首页 > 资讯 > FDA发布两重要GUDFA相关指南草案

出自识林

2014-07-10 FDA, Lachman CONSULTANTS

美国FDA宣布发布关于之前获批申请的补充和其它有关易更正缺陷(ECDs)的两份指南文件。这两份重要的指南文件中包含有许多细微差异,FDA在发布当日同时上线了网络研讨会，请见此处

联邦公报通知声明与之前获批申请的补充（PAS）指南相关的“该指南草案旨在协助申请人为简化新药申请（ANDA）准备提交给FDA的PAS和PAS的增补。指南草案描述了FDA的PAS绩效指标，并澄清了FDA将如何在GDUFA绩效指标下处理一件ANDA的PAS和PAS增补”

对于ECD指南，FDA指出“该指南草案描述了FDA计划如何对重大修改、轻微修改和易更正缺陷（ECDs）。具体地，指南草案定义了增补类型，并描述了各增补层级的GDUFA绩效指标，提交增补的流程，以及关于增补分类的争议解决程序。”

由于每份指南文件的复杂性，将会在后续单独的文章中研究。请仔细阅读每份指南文件，因为使用不适当的提交策略或对补充申请提交多份增补，从延长审评时间上看会花费在审评队列中的宝贵时间。

与其报告我们已经知道的FDA将如何处理GDUFA下的PAS提交，倒不如让我们专注于文件中的微妙之处。

例如，大家应该都知道2015-2017财年对于补充申请提交的GDUFA目标，以及OGD的承诺的百分数：以队列年为期限在6个月（不需要检查）或10个月（如果需要检查目标）内对60%（FY2015）到75%（FY2016）再到90%（FY2017）的提交采取行动，但是你是否意识到拒绝接收（RTR）规定适用于所有PAS提交？如果你的申请没有被接收，你将损失25%的使用者费，且必须在重新提交时缴纳新的费用。另外，如果你作为CBE或CBE-30提交补充申请，FDA认定应当作为PAS提交，那么FDA将发函告诉你此事并将行政撤销你的CBE类型的补充申请。在补充申请作为一件付费的PAS重新提交前将不会确立目标日期。提交日期将是新的PAS补充申请提交到电子网关的日期（如果该提交最终被接收审评）。

此外，可根据提交到补充申请的增补或检查需要修改目标日期。指南讨论了在回应完全回应函时的一级重大和轻微增补（日期从1个一级轻微增补为6个月到1个一级重大增补为10个月），但是5个或更多的轻微增补，或者是二级或三级增补会有更大的影响，并可能（在某些情况下）将PAS从GDUFA目标日期中移除。

该指南草案还讨论了组补充申请（对于相同CMC或其他变更的多份补充申请），并指出就使用者费目前的情况来说每份补充申请作为一份单独的补充申请来处理。因此，如果你提交了一组10份此类补充申请，每份均需要付费。如果仅为领头的补充申请付费，其它的9份将不被接收。FDA表示一组可提交一份付费的可比性方案，接下来，如果FDA批准了该方案，这些补充申请的其余部分可在简化立卷类型与可比性方案一致的基础上提交，对于获批的可比性方案下许可的CBE或CBE-30补充申请不需付费。

FDA还指出，他们将根据以往的检查（成品剂型—2年窗口期，API—3年窗口期，分析实验室—4年窗口期）针对检查需要应用基于风险的评估。如果一份PAS被提交，且被分配了10个月的初始目标日期，因为FDA认为检查时必要的，但之后决定不需要检查，目标日期将从10个月改为6个月，同时将通知申请人。

如果附属设施申请中提到的任何设施没有支付费用并出现在逾期欠款名单中或从未付费，补充申请将不被接收。因此请确保任何引用的设施或附属设施根据GDUFA付费方式的要求更新。还要记住，费用支付仅适用于提交ANDA，不适用于NDA或BLA，并且仅适用于2012年10月1日之后补充申请的原始提交，目标日期仅适用于2014年10月1日或之后提交的补充申请。【2015年8月18日，CDER发布了MAPP 5200.3修订版《关于GDUFA第三年之前的简化新药申请与行业的交流》， 参见 FDA将在与仿制药企业交流与透明度方面大为改进 识林资讯 2015-08-20】

Lachman CONSULTANTS - Bob Pollock先生 2014-07-10
校译：识林-椒 2014-07-11

Two GDUFA Guidances Announced in the Federal Register and Published On CDER's Web Page
Written by Bob Pollock • July 10, 2014

The FDA announced the availability of two Guidance documents – on Prior Approval Supplements (here) and the other concerning Easily Correctable Deficiencies (ECDs) (here). These eagerly anticipated documents have also published on the CDER web page here.

The FR notice states relative to the Prior Approval Supplements (PAS) Guidance that “this draft guidance is intended to assist applicants preparing to submit to FDA PASs and amendments to PASs for abbreviated new drug applications (ANDAs). It describes FDA's performance metric goals for PASs and clarifies how FDA will handle a PAS and amendments to a PAS for an ANDA subject to the GDUFA performance metric goals.”

For the ECD Guidance, FDA notes that “This draft guidance describes how FDA intends to classify major amendments, minor amendments, and easily correctable deficiencies (ECDs). Specifically, the draft guidance defines the types of amendments and describes the GDUFA performance metric goals for the amendment tiers, the process for submitting amendments, and dispute resolution procedures regarding amendment classifications.”

Due to the complexity of each Guidance document, they will be addressed in separate blog posts. Please review each Guidance document carefully as applying an inappropriate submission strategy or submitting multiple amendments to submitted supplements could cost you precious time in the review queue in terms of extension of the review clock.

Rather than report what we already know about how the Agency will handle PAS submissions under GDUFA, let’s concentrate on the subtle points made in the document.

For instance, we should all know about the GDFA goals for supplements submitted in FY 2015-2017 and the percent of OGD’s commitment that rises by cohort year from 60% to 75% to 90% in 6 months or 10 months (if an inspection is needed), but did you realize that the Refuse-to-Receive (RTR) provisions apply to all PAS submissions? If your application is not received, you lose 25% of your user fee and must submit a new fee upon resubmission. Also, if you submit a supplement as a CBE or CBE-30 and FDA decides it should be a PAS, and then FDA will send you a letter telling you that and will administratively withdraw your CBE-type supplement. No goal date will be established until the supplement is resubmitted as a PAS with a paid fee and goes through the RTR evaluation. The submission date will be the date the new PAS supplement hits the electronic gateway (if it is ultimately found acceptable for review).

Also, goal date can change based on amendments submitted to the supplement or the need for inspection. The Guidance discusses Tier 1 Major and Minor Amendments in response to a Complete Response Letter (with dates of from 6 months for a Tier 1 Minor to 10 months for a Tier 1 Major Amendment), but 5 or more Tier on Minors or Tier 2 or Tier 3 amendments have a much greater impact and could (in certain instances) remove the PAS from a GDUFA goal date.

The Draft Guidance also discussed grouped supplements (multiple supplements for the same CMC or other change) and notes that each is handled as a single supplement as far as user fees go. So, if you submit a group of 10 such supplements, each will require a fee. If the fee is only paid for the lead supplement, the other 9 will not be received. FDA indicates that a comparability protocol may be submitted for one of the group with one fee paid and then, if the Agency approved the protocol, the remainder of the supplements may be submitted based on the reduced filing type agreed to in the comparability protocol, with no fee required for the permitted CBE or CBE-30 supplements under the approved comparability protocol.

FDA also notes that they will apply a risk-based evaluation of the need for inspection based on both previous inspections (finished dosage forms – 2 year window, APIs - 3 year window and testing labs - 4 year window) and, if a PAS is submitted and an initial goal date of 10 months is assigned, because FDA believes an inspection is needed but later decides an inspection is not needed, the goal date will be changed from 10 months to 6 months and the applicant will be so notified.

If any facilities named in the application of affiliated facilities have not paid their fees and appear on the arrears lists or have never paid a fee, the supplement will not be received, so please be sure that any referenced facility or their affiliates are up to date on their required GDUFA fee payments. Also remember that payment of fees only apply to supplements submitted to ANDAs and not NDAs or BLAs and only apply to supplements originally submitted after October 1, 2012 and goal dates apply only to supplements submitted on or after October 1, 2014.

There are lots of nuances contained in the Guidance document and FDA has a webinar prepared and available for each of the guidance documents it issued today, which can be found here. If you need assistance sorting through the requirements and potential landmines associated with this or other GDUFA guidance documents, please be sure to contact Joan Janulis at j.janulis@lachmanconsultants.com. We look forward to assisting you with any questions you may have or in dealing with the Agency on your behalf, if necessary.

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