, including identifying appropriate scientific justifications for not conducting an animal toxicity study or for the scope and extent of such a study.


动物毒理学研究的内容和程度根据已知的参比制剂和类似药的信息以及两者已知的相似和差异的程度而定。正如下文IX部分所述，FDA建议申请人提前和审批机构就生物类似药研究计划进行讨论，包括对于不进行动物毒理学研究或者动物毒理学研究的开展内容和程度的论证。






If comparative structural and functional data using the proposed product provide strong support for analytical similarity to a reference product, then limited animal toxicity data may be sufficient to support initial clinical use of the proposed product. Such a study may be non-sacrificial and include endpoints that measure in-life parameters, PD, and PK (with an assessment of immunogenicity).


若所申请产品的结构和功能可比性数据可有力证明其参比制剂相的相似性，则有限的动物毒性数据足以支持所产品的初始临床研究。此类研究是非静态的，包括寿命参数，PD和PK的测量（包括免疫原性评估）。






If the structural and functional data are limited in scope or there are concerns about the proposed product quality, a general toxicology study may be needed that includes full animal pathology, histopathology, PD, PK, and immunogenicity assessments. When animal toxicology studies are conducted, it will be useful to perform a comparative study with the proposed product and the reference product (i.e., comparative bridging toxicology studies). The selection of dose, regimen, duration, and test species for these studies should provide a meaningful toxicological comparison between the two products. It is important to understand the limitations of such animal studies (e.g., small sample size, intra-species variations) when interpreting results comparing the proposed product and the reference product. For a detailed discussion on the design of animal toxicology studies relevant to biological products, see the ICH guidance for industry S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (ICH S6(R1)).


若产品的结构和功能数据范围有限，或对产品的质量存有疑虑，则需要开展一般毒理学研究，包括完整的动物病理学、组织病理学、 PD、PK和免疫原性评估。当开展动物毒理学研究时，对类似药和参比制剂进行可比性研究十分有用（例如交叉毒理学可比性研究）。剂量、给药途径、给药频率和测试对象的选择应对两种产品之间的毒理学有意义。当对类似药和参比制剂之间的结果进行对比分析时，了解动物研究的局限性是十分重要的，例如小样本量、种内变异等。关于生物制品动物毒理学研究设计的讨论，详见ICH工业指导原则：《S6（R1）对生物技术来源药物的临床前安全性评价指南》。






Safety data derived from animal toxicity studies generally are not expected if clinical data (e.g., from studies or marketing experience outside the United States) using the proposed product are available (with the same proposed route of administration and formulation) that provide sufficient evidence for its safe use, unless animal toxicity studies are otherwise needed to address a specific product quality concern.


若生物类似药能提供相同给药途径和剂型产品的临床数据（如来自美国境外的研究数据或上市后案例）充分证明其安全性，则通常不要求进行动物毒理实验，除非特殊制品需要额外的毒理研究。






Animal toxicity studies are generally not useful if there is no animal species that can provide pharmacologically relevant data for the product (i.e., no species in which the biologic activity of the product mimics the human response). For a detailed discussion about demonstrating species relevance, see the criteria described in ICH S6(R1). However, there may be some instances when animal data from a pharmacologically nonresponsive species (including rodents) may be useful to support clinical studies with a proposed product that has not been previously tested in human subjects, for example, comparative PK and systemic tolerability studies. If animal toxicity studies are not warranted based on an acceptable scientific justification, additional comparative in vitro testing (using human cells or tissues when appropriate) is encouraged. Data derived using human cells can provide important comparative information between the proposed product and the reference product regarding potential clinical effects (section VII.B), particularly in situations where there are no animal species available for safety testing.


若没有合适的物种可为某产品提供药理学相关数据（如没有物种可模拟该产品在人类体内的生物反应），则即使动物毒理实验也是无用的。关于物种相关性的详细讨论参见ICH S6（R1）。然而，在某些情况下，无药理反应物种的动物（包括啮齿类动物）实验数据，如比较性PK试验或全身耐受性研究，也可用于未进行过人体试验的生物类似药的临床研究中。若经过科学论证证明动物毒理研究不充分，需要进行额外的体外（如合适，采用人细胞或组织）可比性研究。在临床效用（VII.B部分）方面，人细胞试验数据可以提供生物类似药和参比制剂对比的重要信息，尤其是在没有合适动物物种可用于安全性研究的情况下。






In general, nonclinical safety pharmacology, reproductive and developmental toxicity, and carcinogenicity studies are not warranted when the proposed product and the reference product have been demonstrated to be highly similar through extensive structural and functional characterization and animal toxicity studies (if such studies were conducted).


通常情况下，若通过结构功能分析和动物毒理学研究已证实类似药和参比制剂高度相似，就不必再进行非临床安全性研究、生殖发育毒性研究、和致癌性研究。






2. Inclusion of Animal PK and PD Measures动物PK/PD研究


Under certain circumstances, a single-dose study in animals comparing the proposed product and the reference product using PK and PD measures may contribute to the totality of evidence that supports a demonstration of biosimilarity. Specifically, sponsors can use results from animal studies to support the degree of similarity based on the PK and PD profiles of the proposed product and the reference product. PK and PD measures also can be incorporated into a single animal toxicity study, where appropriate. Animal PK and PD assessment will not negate the need for human PK and PD studies.


某些情况下，类似药和参比制剂采用PK/PD方法进行动物单一剂量研究有助于论证生物相似性。特别指出，申请人可以依据动物PK/PD 研究结果论证两药相似的程度。如适用，PK/PD试验也可用于单次动物毒性研究。动物PK/PD研究并不意味着无需进行人体PK/PD研究。






3. Interpreting Animal Immunogenicity Results动物免疫学研究


Animal immunogenicity assessments are conducted to assist in the interpretation of the animal study results and generally do not predict potential immune responses to protein products in humans. However, when differences in manufacturing (e.g., impurities or excipients) between the proposed product and the reference product may result in differences in immunogenicity, measurement of anti-therapeutic protein antibody responses in animals may provide useful information. Additionally, differences observed in animal immunogenicity assessments may reflect potential structural or functional differences between the two products not captured by other analytical methods.


动物免疫学研究可以用来帮助解释动物研究的结果，但并不能预测蛋白制品在人体内的免疫反应。但是，若类似药和参比制剂生产工艺不同（如杂质或辅料）导致免疫原性反应不同，测试动物的抗体反应可能会能提供某些有用信息。此外，在动物免疫原性研究观察到的差异可能揭示类似药和参比制剂潜在的结构或功能差异，这可能是其他分析方法检测不到的。