FDA发布的仿制药一致性最终指导原则（中英文版） - 药群论坛

The US Food and Drug Administration's (FDA) final guidance on controlled correspondence between the agency and the generic drug industry released Monday includes some changes that address industry questions and comments.
FDA发布：仿制药生产商书面咨询最终指南，解决企业关心的问题
Background
Initially released in August 2014, the draft guidance was the fourth guidance document under the 2012 Generic Drug User Fee Act, and was intended to address formal questions posed to FDA prior to the generic drug review process and to clarify questions capable of affecting a product's review.
背景：

该指南草案发布于2014年8月，是2012年《仿制药申报者付费法案》(Generic Drug User Fee Act，GDUFA)下的第四份指导文件，旨在解答仿制药评审前企业向FDA提出的正式问题，对会影响药品评审的问题做澄清。
This guidance provides additional detail and recommendations for industry on:
what inquiries FDA considers to be controlled correspondence for the purposes of meeting its GDUFA commitment
what information requestors can include in a controlled correspondence
what information FDA will provide in its communications to requestors that have submitted controlled correspondence

该指导原则为企业提供了附加明细和建议:

什么样的咨询FDA认为是符合其GDUFA承诺的书面咨询
什么样的信息可以包含在书面咨询中
FDA在与递交书面咨询人交流时会提供什么样的信息

The agency's definition of "controlled correspondence" encompasses a range of issues that can impact generic manufacturers and related industry (e.g., contract research organizations conducting bioanalytical or bioequivalence (BE) clinical trials, active pharmaceutical ingredient manufacturers, and excipient manufacturers).
FDA对“controlled correspondence”,即本文中的“书面咨询”的定义涵括了一系列可影响仿制药生产商和相关产业的问题(例如进行生物分析或生物等效性(BE)临床试验的CRO，API生产商，还有辅料生产商)

Minor Changes to Draft
Revisions to the draft guidance include explanatory information that will assist generic manufacturers as they submit controlled correspondence to FDA. The final guidance also added a description of how to submit information to FDA’s Inactive Ingredient Database, and a description of enhanced communication to requestors regarding the status of their controlled correspondence.

草案细小改动：
指南草案的修订包含了对解释性信息进行了修订，这些解释性信息将帮助仿制药生产商向FDA提交书面咨询。最终指南增加了“如何向FDA的非活性成分数据库提交信息”的描述，以及根据申请者书面咨询的状态，加强沟与申请者的沟通。
Exclusions
FDA notes in the final guidance three types of inquiries that fall within the definition of controlled correspondence but which the agency has and will continue to treat differently from other inquiries on generic drugs, including (1) requests for recommendations on the appropriate design of BE studies for a specific drug product; (2) requests for review of BE clinical protocols; and (3) requests for meetings to discuss generic drug development prior to Abbreviated New Drug Application (ANDA) submission.

FDA says it will exclude these inquiries from the goal dates in the GDUFA Commitment Letter. Under that letter, FDA action on controlled correspondence letters is set to steadily ramp up from:

FDA will respond to 70 percent of controlled correspondence in 4 months from date of submission in fiscal year (FY) 2015.
FDA will respond to 70 percent of controlled correspondence in 2 months from date of submission in FY 2016.
FDA will respond to 90 percent of controlled correspondence in 2 months from date of submission in FY 2017.
例外情况：

FDA在最终指南中指出三种咨询方式，这三种咨询方式都属于书面咨询的范畴，但FDA仍认为这三种咨询方式与其他仿制药咨询不同。包括

1)申请对特定药品的BE研究设计提供建议;
(2)申请对BE临床方案审核;
(3)在简明新药申请(ANDA)提交之前申请会议讨论仿制药开发FDA表示，这些咨询不包含在GDUFA承诺函的目标时间之内。在这份承诺函中，FDA对书面咨询的回复时间将逐步加快:
2015财年，70%咨询会在自提交日起4个月内得到FDA回复。
2016财年，70%咨询会在自提交日起2个月内得到FDA回复。
2017财年，90%咨询会在自提交日起2个月内得到FDA回复。

Industry Comment
In its comments on the draft guidance, industry group Generic Pharmaceutical Association (GPhA) took particular issue with these exclusions, calling them "unacceptable and inconsistent with the stated GDUFA commitments."
"The GDUFA Commitment Letter in no way contemplated excluding categories critical for information exchange from the controlled correspondence metrics," GPhA says. "In fact, it is because FDA responses to these correspondences have been historically slow, due to resource constraints, industry clearly addressed these concerns in its agreement related to controlled correspondence."

In addition, GPhA takes issue with the guidance's proposal to end communications with requestors when a subject is under consideration but deemed complex.

"This proposal contradicts the fundamental aspects of GDUFA which was designed to enhance the FDA’s scientific knowledge-base and embraced the goals of improving communications and increased transparency," GPhA says. "GPhA respectfully requests FDA to establish a procedure that will assure timely responses to controlled correspondence including those that represent complex issues."
行业意见：

在对草案的意见中，仿制药协会（GenericPharmaceuticalAssociation，GPhA）就这些例外情况提出异议，称它们“不可接受且不符合规定的GDUFA承诺。”此外，GPhA还提出异议，质疑指南建议终止与申请人沟通在研究中的、被认为复杂的问题。“这个建议违背GDUFA的基础：旨在加强FDA的科学知识库，改善沟通，增加透明度，”GPhA说。“GPhA敬请FDA建立制度，确保及时回复书面咨询，包括那些含有复杂问题的咨询。

FDA Response

Though it did not directly address GPhA and its concerns about the exclusions, FDA noted that it received multiple comments requesting that it refrain from excluding requests for product-specific guidance on demonstrating bioequivalence. But the agency says it has declined to revise the guidance in that fashion.

Among other things, FDA says that "the short timeframe contemplated for the controlled correspondence responses is inconsistent with the well-established process for issuing product-specific recommendations described in the guidance for industry on 'Bioequivalence Recommendations for Specific Products (June 2010),' as well as with the principles in the GDUFA Commitment Letter."

FDA also said it received a number of comments on its proposal to respond to requests related to issues for which it has not yet determined a policy.

"Upon review of the comments, FDA is revising its recommendations related to such inquiries... if there is a better mechanism for a requestor to obtain comment from FDA on the subject of the request than through a controlled correspondence, the agency will direct the requestor to such a mechanism, e.g., a pre-abbreviated new drug application meeting request or the Regulatory Science Initiative," FDA adds.

FDA回应：

尽管没有直接解答GPhA关于例外情况的疑问，FDA指出其收到多方意见，要求其不要将特殊药物生物等效性研究指南排除在外。FDA说，“书面咨询回复如此之快与《2010年6月特殊药物的生物等效性研究指南》中“给特殊药物提供建议的完整过程”不一致，也与GDUFA承诺函原则不一致。”

FDA还表示收到了一些意见，关于FDA“如何回复没有相关政策的问题”。

“对于这些意见，FDA正在修改其有关的建议，如果有一个比书面咨询更好的机制可以让申请人从FDA处获得咨询，FDA将会告知申请人，例如，Pre-ANDA会议申请或监管科学计划（Regulatory Science Initiative）