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ANDASubmissions –Refuse-to-Receive Standards Guidance for Industry 行业指南：ANDA申报----拒收标准 U.S.Department of Health and Human Services Food and Drug Administration Center for Drug Evaluationand Research (CDER) December2016 Generics Revision2
ANDASubmissions –Refuse-to-Receive Standards Guidance for Industry 行业指南：ANDA申报----拒收标准 Additional copiesare available from: 更多副本请从以下获取： Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring,MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 U.S. Department of Health and Human Services Foodand Drug Administration Centerfor Drug Evaluationand Research (CDER) 美国卫生福利部食品药品管理局（FDA） 化药审评中心（CDER） December 2016 2016年12月 Generics 仿制药 Revision 2 第二版
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ANDA Submissions – Refuse-to-Receive Standards 行业指南：ANDA申报---拒收标准 | This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page. 本指南代表了FDA目前对此主题的想法。指南并未赋予任何人任何权力，对FDA和公众均不具备约束力。如果满足适用的法律和法规要求，可以使用其它的替代方法。如需对替代方法进行讨论，请联系本指南标题页上列出的FDA负责办公室。 |
INTRODUCTION 概述 This guidance is intended to assist applicantspreparing to submit to FDA abbreviatednew drug applications (ANDAs) and prior approval supplements(PASs) to ANDAs for which the applicantis seeking approval of a new strength of the drug product [2]. The guidance highlights deficiencies that may causeFDA to refuse to receive(RTR) an ANDA [3]. An RTR decisionindicates that FDAdetermined that an ANDAis not substantially complete [4]. A substantially complete ANDA is “an ANDA thaton its face is sufficiently complete to permita substantive review.” [5] 本指南旨在帮助申报人为了获得药品新剂量而准备向FDA提交简略新药申报（ANDA）和ANDA预批准补充申报（PAS）。本指南着重说明了可能会导致FDA拒收（RTR）一份ANDA的缺陷。RTR决定表示FDA判定一份ANDA不是实质上完整的。实质上完整的ANDA是“表面足够完整的ANDA，可以开始进行实质性评审”。 This guidance is not meant to be acomprehensive list of thedeficiencies that may or willlead to an RTR determinationbyFDA. Instead, this guidanceidentifies certain deficiencies andcertain recurrent deficiencies that in FDA’s experiencehave led FDA to RTRan ANDA. Thisguidance also describes how FDA willassess deficiencies identifiedduring FDA’s filing review todetermine whether an ANDA shouldbe received. We note that industry is awareof many of the standardsdescribed in this guidance because FDA hashistorically applied many of thesestandards in its RTR determinations. 本指南无意成为一份可能会或可能引发FDA的RTR决定的所有缺陷清单。相反，本指南只是指出根据FDA经验已经导致FDA拒收ANDA的一些缺陷和反复发生的缺陷。本指南还描述了FDA将如何评估在FDA归档审核期间所发现的缺陷，以确定是否应接受该ANDA。我们注意到制药行业其实明白在本指南中所述的许多标准，因为FDA已经在其RTR决定中采用了这些标准。 FDA’s guidance documents, including this guidance, generallydo not establish legally enforceable responsibilities. Instead,guidances describe FDA’s current thinking on a topic and shouldbe viewed only as recommendations, unless specific regulatory or statutory requirements are cited. FDA的指南文件，包括本指南，通常并不会产生法定强制义务。相反，指南只是描述FDA当前对某个主题的态度，除了所引用的特定法规或法律要求外，其它内容应被当作是建议。 The use of the word“should” in Agency guidancesmeans that something issuggested or recommended, but not required [6]. FDA指南中使用“SHOULD”一词时表示的是建议或推荐某事，但并不是强制要求。 BACKGROUND 背景Pursuant to the enactment of the Generic Drug User Fee Amendments of 2012 (GDUFA) [7],the Office of Generic Drugs (OGD) is tasked with anumber of activities, including the development of “enhanced refusalto receive standards for ANDAs andother related submissions by the end of year 1ofthe program….” [8] Enhanced RTR standards are important because the practice of submitting anANDA that is not sufficiently complete to permit asubstantive review and then “repairing”it in the course of anextended review period thatneeds several cycles ofFDA response and applicantrepair is inherently inefficientand wasteful of resources. In addition,ANDAs that are notsufficiently complete to permit asubstantive review generateextra reviews andletters. 随着2012年GDUFA法案的实施，仿制药办公室（OGD）承担了一系列活动任务，包括“到计划开始的第1年底建立加强ANDA和其它相关申报资料的拒收标准……”。由于提交一份不够完整而无法进行实质性评审的ANDA，然后在深入审核期间进行“修补”，会需要多轮FDA反馈和申报者修补，这样会降低效率，浪费资源，因此加强RTR标准是很重要的。另外，不够完整而无法进行实质性审核的ANDA会产生额外的审核和信函。 FDA evaluates each submitted ANDAindividually to determinewhether the ANDA can bereceived. The receiptof an ANDA means that FDA made athreshold determination that theANDA is a substantially complete application, that is, an ANDA that on its face is sufficiently completeto permit a substantive review [9]. Sufficiently completemeans that theANDA contains all theinformation required under section 505(j)(2)(A) of theFederal Food, Drug, and CosmeticAct (FD&C Act) and doesnot contain a deficiency described in 21 CFR 314.101(d) and(e) [10]. FDA会对收到的ANDA逐个评估，以确定是否可以接受。接受一份ANDA意味着FDA做出了一个决定，确定该ANDA是否是一份实质性完整的申报资料，也就是该ANDA表面上足够完整，可以开始实质性评审。足够完整意味着ANDA包括了所有根据FDCA 505(j)(2)(A)部分中所要求的所有资料，并且没有21 CFR 314.101(d)和 (e)里所述的缺陷。 Ourregulations at 21CFR 314.101 provide the regulatory authority by which FDAmay in certain cases,andwill in others, RTRan ANDAthat does not satisfy thecriteria for a threshold determinationthat the application is substantiallycomplete [11] . 我们在21 CFR 314.101中的法规要求让FDA有权在某些情形下可以拒收不满足确定申报资料实质性完整标准的ANDA。 Between Fiscal Years(FY) 2013 to 2015, FDA refused to receive 379 ANDAs forreasons other thanfailure to pay a GDUFA fee. Of all originalANDA submissions, FDA refused to receive: 在2013财年至2015财年之间，FDA由于GDUFA费用支付以外的原因拒收了379份ANDA。在所有ANDA初始申报中，FDA拒收比例为： Ø 14% in FY2013 Ø 10% in FY2014 Ø 2013财年：14% Ø 2014财年：10% Ø 2015财年：14% In FY 2015,the fivemost frequent bases for an RTRdetermination were (in orderof frequency): inadequate stability data; incomplete information request response;inadequate dissolution; drug product wasnot qualitatively and quantitatively thesame (Q1/Q2 same) as the reference listed drug (RLD); andfailure to respond to information request within the prescribed timeframe). 在2015财年，RTR决定最频繁的5个原因（根据其频繁程度）为：稳定性数据不充分、所需回复信息不完整、溶出度不充分、制剂定量或定性方面与RLD参比制剂不相同（Q1/Q2相同），以及未能在指定时间内回复所要求的资料。 GENERAL POLICY 通则FDA considers the nature(e.g., major orminor) of thedeficiencies, including the numberof deficiencies in the ANDA,in determining whetheran ANDA is incomplete on its face [13]. During FDA’s filingreview of a submitted ANDA, FDA willdetermine if there are any majoror minor deficiencies. Generally, a majordeficiency is one thatin FDA’s judgment is significant in nature suchas certaindeficiencies found in 21 CFR 314.101(d) or 21 CFR 314.101(e) [14];other major deficienciesare discussed in this and otherguidances. Numerous minor deficiencies (discussed below)also constitute a majordeficiency. A majordeficiency will resultin a determination by FDA that the ANDA is incomplete onits face under 21 CFR314.101(d)(3), and FDA willtherefore RTR an ANDA containinga major deficiency. FDA在决定一份ANDA是否表面完整的时候，会考虑ANDA中缺陷的情况，包括缺陷的数量。在FDA对提交的ANDA进行归档审核期间，FDA会决定是否有重大缺陷或轻微缺陷。通常，重大缺陷是FDA认为比较严重的情况，例如发现违反21 CFR 314.101(d) 或 21 CFR 314.101(e)中要求的某些缺陷，其它的重大缺陷将在本指南和其它指南中进行讨论。大量轻微缺陷（以下将进行讨论）也会构成重大缺陷。一个重大缺陷就会使得FDA依据21 CFR 314.101(d)(3)判定该ANDA是表面不完整的，因此FDA将会RTR含有一个重大缺陷的ANDA。 A minor deficiency is one that in FDA’s judgment is minorin nature and can be easilyremedied [15]. As a result,FDA will allow the applicant a prescribed time period (described below in this section)to provide a response to such deficiencies. In particular,if FDAdetermines that anANDA contains fewer than tenminor deficiencies (i.e., nine deficiencies or fewer),FDA will notifythe applicant of thedeficiencies, by phone, fax, orthrough the primary method for communication,which is email. FDA, in its discretion, provides applicants with the opportunity to correctminor deficiencies or amend the ANDA, within seven (7)calendar days [16]. If within 7 calendardays the requested information is not received, FDA will RTR theANDA. 轻微缺陷是指FDA认为情况比较轻微，很容易补正的缺陷。因此，FDA会允许申报者在指定时间段内（在本部分的以下部分说明）提交对这些缺陷的回复。尤其是如果FDA确定一份ANDA含有小于10个轻微缺陷的时候（即，9个缺陷或更少），则FDA会通过电话、传真、或基本沟通方法即电子邮件方式将这些缺陷告知申报者。在通知中，FDA会告知申报人在7个自然日内有机会纠正轻微缺陷或修订ANDA。如果在7个自然日内没有收到所索取的信息，FDA则会拒收该ANDA。 However, if FDA determinesthat an ANDA contains ten or more minor deficiencies or one ormore major deficiencies, FDA will not consider the ANDA to be a substantially completeapplication under 21 CFR 314.101(b)(1). In suchcases, FDA willnotify the applicant that FDA considers the ANDA not to have been“received.” If the applicantdecides to submit additional materials to correct the deficiencies, the resulting amended ANDA willbe considered a new ANDA submission, received as of the date theamended ANDA is submitted(if deemed substantially complete),and the applicant will berequired to pay a new ANDA fee. If an ANDA is not received and theapplicant takes no action,FDA may consider the ANDAwithdrawn after 1 year [17]. An ANDA applicant’sfailure to take action after a refuse-to-receive decision on an ANDA may be considereda request by the applicantto withdraw the ANDA, unlessthe applicant requests an extension of time in which to resubmitthe ANDA [18]. There may be circumstances,however, under which an exception to, or a waiver of, a regulatory requirement may be granted. FDA will considerthe merits of such circumstanceson a case-by-case basis [19]. 但是，如果FDA认为一份ANDA中含有10个或更多轻微缺陷，或1个或更多重大缺陷，则FDA会认为该ANDA根据是21 CFR 314.101(b)(1)实质不完整的。在此情形下，FDA会通知申报人FDA将视该ANDA为未被接收。如果申报人决定提交更多资料来纠正这些缺陷，则所导致的修订后的ANDA会被当作一份新的ANDA来处理，修订后的ANDA提交日期会被作为是申报接收日期（如果修订后的资料是实质性完整的话），FDA会要求申报人支付一份新ANDA的费用。如果提交的ANDA没有被接受，而申报人在收到ANDA被拒收的决定后又没有采取措施，除申报人申请延期提交ANDA以外，视作申报人要求撤回该ANDA。当然，也有一些情形下会有例外，或者是豁免，这时FDA会各案考虑此种情形。 The following sectionsdiscuss deficiencies that FDA considers to be major deficiencies. A selection of minor deficienciesis provided in Appendix A. 下节讨论FDA 认为重大的缺陷。附录A中给出了轻微缺陷项目。
[1] This guidancehas been preparedby the Office of Generic Drugsin the Center for Drug Evaluation and Research at the Food and Drug Administration. 本指南由食品药品管理局（FDA）的化药评审中心（CDER）的仿制药办公室（OGD）起草制订。
[2] Forpurposes of this guidance, the use of the term “ANDA” will mean ANDAs andnew-strength PAS submissions. 在本指南中，ANDA一词代表ANDA和新剂量PAS申报。
[3] An RTR determination shouldnot be confusedwith a refuse-to-approve determination. 不应将拒收（RTR）决定与拒绝批准决定相混淆。
[4] 21 CFR 314.101(b)(1).
[6] At various points in thisguidance, it isnoted that when a particular type of deficiency in an ANDA is seen, FDA will RTR the ANDA. It is important to understand that these statements do not create legal obligations, on applicants or on FDA, but ratherare included for purposes of transparency. This means that FDA, in the normal course,will RTR an ANDA on the groundsdescribed in this guidance.This guidance does not preclude the possibility that an ANDA applicant may be able to demonstrate, in particular circumstances, that the regulatory requirements for receiving an ANDA have been met even when, as described in this guidance, FDA would in the normalcourse find the application not sufficiently complete to permit a substantive review and RTR it. 在本指南的不同地方，要注意如果FDA在一份ANDA中发现了某种类型的缺陷，则会拒收该ANDA。因此，理解这些声明并不对申报人或FDA产生任何法律义务，而只是为了使得程序更为透明。这意味着FDA在通常程序下会根据本指南所述拒收某份ANDA。本指南并不排除ANDA申报人可能在特殊情形下证明一份ANDA符合本指南中所述的法规接收要求，但FDA仍在正常流程中发现申报资料不够完整无法开始实质性评审，从而拒收的可能性。
[7] Generic Drug User Fee Amendments of 2012 (GDUFA)(Public Law 112-144,Title III). 2012年仿制药用户费用修正案（GDUFA）（公共法112-114，标题III）。
参见仿制药费用法案项目绩效目标和程序。
[9] See 21 CFR 314.101(b)(1) and 314.3(b).
[11] See 21 CFR 314.101(d)-(e).
参见2015财年FDA呈交议会的《仿制药费用修订案》绩效报告，可以从上述网址获得。
[13] 21 CFR 314.101(d)(3).
[14] Pursuant to 21CFR 314.101(d), FDA “may” not consideran ANDA to be received if any of the deficiencies under that regulation applies. FDA will determineon a case-by-case basiswhether a deficiency under certain provisions of § 314.101(d) is a major or minor deficiency, in accordance with the principles described in this guidance. 根据21 CFR 314.101(d)，如果根据适用的法规被判定为缺陷，则FDA可以认为该ANDA不能被接收。FDA会按照本指南中所述的原则，依据§ 314.101(d)的某些条款各案决定一个缺陷是重大缺陷还是轻微缺陷。
[15] Though thefocus of this guidance is to highlight major deficiencies, selectminor deficiencies are listed in Appendix A — the list is not acomprehensive list of minor deficiencies. 尽管本指南重点是强调重大缺陷，但在附录A中仍列出了一些轻微缺陷-----该清单并不是轻微缺陷的穷尽列表。
[16] The responseperiod will begin the day after notification is provided. If the 7th calendar day falls on a Saturday, Sunday, or Federal holiday, the deadlinefor amending the ANDA to correctthe deficiencies will be the next day that is not a Saturday,Sunday, or Federal holiday. 回复期限从发出通知日起算。如果第7个自然日是周六、周日或联邦假日，则补正ANDA的时间期限依次顺延至周末或假期后第一个工作日。
[17] 21 CFR 314.101(b)(3)(iii).
[18] Abbreviated New Drug Applications and 505(b)(2)Applications; Final Rule, 81 FR 69580, 69622 (October6, 2016). 简略新药申报和505(b)(2)申报。最终规则 ，81FR 69580, 69622 (2016年10月6日)
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