首页 > 资讯 > FDA新发布生物类似物标签说明指南―在很大程度上遵循仿制药模式

出自识林

2016-04-19 Sidley

今年3月31日，FDA发布了外界期待已久的《生物类似物药品标签说明指南草案》。 尽管指南草案确实要求醒目地标签声明标明药品为生物类似物，但另一方面，在设计生物类似物标签说明方面，FDA似乎倚赖于仿制药的模式，尽可能地与参照药品标签说明类似。

该指南草案有效地排斥了生物类似物标签说明应包括被认为对医疗保健提供方相当重要的涉及生物类似物或其它信息的临床数据。例如，FDA明确指出，生物类似物标签说明不必包括说明生物类似物是否涵盖参照药品所有适用症状，或少于所有适用症状的情况下得以批准；也勿需披露生物类似物的适用症状是否根据外推获得批准。该指南草案不主动鼓励生物类似物的研发者在标签说明中纳入任何与用于支持FDA就生物类似物做出决定的数据类型或范围。指南草案并未讨论与可互换性有关的标签说明，留待将来的指南。

指南草案内容一览

《生物制品价格竞争与创新法案》（公法第111-148，§§ 7001-7003, 124 Stat. 119, 804-21（2010））规定，决定生物类似意味着“提出的产品与参照产品在安全性、纯度和效力方面，临床上不存在有意义的差别。”FDA依据这一表述，断定生物类似产品标记应基于“来自于参照产品标识的相关数据和信息资料”，只是允许有限的针对“安全和使用生物类似产品”所必需的“适用的具有产品专属性的修改。”（参见指南草案页码3, 5）。

为了支持这一做法，指南草案确认生物类似物标签说明中包含三类信息。第一类是来自于参考产品标签的信息。第二类是旨在告知生物类似物与参照产品 “不存在有意义的差别。”这包括在标签说明的突出部分的“生物类似性声明”，这一部分内容确定药品是生物类似的，确认参照产品，并整合生物类型性的概念。第三部分是具体针对生物等效的有限制的信息，适用条件是该信息“对提供产品安全、有效使用是必需的，可包括并不排斥证明生物等效性的给药、制备、存放或安全性方面存在差异的信息。” （参见指南草案页码3, 5）。

该指南草案明确指出，第三个类别（即，具体针对生物类似的信息）范围有限，不包括为获得许可批准所开展的研究:“考虑到支持授予生物类似产品许可的临床研究通常并不是旨在证明产品的安全与有效性，一般而言，FDA的看法认为，生物类似物产品不应包括来自于提出的生物类似物产品的数据说明。”（参见指南草案页码3, 5）。

根据FDA的看法，对第三个类别予以限制，对于避免部分医疗保健从业者对生物类似物的状况及意义产生混淆是必要的。在FDA药品审评与研究中心负责治疗性生物制品的副主任Leah Christl 博士的一篇博文中，进一步指出，这一做法旨在“避免（对关系到生物类似物临床数据）可能的混淆或误解，总体上不太可能关系到医疗保健提供方的处方考虑。”

为明确标签信息是否涉及的针对参照产品或参照产品与生物类似物的生物相似性，指南草案提供了一组有关何时使用生物类似物产品的商品名、参照产品的商品名和所谓的 “建议核心名（core name）”（即FDA相关指南所阐述的后缀之前的非专有名称）。这些建议的结果是，生物类似物标签说明 将适用于单份包装说明书指引中不少于三个不同的药名的情况。

最后，指南草案明确，将“任何针对可互换生物制品标签说明的具体建议，包括类似于生物类似性声明的声明”，留待将来的指南解决。（参见指南草案页码12）。

更多背景

这一份指南草案反映了美国FDA从2106年3月批准首个生物类似物产品Zarxio以来的一直做法。生物类似物Zarxio（filgrastim-sndz，非格司亭-sndz）的标签引用了优保津（filgrastim，非格司亭），但不包含表明该产品为生物类似的声明，标签也未包括优保津的商品名。2016年4月5日，指南草案公布不到一周后，FDA批准了第二个生物类似物，类可（英夫利昔单抗）的生物类似物Inflectra（infliximab-dyyb）。与Zarxio有所不同， Inflectra的正式标签包含生物等效性语句和参照产品的商品名。

下一步举措

FDA正就指南草案征求意见建议，具体而言，其中包括针对患者的标签是否应包括类似于指南草案中所阐述的生物相似性声明。征询期截止期为今年6月3日。

翻译：识林-Kapok
原文作者：盛德国际律师事务所的Emily Marden, Peter Choi和Coleen Klasmeier律师
感谢Anya Zhang（张晓鹏）女士的推荐

英文原文

New FDA Draft Guidance on Biosimilar Labeling Largely Follows Generic Drug Approach
Emily Marden, Peter Choi and Coleen Klasmeier 原文地址

On March 31, the U.S. Food and Drug Administration (FDA) published its long-awaited draft guidance, “Labeling for Biosimilar Products.” While the draft guidance does require a prominent labeling statement identifying a product as a biosimilar, FDA otherwise appears to rely on the generic drug model in designing biosimilar labeling that is as similar as possible to the reference product labeling.

The draft guidance effectively rejects arguments that biosimilar labeling should include clinical data regarding the biosimilar or other information thought to be important to healthcare providers. For instance, FDA makes it clear that biosimilar labeling need not include statements indicating whether the biosimilar is licensed for all, or fewer than all, of the reference product’s conditions of use; nor must biosimilar labeling disclose whether the biosimilar’s conditions of use were licensed based on extrapolation. The draft guidance also actively discourages biosimilar developers from including in labeling any information regarding the type or extent of data used to support FDA’s biosimilarity determination. Labeling regarding interchangeability is not discussed and left to a future guidance.

The Draft Guidance

The Biologics Price Competition and Innovation Act, Pub. L. No. 111-148, §§ 7001-7003, 124 Stat. 119, 804-21(2010), provides that a biosimilarity determination means that “there are no clinically meaningful differences between the proposed product and the reference product in terms of safety, purity, and potency.” FDA relies on this language to conclude that a biosimilar product’s labeling should be based on “relevant data and information from the reference product labeling” with only limited “appropriate product-specific modifications” necessary for “the safe and effective use of the biosimilar product.” Draft guidance at 3, 5.

In support of this approach, the draft guidance identifies three categories of information to be included in biosimilar labeling. The first category comprises information from the reference product’s labeling. The second is information intended to communicate that there are “no clinically meaningful differences” between the biosimilar and the reference product. This includes the “biosimilarity statement” in the Highlights section of the labeling, which would identify the drug as a biosimilar, identify the reference product and incorporate a definition of biosimilarity. Third is limited information specific to the biosimilar, provided that this information is “necessary to inform safe and effective use of the product, which could include differences such as administration, preparation, storage, or safety information that do not otherwise preclude a demonstration of biosimilarity.” Draft guidance at 5.

The draft guidance makes it clear that the scope of the third category (i.e., biosimilar-specific information) is narrow and does not include studies conducted for licensure: “[a]s a general matter, it is FDA’s view that biosimilar product should not include a description of [data from a clinical study of a proposed biosimilar product], given that a clinical study supporting the licensure of the biosimilar product generally would not be designed to independently demonstrate the safety and efficacy of the product ....” Draft guidance at 3 (emphasis added).

According to FDA, limiting the third category is necessary to avoid confusion on the part of healthcare practitioners regarding the status and meaning of biosimilars. In a blog post about the draft guidance, Leah Christl, Ph.D., Associate Director for Therapeutic Biologics in the Center for Drug Evaluation and Research, states further that its approach is intended “to avoid potential confusion or misinterpretation” of clinical data regarding biosimilars, which in general “are not likely to be relevant to a healthcare provider’s prescribing considerations.”

To make clear whether information in the labeling pertains to the biosimilar, to the reference product or to both, the draft guidance provides a set of recommendations regarding when to use the biosimilar product’s trade name, the reference product’s trade name and the so-called “core name” (i.e., the portion of the nonproprietary name before the product-specific suffix described in prior FDA guidance). The result of these recommendations is that biosimilar labeling will refer to no fewer than three different drug names in the course of a single package insert.

Finally, the draft guidance expressly defers to future guidance “any specific recommendations for labeling for interchangeable biological products, including any interchangeability statement similar to the biosimilarity statement” in the draft guidance. Draft guidance at 12.

Broader Context

The draft guidance reflects a change in FDA’s approach to biosimilar labeling since the agency licensed its first biosimilar product, Zarxio, in March 2016. The labeling for Zarxio (filgrastim-sndz), a biosimilar referencing Neupogen (filgrastim), does not contain a statement indicating that the product is a biosimilar, nor does the labeling include the Neupogen brand name. On April 5, 2016, less than a week after the publication of the draft guidance, FDA licensed a second biosimilar, Inflectra (infliximab-dyyb), a biosimilar to Remicade (infliximab). Unlike Zarxio, the official labeling for Inflectra contains the biosimilarity statement and the reference product trade name.

Next Steps

FDA is soliciting comments on the draft guidance, including, specifically, the question of whether patient labeling should include a biosimilarity statement similar to the statement described in the draft guidance. Comments on the draft guidance should be submitted by June 3.