FDA生物類似葯指導原則之：治療性蛋白製品與參比製劑生物相似性論證中的質量方面考量（一）

INTRODUCTION 引言

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.

本指導原則旨在闡述， FDA對於治療性蛋白製品（下稱「擬上市產品或擬上市生物類似葯」）按照美國《公共健康服務法》（Public Health Service Act，PHS Act）的351（k）章節規定申請上市時，應如何證明其與參比製劑的高度相似性所提出的意見與建議。尤其是指導申請人如何根據351（k）提供CMC部分（chemistry, manufacturing, and controls）的科學和技術信息。

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.」

2009年的《生物製品價格競爭和創新法》（Biologics Price Competition and Innovation Act，BPCI Act）修訂了PHS Act等法案，在法案351（k）部分為那些能證明與參比製劑相比具有生物相似或可替代性的生物製品提供一條簡要的上市申請途徑（詳見《患者保護和支付醫療法案》（Patient Protection and Affordable Care Act (Affordable Care Act)）7001-7003部分）。BPCI Act也將「蛋白製品」（除化學合成多肽外）的概念增加到生物製品的定義中。擬上市生物類似葯的351（k）申請必須包含生物相似性的證明性數據和其他信息，包括證明其與參比製劑相比儘管在非活性成分有微小差異但是存在高度的相似性的相關研究信息。

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.

351（k）申請主要適用於生物製品，但本指南主要對於治療性蛋白製劑以及在證明與參比製劑相似性時的分析性因素考慮。

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:

本指南作為FDA為執行《生物葯價格競爭與創新法》（BPIC Act）所發布的指南之一，這些指南旨在為以下幾個問題提供了總體思路：

√ Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product；證明治療性蛋白製品和參比製劑生物相似性的質量考慮；

√ Scientific Considerations in Demonstrating Biosimilarity to a Reference Product；證明與參比製劑生物相似的科學考慮；

√ Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009；生物類似葯：執行BPIC Act過程中的問與答；

√ Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants；FDA和生物類似葯申請人的正式會議；

√ Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product；證明和參比製劑相比具有生物相似性的臨床藥理學數據。

When applicable, references to information in the above guidances are included in this guidance.

上述指南文件的部分參考信息將包括在本指導原則中。

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.

通常，FDA的指導原則並不強制執行，相反，指導文件反應了FDA對某一問題的當前看法，除被收錄到法律法規當中，否則僅作為指導使用。FDA相關指導原則中，「should」是指建議而不是要求。

BACKGROUND背景

In the 1980s, FDA began to receive marketing applications for biotechnology-derived protein products, mostly for recombinant DNA-derived versions of naturally sourced products. Consequently, FDA established a regulatory approach for the approval of recombinant DNA-derived protein products, which was announced in the Federal Register (51 FR 23302, June 26, 1986), in conjunction with a 1985 document titled Points to Consider in the Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA Technology. This approach addresses the submission of an investigational new drug application (IND) to FDA for evaluation before initiation of clinical investigations in human subjects and submission and approval of a new drug application (NDA) or biologics license application (BLA) before marketing products made with recombinant DNA technology, even if the active ingredient in the product is thought to be identical to a naturally occurring substance or a previously approved product. The policy set forth in those documents was developed in part because of the challenges in evaluating protein products solely by physicochemical and functional testing and because the biological system in which a protein product is produced can have a significant effect on the structure and function of the product itself. Because of the complexities of protein products, FDA has, as a matter of policy, generally required submission of an NDA (in accordance with section 505(b)(1) of the Federal Food Drug and Cosmetic Act (FD&C Act)) or a BLA (in accordance with section 351(a) of the PHS Act) containing product-specific full safety and efficacy data for recombinant DNA-derived protein products. FDA has recognized, however, that 「[i]n some instances complete new applications may not be required」 (51 FR 23309, June 26, 1986).

十九世紀八十年代，FDA開始接收生物技術來源的蛋白製品的上市申請，大多數是天然產物的DNA重組品。後來FDA於1986年6月26日在聯邦公告上公布了一個重組DNA蛋白製品的指南文件，和1985年頒布的《生產和檢測重組DNA技術製備的新葯和生物製品的考慮要點》聯合執行。此指南文件就重組DNA技術產品的臨床前IND申請以及NDA申請或BLA許可申請提供指導意見，即使通過重組DNA技術生產的活性成分與天然來源的物質或者已上市產品相同，也同樣適用於該指南。由於在蛋白製品評價中僅考慮物理化學或功能性試驗存在困難，同時蛋白製品產生的生物系統對其結構和功能具有顯著影響，因此上述指南中的政策僅有部分能順利執行。由於蛋白製品的複雜性，FDA頒布了一系列指南，通常需要按照《聯邦食品、藥品和化妝品法案》（Federal Food Drug and Cosmetic Act，FD&C Act）505（b）（1）部分進行NDA申請，或按照PHS Act 351（a）部分進行BLA申請，包括產品的所有安全性和有效性資料。但是，某些情況下不需要完整新申請（51 FR 23309）。

Improvements in manufacturing processes, process controls, materials, and product testing, as well as characterization tests and studies, have led to a gradual evolution in the regulation of protein products. For example, in 1996, FDA provided recommendations in its FDA Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology Products, which explains how a sponsor may demonstrate, through a combination of analytical testing, functional assays (in vitro and/or in vivo), assessment of pharmacokinetics (PK) and/or pharmacodynamics (PD) and toxicity in animals, and clinical testing (clinical pharmacology, safety, and/or efficacy), that a manufacturing change does not adversely affect the identity, purity, or potency of its FDA-approved product.

製造過程、工藝控制、材料、樣品檢測，以及特徵實驗研究的不斷改進，使蛋白製品的監管法規不斷演變。比如，1996年，FDA在《關於人用生物製品（包括治療性生物製品）可比性確證的指南》中列出了幾點具體建議，該指南解釋了申請人怎樣通過分析實驗、體內體外藥理實驗、葯代動力學PK及藥效動力學PD實驗、動物毒性試驗、臨床試驗（臨床藥理、安全性和有效性）評估是否生產工藝的變化對樣品的特性、純度、藥效產生了不良影響。

Since 1996, FDA has approved many manufacturing process changes for licensed biological products based on a demonstration of product comparability before and after the process change, as supported by quality criteria and analytical testing and without the need for additional nonclinical data and clinical safety and/or efficacy studies. In some cases, uncertainty about the effect of the change and/or the results of the biochemical/functional comparability studies has necessitated assessment of additional data, including nonclinical and/or clinical testing, to demonstrate product comparability. These concepts were further developed in the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use and resulted in the ICH guidance for industry Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process.

1996年以來，FDA已批准多項已獲批的生物製品的生產工藝變更，以一定的質量標準和分析檢測結果證明工藝變更前後產品的可比性，無需另外的非臨床補充實驗和臨床安全性和有效性研究。但某些情況下，如果工藝變化的影響或生物研究和功能試驗的結果有不確定性，就需要進行額外的補充實驗，如非臨床或臨床研究。這些概念在ICH人用藥品註冊技術指南文件中有進一步闡述，並出台了ICH Q5E工業指南《生物技術產品或生物製品生產工藝變更可比性》。

Although the scope of ICH Q5E is limited to an assessment of the comparability of a biological product before and after a manufacturing process change made by the same manufacturer, certain general scientific principles described in ICH Q5E are applicable to an assessment of biosimilarity between a proposed product and its reference product. However, demonstrating that a proposed product is biosimilar to an FDA-licensed reference product manufactured by a different manufacturer typically will be more complex and will likely require more extensive and comprehensive data than assessing the comparability of a product before and after a manufacturing process change made by the product』s sponsor. 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 will likely have a different manufacturing process (e.g., different cell line, raw materials, equipment, processes, process controls, acceptance criteria) from that of the reference product and no direct knowledge of the manufacturing process for the reference product.

雖然ICH Q5E僅針對關於同一製造商生產的生物製品在生產工藝的前後變化的可比性研究，但ICH Q5E某些通用的科學技術原則可用於類似葯和參比製劑的生物相似性比較研究，然而該論證相比論證不同生產工藝可比性要複雜的多，也要求申請人提供更多有比較意義的數據。因為同一製造商對自身產品以及生產工藝更為了解，包括已建立的質控和可接受的參數；相比之下，類似葯生產工藝通常與參比製劑生產工藝不同（如細胞、原材料、設備、生產過程、過程式控制制、可控標準），而且生產商對參比製劑的生產工藝沒有直觀的理解。

In October 1999, FDA issued the draft guidance for industry Applications Covered by Section 505(b)(2), which, among other things, states that FDA may accept an application submitted through the approval pathway described by section 505(b)(2) of the FD&C Act for a drug product containing an active ingredient(s) derived from natural sources or recombinant DNA technology. For example, FDA approved a 505(b)(2) application for a follow-on recombinant DNA-derived human growth hormone product in May 2006. Greater knowledge as a result of advances in science and technology and improvements in manufacturing processes, process controls, materials, and product testing, as well as characterization tests and studies, may support the use of an abbreviated pathway for the approval of a protein product.

1999年10月，FDA發布《505(b)(2)項下的上市申請》指南，指南闡明FDA聲明亦接收按照FD&C Act 505(b)(2)部分要求申請，如含有活性成分的天然或重組DNA產品。比如，2006年5月，FDA批准了一個人生長激素重組DNA衍生製品的505(b)(2)申請。科學技術的推進以及生產工藝、工藝過程式控制制、原材料、產品檢測、表徵試驗研究的提高有利於蛋白製品的簡化申請。

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 a biosimilar product application.

2010年3月23日，BPCI Act發布，作為《可支付醫療法案》的一部分。BPCI Act為能夠證明與參比製劑生物相似的生物類似葯的申請提供了一個簡化申請途徑。PHS Act（42U.S.C.262(k)）351（k）部分作為BPCI Act的補充，為生物類似葯的申請提供了更多的指導信息。

PHS Biosimilarity is defined in section 351(i) of the PHS Act 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 differences6 between the biological product and the reference product in terms of the safety, purity, and potency of the product (see section 351(i)(2) of the PHS Act). Comparative analytical data provide the foundation for a development program for a proposed biosimilar product intended for submission under section 351(k) of the PHS Act.Act 351（i）

部分對「生物相似性」的定義為：即使臨床非活性成分存在微小差異，生物類似葯和參比製劑高度相似，且兩者在安全性、純度和效果方面無臨床有意義差別（詳見PHS Act 351（i）（2）部分）。生物相似性研究可比性為一個想要按照PHS Act 351（k）申請的生物類似葯研發提供了基礎。

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