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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(下)
本文转载自FDA2017-05-11 17:29:04 收藏

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。


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。


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。


D.Clinical Studies – General Considerations临床研究——一般考虑


The sponsor of a proposed product must include in its submission to FDA information demonstrating 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.”

申请人提交给FDA的信息必须能够证明“类似药和参比制剂在其安全性、纯度和效力方面无临床有意义差别。”


The nature and scope of the clinical study or studies will depend on the nature and extent of residual uncertainty about biosimilarity after conducting structural and functional characterization and, where relevant, animal studies. The frequency and severity of safety risks and other safety and effectiveness considerations (e.g., poor relationship between pharmacologic effects and effectiveness) for the reference product may also affect the design of the clinical program. The scope of the clinical program and the type of clinical studies (i.e., comparative human PK, PD, clinical immunogenicity, or clinical safety and effectiveness) should be scientifically justified by the sponsor.

临床研究或试验的性质和范围取决于进行结构和功能特征以及相关的动物研究后存在的生物相似性不确定因素的性质和程度。参比制剂安全风险的频率和严重程度以及其他安全性和有效性的因素(如药理作用和有效性间缺乏相关性)也可能影响临床试验的设计。申请人应科学合理的确定临床项目范围及临床研究的类型(如人体PK/PD对比研究、临床免疫原性或临床安全性和有效性研究)。


As a scientific matter, FDA expects a sponsor to conduct comparative human PK and PD studies (if there is a relevant PD measure(s)) and a clinical immunogenicity assessment. In certain cases, the results of these studies may provide adequate clinical data to support a conclusion that there are no clinically meaningful differences between the proposed biosimilar product and the reference product. However, if residual uncertainty about biosimilarity remains after conducting these studies, an additional comparative clinical study or studies would be needed to further evaluate whether there are clinically meaningful differences between the two products.

从科学角度看,FDA鼓励申请人进行人体PK/PD比较性研究(若有相关的PK研究)和临床免疫原性评估。在某些情况下,这些研究的结果可以为生物类似药和参比制剂无临床有意义差异提供充分的临床数据。然而,如果在进行这些研究后仍存在对生物相似性的不确定,则需要进行额外的临床比较研究或试验来进一步评价两种药品之间是否存在临床有意义差异。


1.Human Pharmacology Data人体药理学数据

Human PK and PD profiles of a protein product often cannot be adequately predicted from functional assays and/or animal studies alone. Therefore, human PK and PD studies comparing a proposed product to the reference product generally are fundamental components in supporting a demonstration of biosimilarity. Both PK and PD studies (where there is a relevant PD measure(s)) generally will be expected to establish biosimilarity, unless a sponsor can scientifically justify that such a study is not needed.  Even if relevant PD measures are not available, sensitive PD endpoints may be assessed if such assessment may help reduce residual uncertainty about biosimilarity.

通常,仅通过功能测定和/或动物研究不能充分评估某种蛋白制品的人体PK和PD。因此,类似药和参比制剂的人体PK 和PD 比较数据是支持生物相似性的基本组成,也是必须的,除非申请人科学论证其不必要性。即使没有PD研究方法,也可以通过评估PD敏感终点来帮助减少生物相似性的不确定性。


Sponsors should provide a scientific justification for the selection of the human PK and PD study population (e.g., patients versus healthy subjects) and parameters, taking into consideration the relevance and sensitivity of such population and parameters, the population and parameters studied for the licensure for the reference product, as well as the current knowledge of the intra-subject and inter-subject variability of human PK and PD for the reference product. For example, comparative human PK and PD studies should use a population, dose(s), and route of administration that are adequately sensitive to allow for the detection of differences in PK and PD profiles. FDA recommends that, to the extent possible, the sponsor select PD measures that (1) are relevant to clinical outcomes (e.g., on mechanistic path of MOA or disease process related to effectiveness or safety); (2) are measurable for a sufficient period of time after dosing to ascertain the full PD response and with appropriate precision; and (3) have the sensitivity to detect clinically meaningful differences between the proposed product and the reference product. Use of multiple PD measures that assess different domains of activities may also be of value.

申请人要说明PK 和PD 研究中试验人群(如患者和健康人的比例)和参数选择的科学合理性,要综合考虑这些人群和参数之间的关联度和灵敏度、服用参比制剂的人群和参数研究以及参比制剂在受试者体内或受试者之间PK 和PD的相关变化。例如,人类PK/PD比较性研究采用的人群、剂量和给药途径应具有足够灵敏度,以检测PK/PD的差异性。FDA建议,PD参数应选择:(1)和临床结果相关,例如与MOA作用机制或疾病发展过程的安全性或有效性相关;(2)给药后的一段时间内可测性,确保全PD反应的精确测定;(3)足够灵敏,可以检测到两药之间的差异。使用多个PD指标来评估不同反应活动也可能可取的。


When there are established dose-response or systemic exposure-response relationships (response may be PD measures or clinical endpoints), it is important to select, whenever possible, a dose(s) for study on the steep part of the dose-response curve for the proposed product. Studying doses that are on the plateau of the dose-response curve is unlikely to detect clinically meaningful differences between the two products. Sponsors should predefine and justify the criteria for PK and PD parameters for studies included in the application to demonstrate biosimilarity

当存在确定的剂量-反应或全身暴露-反应关系时(这些反应可能是PD指标或者临床重点),应尽量选择生物类似药试验中研究剂量-反应曲线陡峭部分的剂量。研究剂量-反应曲线的平台剂量无法检测出两种药品之间是否具有临床有意义差异。申请者应事先定义并证明包括用于证明生物相似性试验的PK/PD参数的标准。


A human PK study that demonstrates similar exposure (e.g., serum concentration over time) for the proposed product and the reference product may provide support for a demonstration of biosimilarity. A human PK study may be particularly useful when the exposure correlates with clinical safety and effectiveness. A human PD study that demonstrates a similar effect on a relevant PD measure(s) related to effectiveness or specific safety concerns (except for immunogenicity, which is evaluated separately) represents even stronger support for a biosimilarity determination.

人体PK试验能证明二者有相似暴露量的(如血浆时间浓度),可以为生物相似性提供依据,当其反应与临床安全性和有效性的相关性时尤其有用。当PD研究能证明与有效性或特殊安全因素(除免疫原性,其单独评价)相关的PD测量值相似时,其对于证明生物相似性更有有力。


In certain cases, establishing a similar clinical PK, PD, and immunogenicity profile may provide sufficient clinical data to support a conclusion that there are no clinically meaningful differences between the two products. PK and PD parameters are generally more sensitive than clinical efficacy endpoints in assessing the similarity of two products. For example, an effect on thyroid stimulating hormone (TSH) levels would provide a more sensitive comparison of two thyroxine products than an effect on clinical symptoms of euthyroidism.

在某些情况下,建立相似的临床PK、PD以及免疫原性反应足以提供临床数据证明类似药和参比制剂间无临床有意义差异。在评估其生物相似性时,PK、PD参数通常比临床疗效终点更敏感。例如,甲状腺素类似药和参比制剂生物相似性比较中,促甲状腺激素(TSH)水平相较于临床甲状腺功能亢进症状而言更敏感。

In cases where there is a meaningful correlation between PK and PD results and clinical effectiveness, convincing PK and PD results may make a comparative efficacy study unnecessary. For example, similar dose-response curves of the proposed product and the reference product on a relevant PD measure, combined with a similar human PK profile and clinical immunogenicity profile, could provide sufficient evidence to support a conclusion of no clinically meaningful differences. Even if there is still residual uncertainty about biosimilarity based on PK and PD results, establishing a similar human PK and PD profile may provide a scientific basis for a selective and targeted approach to subsequent clinical testing.

当PK/PD结果与临床疗效间存在正相关且有说服力时,就没有必要进行有效性研究。如,生物类似药和参比制剂相关PD研究的剂量-反应曲线相似,人体PK特征及临床免疫原性特征相似,足以说明类似药和参比制剂无临床有意义差别。即使PK/PD结果显示二者的生物相似性仍存在一定的不确定性,建立相似的人体PK/PD曲线可为后续针对性的选择临床试验提供科学依据。


For PD studies using products with a short half-life (e.g., shorter than 5 days), a rapid PD response, and a low incidence of immunogenicity, a crossover design is appropriate, when feasible. For products with a longer half-life (e.g., more than 5 days), a parallel design will usually be needed. Sponsors should provide a scientific justification for the selection of study dose (e.g., one dose or multiple doses) and route of administration.

对于半衰期较短的药品(如短于5天),快速PD反应、低免疫原性发生率及交叉设计的PD试验更适合。对于半衰期较长的药品(如超过5天),通常需要设计平行PD试验。申请人应提供研究剂量(单剂量或多剂量)和给药途径选择的科学依据。

FDA recommends that sponsors consider the duration of time it takes for a PD measure to change and the possibility of nonlinear PK. FDA also encourages consideration of the role of modeling and simulation in designing comparative human PK and PD studies.

FDA建议申请者考虑PD研究的持续时间和非线性PK的可能性,同时FDA还强调在人体PK/PD试验设计中建模和模拟试验的重要性。


2.Clinical Immunogenicity Assessment临床免疫学评价

The goal of the clinical immunogenicity assessment is to evaluate potential differences between the proposed product and the reference product in the incidence and severity of human immune responses. Immune responses may affect both the safety and effectiveness of the product by, for example, altering PK, inducing anaphylaxis, or promoting development of neutralizing antibodies that neutralize the product as well as its endogenous protein counterpart. Thus, establishing that there are no clinically meaningful differences in immune response between a proposed product and the reference product is a key element in the demonstration of biosimilarity. Structural, functional, and animal data are generally not adequate to predict immunogenicity in humans. Therefore, at least one clinical study that includes a comparison of the immunogenicity of the proposed product to that of the reference product will be expected. FDA encourages that, where feasible, sponsors collect immunogenicity data in any clinical study, including human PK or PD studies.

临床免疫学评价的目的是评估类似药和参比制剂人体免疫反应发生率和严重程度的差别。免疫反应可能会影响药物的安全性和有效性,例如,它可能改变PK、诱发过敏反应,或者促使中和抗体和内源性蛋白类似物的产生。因此,人体免疫学反应没有临床有意义差异也是论证生物相似性的关键因素。结构、功能和动物试验数据通常不能完全测定人体免疫学反应。因此至少需要进行一个免疫性比较的临床试验。FDA建议在可行的情况下,申请人应在临床研究(包括人体PK或PD研究)中收集免疫原性数据。


The extent and timing of the clinical immunogenicity assessment will vary depending on a range of factors, including the extent of analytical similarity between the proposed product and the reference product, and the incidence and clinical consequences of immune responses for the reference product. For example, if the clinical consequence is severe (e.g., when the reference product is a therapeutic counterpart of an endogenous protein with a critical, nonredundant biological function or is known to provoke anaphylaxis), a more extensive immunogenicity assessment will likely be needed to support a demonstration of biosimilarity. If the immune response to the reference product is rare, a premarketing evaluation to assess apparent differences in immune responses between the two products may be adequate to support biosimilarity. In addition, in some cases certain safety risks may need to be evaluated through postmarketing surveillance or studies.

临床免疫学试验方案的内容和时间受多种因素的影响,如类似药和参比制剂生物相似性的程度、参比制剂免疫反应发生率和临床后果。例如,若临床后果十分严重(比如参比制剂是一种具有关键、不可替代性生物功能的内生蛋白质的治疗替代物,或该参比制剂会引发过敏反应),则需要进行更深入的免疫性评估。若参比制剂免疫反应很少,则对类似药和参比制剂上市前免疫应答差异性评估可以支持其生物相似性。此外,在某些情况下,某些安全风险可能需要通过上市后监管或研究进行评估。


The overall immunogenicity assessment should consider the nature of the immune response (e.g., anaphylaxis, neutralizing antibody), the clinical relevance and severity of consequences (e.g., loss of efficacy of life-saving therapeutic and other adverse effects), the incidence of immune responses, and the population being studied. FDA recommends use of a comparative parallel design (i.e., a head-to-head study) in treatment-naïve patients as the most sensitive design for a premarketing study to assess potential differences in the risk of immunogenicity. However, depending on the clinical experience of the reference and proposed products (taking into consideration the conditions of use and patient population), a sponsor may need to evaluate a subset of patients to provide a substantive descriptive assessment of whether a single cross-over from the reference product to the proposed biosimilar would result in a major risk in terms of hypersensitivity, immunogenicity, or other reactions. The design of any study to assess immunogenicity and acceptable differences in the incidence and other parameters of immune response should be discussed with FDA before initiating the study. Differences in immune responses between a proposed product and the reference product in the absence of observed clinical sequelae may be of concern and may warrant further evaluation (e.g., extended period of follow-up evaluation).

整体免疫原性评估应考虑免疫应答的性质(如过敏反应、中和抗体)、临床相关性和临床后果严重性(如急救措施无效和其他不良反应)、免疫应答的发生和研究对象。FDA建议在上市前研究中采用受治疗患者可比性平行研究(即直接研究)作为最灵敏的方法来评估免疫原性风险的潜在差异。然而根据参比制剂和类似药的临床实际(考虑到使用条件和患者群体),申请者应充分评估某些患者,来实际描述两种药品单一交叉是否会产生超敏性、免疫原性或其他反应方面风险。在开始研究之前,申请人应与FDA讨论免疫原性研究的设计以及免疫反应发生和其他参数产生差异的可接受标准。在没有观察到临床后遗症的情况下,生物类似药和参比制剂间任何的免疫应答差异都需要被关注,且进行进一步评估(如延长后续评价期)。


The study population used to compare immunogenicity should be justified by the sponsor and agreed to by the Agency. If a sponsor is seeking to extrapolate immunogenicity findings for one condition of use to other conditions of use, the sponsor should consider using a study population and treatment regimen that are adequately sensitive for predicting a difference in immune responses between the proposed product and the reference product across the conditions of use. Usually, this will be the population and regimen for the reference product for which development of immune responses with adverse outcomes is most likely to occur (e.g., patients on background immunosuppressants would be less likely to develop immune responses than patients who are not immunosuppressed).

申请人应对参与免疫性比较试验人群的选择进行论证,并得到FDA的同意。如果申请人想要将一情况下的免疫性反应结果外推到另一情况,申请人应选择足够灵敏的试验人群和治疗方案以预测类似药和参比制剂在两种情况下的免疫反应差异。通常,使用参比制剂的人群和治疗方案更容易产生不良的免疫反应(例如患自身免疫抑制病患者比未免疫抑制患者更容易发生免疫反应)。

 

The selection of clinical immunogenicity endpoints or PD measures associated with immune responses to therapeutic protein products (e.g., antibody formation and cytokine levels) should take into consideration the immunogenicity issues that have emerged during the use of the reference product. Sponsors should prospectively define the clinical immune response criteria (e.g., definitions of significant clinical events such as anaphylaxis), using established criteria where available, for each type of potential immune response and should obtain agreement from FDA on these criteria before initiating the study.

临床试验终点或PD测量值的选择与治疗性蛋白质免疫应答(如抗体形成和细胞因子水平)关联时应考虑到参比制剂使用过程中已经出现的免疫性问题。申请人要事先确定临床免疫反应的标准(比如定义显著临床事件,如过敏),针对每种类型的潜在免疫应答使用已有的标准,在试验开始前应获得FDA的同意。


The duration of follow-up evaluation should be determined based on (1) the time course for the generation of immune responses (such as the development of neutralizing antibodies, cell-mediated immune responses) and expected clinical sequelae (informed by experience with the reference product), (2) the time course of disappearance of the immune responses and clinical sequelae following cessation of therapy, and (3) the length of administration of the product. For example, for chronically administered agents, the follow-up period is recommended to be 1 year unless a shorter duration can be scientifically justified based on the totality of the evidence to support biosimilarity.

试验随访时间取决于:(1)免疫反应发生的进程(如中和抗体和细胞介导免疫反应的产生),和预期的临床后遗症(从参比制剂使用历史中获得);(2)治疗停止后,免疫反应停止的进程和临床后遗症;(3)给药疗程。例如,长期给药制剂最短的随访时间是1年,除非根据生物相似性的数据足以论证缩短疗程的合理性。


As a scientific matter, a sponsor should evaluate the following antibody parameters in the clinical immunogenicity assessment:

从科学角度看,临床免疫性研究评价中应对以下几个抗体参数进行评估:

(1)Titer, specificity, relevant isotype distribution, time course of development, persistence, disappearance, impact on PK, and association with clinical sequelae效价(滴定度)、特异性、相关同型的分布、发生进程、持续时间、消失进程、对PK的影响以及和临床后遗症的联系。

(2)Neutralization of product activity: neutralizing capacity to all relevant functions (e.g., uptake and catalytic activity, neutralization for replacement enzyme therapeutics) 产物活性的中和:对所有相关功能的中和能力(例如,摄取和催化活性,替代酶治疗剂的中和)。


The sponsor should develop assays capable of sensitively detecting immune responses, even in the presence of the circulating drug product (proposed product and reference product). The proposed product and the reference product should be assessed in the same assay with the same patient sera whenever possible. FDA recommends that immunogenicity assays be developed and validated early in development, and the validation should consider both the proposed product and the reference product. Sponsors should consult with FDA on the sufficiency of assays before initiating any clinical immunogenicity assessment.

申请人所进行的试验分析应足够灵敏以检出免疫反应,即使类似药和参比制剂产品仍在体内循环过程中。应尽量使用相同病人的血清以及采用相同的分析方法对类似药和参比制剂进行免疫性分析。FDA 建议研发早期就应对所申请产品和参比制剂进行免疫学分析。在进行任何临床免疫学研究之前,申请人都要咨询FDA。


Ⅶ DEMONSTRATING BIOSIMILARITY生物相似性的论证


D. Clinical Studies – General Considerations临床研究——一般考虑

3. Comparative Clinical Studies临床可比性研究

As a scientific matter, a comparative clinical study will be necessary to support a demonstration of biosimilarity if there is residual uncertainty about whether there are clinically meaningful differences between the proposed product and the reference product based on structural and functional characterization, animal testing, human PK and PD data, and clinical immunogenicity assessment. A sponsor should provide a scientific justification if it believes that a comparative clinical study is not necessary.

如果类似药和参比制剂在结构和功能特性分析、动物试验、人体PK/PD 研究和临床免疫性评价之后,仍然存在临床有意义差别的不确定性,就需要进行临床可比性研究。若申请人认为不必要进行临床研究,就必须提供一个科学合理的解释。


The following are examples of factors that may influence the type and extent of the comparative clinical study data needed:

临床可比性研究的类型和程度可能受以下几个因素影响:

a. The nature and complexity of the reference product, the extensiveness of structural and functional characterization, and the findings and limitations of comparative structural, functional, and nonclinical testing, including the extent of observed differences. 参比制剂的性质和复杂性,结构和功能特性,结构功能比较分析的结果和限制条件,非临床研究(包括两药差异)。

b. The extent to which differences in structure, function, and nonclinical pharmacology and toxicology predict differences in clinical outcomes, in conjunction with the degree of understanding of the MOA of the reference product and disease pathology. 结构、功能、非临床药理学和毒理学方面的差异能够预测临床结果差别的程度,以及对参照药作用机制和疾病药理的理解程度。

c.The extent to which human PK or PD is known to predict clinical outcomes (e.g., PD measures known to be relevant to effectiveness or safety).已知人体PK/PD 数据能够预测临床结果的程度(比如,PD结果和临床有效性相关)。

d.The extent of clinical experience with the reference product and its therapeutic class, including the safety and risk-benefit profile (e.g., whether there is a low potential for off-target adverse events), and appropriate endpoints and biomarkers for safety and effectiveness (e.g., availability of established, sensitive clinical endpoints).参比制剂临床使用历史和治疗类别,包括安全性和风险效益比(例如无效案例的概率是否够低),以及是否有合适的安全性和有效性终点和生物标志物(如,已经建立的、敏感的临床终点)。

e.The extent of any other clinical experience with the proposed product (e.g., if the proposed product has been marketed outside the United States).试验药物的临床使用历史(例如,该产品是否已在美国以外地区销售)


A sponsor should provide a scientific justification for how it intends to use these factors to determine what type(s) of clinical study(ies) are needed and the design of any necessary study(ies). For example, if a comparative clinical study is needed, a sponsor should explain how these factors were considered in determining the design of such a study, including the endpoint(s), population, similarity margin, and statistical analyses.

申请人应科学论证如何应用这些因素确定临床试验的类型及其设计。例如对于临床可比性研究,申请人应论述如何应用上述因素确定临床试验的设计,包括试验终点、受试人群、相似性参数和统计分析等因素的设计。


Additionally, specific safety or effectiveness concerns regarding the reference product and its class (including history of manufacturing- or source-related adverse events) may warrant more comparative clinical data. Alternatively, if there is information regarding other biological products that could support a biosimilarity determination (with marketing histories that demonstrate no apparent differences in clinical safety and effectiveness profiles), such information may be an additional factor supporting a selective and targeted approach to the clinical program.

此外,若想详细了解参比制剂及其类别(包括与生产工艺或来源相关的不良反应的历史)的安全性和有效性问题,可能需要更多的可比性临床数据。若有其他生物制品的信息可以支持其生物相似性的论证(如可证明临床安全性和有效性无明显差异的销售历史),这些信息可以作为有选择性和目的性临床研究的支持信息。


Endpoints试验终点:

A sponsor should use endpoints that can assess clinically meaningful differences between the proposed product and the reference product in a comparative clinical study. The endpoints may be different from those used as primary endpoints in the reference product’s clinical studies if they are scientifically supported. As discussed in section VII.D.1, certain endpoints (such as PD measures) are more sensitive than clinical endpoints and, therefore, may enable more precise comparisons of relevant therapeutic effects. There may be situations when the assessment of multiple PD measures in a comparative clinical study will enhance the sensitivity of the study. The adequacy of the endpoints depends on the extent to which PD measures correlate with clinical outcome, the extent of structural and functional data support for biosimilarity, the understanding of MOA, and the nature or seriousness of outcome affected.

在类似药和参比制剂临床比较研究实验中,申请者应使用可评估两者之间临床有意义差异的终点。如有科学依据,可比性临床研究中的终点可与参比制剂临床研究中的不同。如第VII.D.1节中所讨论的,某些终点(如PD测量值)比临床终点更为灵敏,因此可以实现相关治疗疗效更精确的比较。有时临床比较试验中多个PD研究的评估可能会增强试验的灵敏度。试验终点的完善性取决于PD测量值与临床结果的相关度,分子结构和功能数据对生物相似性的支持度、对MOA的理解以及临床结果的性质和严重程度。


Study Population受试人群:

The choice of study population should allow for an assessment of clinically meaningful differences between the proposed product and the reference product. Often the study population will have characteristics consistent with those of the population studied for the licensure of the reference product for the same indication. However, there are cases where a study population could be different from that in the clinical studies that supported the licensure of the reference product. For example, if a genetic predictor of response was developed following licensure of the reference product, it may be possible to use patients with the response marker as the study population.

受试人群的选择应可评估生物类似药和参比制剂之间的临床差异,通常,生物类似药的受试群体特征应与参比制剂临床研究受试群体的相同。然而,也有例外的情况,比如,若在参比制剂获得许可后发现可应答的基因预测因子,则可以使用带有应答标记的患者作为受试人群。


Sample Size and Duration of Study样本量和试验周期:

The sample size for and duration of the comparative clinical study should be adequate to allow for the detection of clinically meaningful differences between the two products. As discussed in section VII.D.1, certain endpoints, such as PD measures, may be more sensitive than clinical endpoints and facilitate the conduct of a smaller study of limited duration. In such cases where the size and duration of the comparative clinical study may not be adequate for the detection of relevant safety signals, a separate assessment of safety and immunogenicity may be needed.

临床比较研究的样本量和试验周期应足以检测出两种药品之间是否具有临床有意义差异。如第VII.D.1节中所讨论的,某些终点(如PD测量值)比临床终点更为敏感,便于开展短周期小型研究。若临床比较研究的样本量和周期内不足以支撑安全性研究,则需要单独评估安全性和免疫原性。


Study Design and Analyses研究设计和分析:

A comparative clinical study for a biosimilar development program should be designed to investigate whether there are clinically meaningful differences between the proposed product and the reference product. The design should take into consideration the nature and extent of residual uncertainty that remains about biosimilarity based on data generated from comparative structural and functional characterization, animal testing, human PK and PD studies, and clinical immunogenicity assessment.

生物类似药开发项目的临床可比性研究设计应能揭示类似药和参比制剂之间是否具有临床有意义差异。研究设计应根据结构比较、功能表征、动物测试、人体PK/PD试验和临床免疫原性评估结果后生物相似性残余的不确定性的性质和程度来考虑。


Generally, FDA expects a clinical study or studies designed to establish statistical evidence that the proposed product is neither inferior to the reference product by more than a specified margin nor superior to the reference product by more than a (possibly different) specified margin. Typically, an equivalence design with symmetric inferiority and superiority margins would be used. Symmetric margins would be reasonable when, for example, there are dose-related toxicities.

一般而言,FDA期望所设计的临床试验所建立的统计学证据能证明试验药不低于也不高于参比制剂超过一定范围。一般情况下,应使用具有对称性优效和劣效性等价设计。当存在剂量-相关毒性时,对称边缘便是合理的。


In some cases, it would be appropriate to use an asymmetric interval with a larger upper bound to rule out superiority than lower bound to rule out inferiority. An asymmetric interval could be reasonable, for example, if the dose used in the clinical study is near the plateau of the dose-response curve and there is little likelihood of dose-related effects (e.g., toxicity). In most cases, use of an asymmetric interval would generally allow for a smaller sample size than would be needed with symmetric margins. However, if there is a demonstration of clear superiority, then further consideration should be given as to whether the proposed product can be considered biosimilar to the reference product.

某些情况下,使用较大上界的不对称区间来排除优效比使用较低下界来排除劣效更合理。若临床研究中使用的剂量接近剂量-反应曲线的平台并且无剂量相关反应(如毒性),不对称区间就是合理的。大多数情况下,使用不对称区间样本量通常比对称边缘所需样本量更小。然而,若类似药被证明有明显的优势,则应进一步提交生物类似药和参比制剂生物相似性的证据。


In some cases, depending on the study population and endpoint(s), ruling out only inferiority may be adequate to establish that there are no clinically meaningful differences between the proposed product and the reference product. For example, if it is well established that doses of a reference product pharmacodynamically saturate the target at the clinical dose level and it would be unethical to use lower than clinically approved doses, a non-inferiority (NI) design may be sufficient.

某些情况下,根据受试人群和试验终点的情况,只排除不良结果即可证明类似药和参比制剂间无临床有意义差别。例如,如果参比制剂的可达到临床剂量水平的药代指标,而低于临床剂量的行为是不道德的,则开展非-劣效性(NI)设计足够充分。


A sponsor should provide adequate scientific justification for the choice of study design, study population, study endpoint(s), estimated effect size for the reference product, and margin(s) (how much difference to rule out). Sponsors should discuss their study proposal(s) and overall clinical development plan with FDA before initiating the comparative clinical study(ies).

申请人应为研究设计、受试人群、试验终点、参比制剂预期效应范围和阈值(要排除的差异)提供足够的科学论证。在开始临床比较研究之前,申请人应与FDA讨论其研究建议和整体临床研究计划。


4. Extrapolation of Clinical Data Across Indications临床数据在不同适应症之间的外推

If the proposed product meets the statutory requirements for licensure as a biosimilar product under section 351(k) of the PHS Act based on, among other things, data derived from a clinical study or studies sufficient to demonstrate safety, purity, and potency in an appropriate condition of use, the applicant may seek licensure of the proposed product for one or more additional conditions of use for which the reference product is licensed. However, the applicant would need to provide sufficient scientific justification for extrapolating clinical data to support a determination of biosimilarity for each condition of use for which licensure is sought.

在PHS Act 351(K)项下,如果类似药的安全性、纯度和效力等研究结果表明其和参比制剂在一适应症下具有生物相似性,那么类似药申请用于与参比制剂获批的其他适应症的许可。但是,申请人需要提供科学合理的理由,说明该临床数据能够支持其他适应症的生物相似性。


Such scientific justification for extrapolation should address, for example, the following issues for the tested and extrapolated conditions of use:

外推的适应症,应对以下几个问题进行说明:

The MOA(s) in each condition of use for which licensure is sought; this may include 每种适应症的作用机制,包括:

--The target/receptor(s) for each relevant activity/function of the product相关活性或功效的作用靶点或受体;

  --The binding, dose/concentration response, and pattern of molecular signaling upon engagement of target/receptor(s) 作用靶点或受体的结合、剂量/浓度反应和分子信号模式;

  --The relationships between product structure and target/receptor interactions 药物结构和靶点/受体相互作用的关系;

  --The location and expression of the target/receptor(s) 靶点/受体的位置和表达。

The PK and bio-distribution of the product in different patient populations (Relevant PD measures may also provide important information on the MOA.) 不同患者中药物的PK和分布参数(相关PD测量值可能也会提供作用机制的重要信息)。

The immunogenicity of the product in different patient populations 不同患者群体中产品的免疫原性。

Differences in expected toxicities in each condition of use and patient population (including whether expected toxicities are related to the pharmacological activity of the product or to off-target activities) 每种适应症和患者群体中毒理学的差异,包括药理活性和非药理活性相关的毒性。

Any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which licensure is sought 其他任何可能影响所申请适应症的安全性或有效性的因素。


Differences between conditions of use with respect to the factors described above do not necessarily preclude extrapolation. A scientific justification should address these differences in the context of the totality of the evidence supporting a demonstration of biosimilarity. 

不同适应症下上述提到的因素可能会不同,但并不意味着外推法不适用,申请人应在“整体证据法”项下对这些差异进行科学论证以支持生物相似性。


In choosing which condition of use to study that would permit subsequent extrapolation of clinical data to other conditions of use, FDA recommends that a sponsor consider choosing a condition of use that would be adequately sensitive to detect clinically meaningful differences between the two products.

在选择可外推的适应症时,FDA建议申请人应对选择一个对类似药和参比制剂的临床意义差异灵感度足够高的适应症。


The sponsor of a proposed product may obtain licensure only for a condition of use that has been previously licensed for the reference product. If a reference product has a condition of use that was licensed under section 506(c) of the FD&C Act and 21 CFR part 601, subpart E (accelerated approval), and the reference product’s clinical benefit in this condition of use has not yet been verified in postmarketing studies, the proposed product sponsor should consider studying another condition of use for which the reference product is licensed to avoid potential complications in the event that postmarketing studies fail to verify the clinical benefit of the reference product for the condition of use.

申请人获取的许可只能是参比制剂已获批的适应症。若参比制剂的某适应症根据FD&C Act第506(c)节和21 CFR第601部分E子部分(加速审批)获得许可,但参比制剂该适用证的临床优势尚未在上市后研究中被验证,那么申请人应考虑研究参比制剂获得许可的另一适用证,以避免在参比制剂该适应症上市后监测中未能验证其临床优势或有潜在的并发症。


Ⅷ POSTMARKETING SAFETY MONITORING CONSIDERATIONS上市后安全性监测


Robust postmarketing safety monitoring is an important component in ensuring the safety and effectiveness of biological products, including biosimilar therapeutic protein products.

持续的上市后安全性监测对于保证生物制品的安全性和有效性十分重要,包括治疗性蛋白类似药。


Postmarketing safety monitoring should first take into consideration any particular safety or effectiveness concerns associated with the use of the reference product and its class, the proposed product in its development and clinical use (if marketed outside the United States), the specific condition of use and patient population, and patient exposure in the biosimilar development program. Postmarketing safety monitoring for a proposed product should also have adequate mechanisms in place to differentiate between the adverse events associated with the proposed product and those associated with the reference product, including the identification of adverse events associated with the proposed product that have not been previously associated with the reference product. Rare, but potentially serious, safety risks (e.g., immunogenicity) may not be detected during preapproval clinical testing because the size of the population exposed likely will not be large enough to assess rare events. In particular cases, such risks may need to be evaluated through postmarketing surveillance or studies. In addition, as with any other biological product, FDA may take any appropriate action to ensure the safety and effectiveness of a proposed product, including, for example, requiring a postmarketing study or clinical trial to evaluate certain safety risks. 

上市后安全性监测应首先考虑在参比制剂及其类别使用时、类似药药研发和临床应用(若在美国境外销售)时的安全和有效性问题,以及药物特殊使用条件和患者人群、生物类似药研发过程中的患者暴露等因素。类似药的上市后安全性监测应建立一个机制,以区分不良反应是与类似药相关还是与参比制剂相关,以及界定那些参比制剂没有出现过的不良反应。由于上市前临床试验中受试人群有限,某些潜在的罕见严重安全性问题(比如免疫原性反应)未必能被发现,因此就需要通过上市后药物警戒来进行评估。另外,与其他生物制品一样,FDA 会采取措施以确保某类似药的安全性和有效性,比如要求针对某些安全性风险问题进行上市后研究或临床试验。


Because some aspects of postmarketing safety monitoring are product-specific, FDA encourages sponsors to consult with appropriate FDA divisions to discuss the sponsor’s proposed approach to postmarketing safety monitoring.

由于药品上市后安全监测的内容是因产品而异的,因此,FDA鼓励申请人和相应的FDA部门讨论上市后的安全监测方法。


Ⅸ CONSULTATION WITH FDA  FDA咨询


Many product-specific factors can influence the components of a product development program intended to establish that a proposed product is biosimilar to a reference product. Therefore, FDA will ordinarily provide feedback on a case-by-case basis on the components of a development program for a proposed product. In addition, it may not be possible to identify in advance all the necessary components of a development program; and the assessment of one element (e.g., structural analyses) at one step can influence decisions about the type and amount of subsequent data for the next step. For these reasons, FDA recommends that sponsors use a stepwise approach to establish the totality of the evidence that supports a demonstration of biosimilarity.

由于每个产品有各自的特点,这将影响类似药的生物相似性评价方案的组成。因此,FDA依据具体案例对每一个类似药的研究方案给予反馈。此外,提前确定研究方案的所有必需内容是不太可能的,并且每一步骤中某一个因素的评价(例如结构分析)都会影响到下一步骤的设计。所以,FDA 建议采取阶梯式方法进行生物相似性评价。


FDA also 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 the approaches to providing adequate scientific justifications will facilitate biosimilar development.

FDA 还建议申请者先向FDA 说明其研究方案,并建立关键咨询讨论的时间表。FDA 认为,提前沟通讨论研发计划及资料递交方法有助于类似药的研究与审批。

附录:

GLOSSARY相关术语


As used in this guidance, the following terms are defined below 本指南中使用的术语如下:


Biological product生物制品:“a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.” 用以预防,治疗,诊断疾病或人体机能的病毒、治疗性血清、毒素、抗毒素、疫苗、血液、血液成分或衍生物,引起过敏的产品、蛋白质(化学合成多肽除外),或者类似产品,或胂凡纳明及其衍生物(或其他三价有机砷化物)。


Biosimilar or biosimilarity生物相似或生物相似性:“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.” 尽管临床非活性成分存在微小差异,一种生物制品和参比制剂高度相似,且两种产品在安全性、纯度和效力方面无临床有意义差别。


Chemically synthesized polypeptide化学合成多肽:any alpha amino acid polymer that (a) is made entirely by chemical synthesis and (b) is less than 100 amino acids in size. 完全由化学合成的,氨基酸少于100个的α-氨基酸聚合物。


Product产品:when used without modifiers in this guidance, is intended to refer to the intermediates, drug substance, and/or drug product, as appropriate. The use of the term product is consistent with the use of the term in ICH Q5E. 本指南中的“Product(不带修饰语时)”可以指中间体、原料药、和/或药品。和ICH Q5E中的定义一致。


Protein蛋白质:any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size. 由超过40 个氨基酸按照特定序列构成的α-氨基酸聚合物。


Reference product参比制剂:the single biological product licensed under section 351(a) of the PHS Act against which a biological product is evaluated in a 351(k) application. 按照PHS Act351(a) 路径获批的生物制品,其他生物制品通过351(k)路径申请时以其作为对比对象。




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