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出自识林

2013-10-03 FDA,Lachman CONSULTANTS

概述
9月30日 FDA发布新的行业指南草案“ANDA申请提交 – 拒收标准”ANDA Submissions – Refuse-to-Receive (RTR) Standards，以帮助申请人提高ANDA申请提交的质量。FDA认为，明晰所有标准将有助于提高ANDA申请的整体水平。对于完整性和可接受性审评过程，指南将缺陷分为重大（将自动触发RTR）和轻微（可以有5天修订）类别。如果一份ANDA含有1个重大缺陷或10个或更多轻微缺陷，FDA将拒收该申请。申请人将损失25%的GDUFA付费作为惩罚。FDA自2011年开始每季度更新"ANDA申请的完整性和可接受性核对清单"ANDA Filing Checklist for Completeness and Acceptability of an Application (ANDA checklist)，并定期与GPhA开会讨论提交完整申请的最新信息。希望获得最为完整的申请提交，从而使申请审评更加有效。但是最开始时许多企业只是希望有一些东西递交给FDA以开始计时或者试图抓到首个提交的排队机会。指南回顾了过去4年OGD拒收了497份ANDA，FDA的拒收率为2009年12%，2010年18%，2011年15.5%，2012年9.4%（2012年的拒收率是基于不完整数据）。

企业如何看呢？对于企业，尤其是海外企业，最大的挑战是留给企业的缺陷回复时间。ANDA缺陷由FDA通过美国代理人联系到企业的时间通常是2-3天，FDA从电话联系代理人的那一刻开始计时。如果涉及到第三方和签字，并且如果签字人（通常是大老板）不在，交流是最大的挑战。例如，某个缺陷涉及到包装材料（玻璃瓶或瓶盖和胶塞、着色剂、瓶盖衬垫和密封垫等）的DMF授权信（LoA）。理论上LoA应交给ANDA持有人而不是药品生产商（有时两者是不一样的），但是玻璃瓶供应商没有联系ANDA持有人，他们将玻璃瓶卖给药品生产商，因此LoA是交给生产商的。持有人提交ANDA时，如果FDA要求DMF LoA交给ANDA持有人，这将涉及第三方交流。ANDA持有人没有办法在第5天结束时将回复放在审评人的办公桌上。eCTD/ESG电子提交有时也会出现问题，如果出现问题，可能会拖延整个过程。另外，每次提交都需要FDA 356h表，现在需要企业负责办公室和美国代理人共同签署，正反面签署356h表格同样花费时间，更不要说可能会出错。过去企业的缺陷回复时间是10天，根据企业实践，已经比较紧张，而现在缩短到5天，这对于企业的压力非常大。企业抱怨道，当我们付清了所有费用，FDA却开始让ANDA申请变的更加困难！

不管怎么样，紧跟上周发布的关于“未决申请问询的MAPP”【识林资讯 2013-9-26】接踵而至的这份指南这可能是一件好事。随着越来越多的GDUFA措施的落实，包括MAPP和拒收指南，我们饶有兴趣的等待随之而来的是ANDA质量的提高还是问题依然存在？

识林-椒 2013-10-3

Time to Tighten Your Belts and Pay Attention to Quality

Written by Bob Pollock • October 01, 2013
This is not the first time that the Office of Generic Drugs (OGD) has issued a guidance document that requires firms to assure that they have essential information in their original abbreviated new drug applications to permit a substantive scientific review. Remember prior to the 1992 Hatch-Waxman final rule when an ANDA could be submitted with just a bioequivalence protocol and the actual biostudy could be submitted as an amendment? Or even prior to that when ANDAs were accepted with one month stability data and the remainder of the data could be submitted as it became available? The Center for Drug Evaluation and Research sent several letters telling firms to improve their submissions. One such letter was dated November 1, 1990 (here).

Over the years, OGD has issued Completeness and Acceptability checklists in an effort to make ANDA applicants aware of the latest requirements for submission. In addition, OGD often holds joint meeting with GPhA to provide industry with the most recent information necessary to file complete applications. All of these efforts have been undertaken to improve the efficiency of the ANDA review and approval process. The goal is to have the most complete application submitted, and thus, making the review of the application, hopefully, a one or two cycle process. You send OGD the application, they tell you what is wrong with it, and then fix it. Thse meeting and exchanges are essential for successful submissions.

Unfortunately, history really does repeat itself. The first series of letters and advice to industry relative to the need to submit a complete application was to level the playing field and assure that every firm was doing the necessary work to submit a complete application, as many firms were just trying to get something into the Agency to get the clock started or to try to capture the first-to-file place in line.

Well now we are right back to where we were in the late 80s when firms tried get the clock started by submitting an ANDA that might not quite be what they really want in terms of potential conditions of marketing. For instance, a firm may submit an application with one source of API, but really want to use another. They may not really want to commercialize a product from the filed manufacturing site or they may want to use a different contract packager for commercial operations. GUDFA takes care of that to a certain extent by adding review time penalties for major and multiple minor amendments to the application. But the question of what gets you in the door first still matters.

On September 30, 2013, OGD issued a draft guidance for industry entitled, ANDA Submissions – Refuse-to-Receive (RTR) Standards, that outlines how your application will be evaluated for receipt purposes. The Guidance divides deficiencies into major (for which a RTR will automatically be triggered) and minor (for which you may have 5 days to correct) categories for the completeness and acceptability review process. Have 1 major or 10 or more minor deficiencies and your application will not be received. Penalty for such a determination is a loss of 25% of the ANDA user fee.

The guidance document (here) discusses the RTR history over the last four year where OGD has RTRed some 497 ANDAs with the % of RTRs actually falling from 18% in 2010, to 15.5% in 2011, and 9.4% in 2012 (however, the 2012 figures are based on incomplete data, given many of the ANDA submitted in 2012 have not yet completed their completeness and acceptability review). Most of the 100 RTR letters in 2012 fell into one of three categories, serious bioequivalence issues accounting for 40%, 36% for serious chemistry issues, and 13% for format or organizational flaws.

The 9/30/13 guidance will likely result in an initial increase in the rate of RTR letters for 2013 submissions. This will likely be compounded by the upcoming increase in stability requirements to take effect in June of 2013; however, at least firms are now on notice about current expectations. In addition, OGD updates its ANDA checklist quarterly to capture new areas of concern and focus. The most recent ANDA checklist for Quarter 2 of 2013 can be found here.

原文请见 Time to Tighten Your Belts and Pay Attention to Quality 2013-10-1
相关链接 Refuse-to-Receive ANDA Guidance Issued 2013-10-8