资讯 - 识林

06-13 FDA发布重要指南草案—ANDA申请的内容与格式

2014-06-13 Lachman CONSULTANTS

联邦公报（Federal Register, FR）12日的预发布清单中，FDA通告将发布一份题为“简化新药申请：ANDA申请的内容与格式”指南草案。FDA在联邦公报的通告中表示“为增加FDA可以接收的原始ANDA的初始提交数量，并减少批准上市所需的审评轮数，FDA准备了这份指南以提高原始ANDA提交的质量。FDA致力于在审评流程早期提供全面而广泛的协助，以确保原始ANDA包含FDA完成一轮审评所需的所有信息”

联邦公报中还表示：

“本指南旨在按照《联邦食品、药品和化妆品法案》协助申请者，准备提交给FDA的完整且高质量的原始ANDA。本指南概述了对ANDA的法规和监管要求，在参考了现有指南文件的基础上，包含了对于ANDA申请在内容和格式上的附加建议。本指南描述了人用药品申请的通用技术文件格式，并详细说明了在申请的每一部分需要提交的资料。”

本指南实际上是6月11日（美国东部时间）当天发布，11日早晨就已经贴在了FDA网站上。这份32页的文件通过对CTD格式中逐个模块、逐个章节一一说明的方法，纲要地列出了OGD对于提交文件的预期和要求。FDA表示“本指南标识出了申请者在一份提交给FDA的完整的、高质量的申请中所应包含的信息。FDA先前已经发布了关于提交流程的指南，包括拒绝接收标准，都应仔细通读，以避免在ANDA提交中出现普遍缺陷。”

这份指南文件将有关提交申请预期、标准和要求中精心琢磨的细节综合起来，并将此前分散在许多指南文件、联邦公报、FDA展示陈述和一般常识性问题中的各种信息资料集合到一处，而这些信息可能不会有任何一个地方像这份文件一样，把它们放在一起确切地写出。本指南也将大量其它指南和法规法则在合适的地方援引标注出来。

在这份文件的附录A中列出了所有引用的指南参考文件，附录B中提供了一份说明信模板，概括了最少17个特定段落，以提供应在说明信中覆盖的适当信息。

即使有了这份出色的文件（但确实没有什么太多新的东西），但仍然有几个问题可能被这份指南草案弄得模糊不清。

虽然有要求提交批记录和空白批记录，但没有明确指出：要求所有支持ANDA申请的申报批 / 初期稳定性试验批的批记录都必须囊括在内。
在稳定性部分，指南指出“对于液体制剂和半固体制剂，申请人应提交加速稳定性试验数据，以至少能反应最差储存条件（与产品朝向有关）” 这似乎与要求了垂直和倒置/水平储存朝向的稳定性指南问答相矛盾。这意味着OGD只想要加速稳定性试验中最差的情况而不是室温中两个产品朝向的研究吗？这需要在指南终稿中予以澄清。

OGD承认，如果他们想很好的处理那些依然非常大量的待批准积压，需要在第一轮审评中审评批准更多申请，而他们也为了达到这一目的，正在努力发布指南和建议，来帮助ANDA申请人提交更为完整和高质量的申请。OGD必须记住的是，现在有许多申请已经在排队，而正如我们所说，同时有更多的申请正在向OGD涌来。在这份指南指导下申请质量的提高可能在至少一年后才见成效，因为大多数在提交时考虑到本指南的ANDA直到那时才会被审评。让我们拭目以待，OGD对申请要求说话算数，当申请人确实提交了适合及必要的资料后，首轮ANDA批准的数量能够有所增加。如果历史是一面镜子，并且告诉我们这份指南真的没有带来什么新东西的话，我仍抱有疑问。

Lachman CONSULTANTS - Bob Pollock先生 2014-06-11
识林-柯 2014-06-12

GET READY and Pay Attention to Important ANDA Guidance Issued today
Written by Bob Pollock • June 11, 2014

In the Federal Register (FR) Pre-Publication listing this morning (here), FDA is announcing the issuance of a Draft Guidance entitled, Abbreviated New Drug Applications: Content and Format of Abbreviated New Drug Applications. The FDA says in the FR notice that “[I]n an effort to increase the number of original ANDAs that the Agency can receive upon initial submission and to decrease the number of review cycles required to approve an application for marketing, FDA prepared this Guidance on improving the quality of original ANDA submissions. FDA is committed to providing comprehensive assistance in the early stages of the application process to ensure that an original ANDA contains all information necessary for FDA to complete its review in one review cycle.“

The FR notice goes on to state:

“The guidance document is intended to assist applicants in preparing complete and high-quality original abbreviated new drug applications (ANDAs) for submission to FDA under the Federal Food, Drug, and Cosmetic Act. The guidance summarizes the statutory and regulatory requirements for ANDAs, references existing guidance documents, and incorporates additional recommendations on the content and format of ANDA submissions. This guidance describes the Common Technical Document format for human pharmaceutical product applications and specifies the information to be submitted in each section of the application.”

The Guidance actually issues today and was posted on the FDA website this morning. The 32 page document (here) outlines the Office of Generic Drugs (OGD) expectations and requirements for submission in a Module-by-Module and section-by section approach used in the CTD format. FDA states that “[T]his guidance identifies the information an applicant should include to ensure that a complete, high-quality application is submitted to FDA. FDA has previously published guidance on the filing process, including the refuse-to-receive standards, which should be reviewed thoroughly to avoid common deficiencies found in ANDA submissions.”

The Guidance Document goes into exquisite detail relative to the submission expectations, standards and requirements and brings together information in one place that has been previously scattered throughout many Guidance documents, FR publications, FDA presentations and some general knowledge issues that may not actually be written down in any one place like they are in this document. It also provides reference to numerous other Guidance and regulations and statutes where appropriate.

The Document also provides an Appendix A listing all references relative to the citations in the Guidance and an Appendix B that provides a cover letter template that outlines a minimum of 17 specific paragraphs that should be used to provide appropriate information to include in the cover letter.

Even with the specificity of this outstanding document (and there is really not a lot new here), but there are a couple of issues that may have been muddied by this Draft Guidance document.

While there is reference to the need to submit executed batch records and blank batch records, there is not a specific statement that batch records for all of the exhibit / primary stability batches to support the ANDA must be included.
In the stability section this Guidance states “For liquid or semisolid products, applicants should submit accelerated stability data reflecting the worst-case storage conditions (related to orientation), at minimum.” This seems to contradict the Q&A stability guidance where upright and inverted/horizontal storage orientations are recommended. Does this mean OGD wants only worst case for accelerated but both orientations for room temperature studies? This needs to be clarified in the final guidance.

OGD recognizes it needs to review to approval more applications in the first review cycle if it hopes to get a good handle on the still huge backlog of pending applications, and is working hard to issue guidance and recommendations to help ANDA sponsors submit more complete and higher quality applications to meet that end. OGD must also remember that many applications are already in the queue and that many more are on the way into OGD as we speak. Improvement in submissions under this guidance may not be evident for at least a year since it is not expected that most ANDAs submitted taking this Guidance into consideration won’t be picked up until then. Let’s hope that OGD means what it says about application requirements and that is an applicant does submit the appropriate and necessary information there will be an increasing number of first cycle ANDA approvals. If history is an indicator and given that there is really nothing that new in the Guidance, I still have some doubts.