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[url=]B. How Are the Amendment Goals Applied?[/url]修订目标是如何应用的?
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8 e# d- `4 @8 P f! E* b& }- M' uPerformance metric goals are applied to the date of submission of the amendment; amendment goals may or may not change the original ANDA’s review goal date.[1] Amendments submitted during the application review either extend or do not change the ANDA goal date.
5 o8 z$ }6 x: G绩效指标应用于修订递交的日期,修订目标可能会改变原始ANDA审核的目标日期.申请审核期间递交的修订不会延迟或者改变ANDA目标日期.
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1. Which amendments are subject to the performance metric goals described in this guidance?哪些修订受到本指南中描述的绩效指标的影响?* |) U4 M0 V' G) v
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The cohort year of the original ANDA or PAS determines the subsequent amendment’s performance metric goals. Only ANDAs and PASs filed in cohort years 3 through 5 (FYs 2015, 2016, and 2017) are assigned goal dates. Accordingly, the amendment goal dates apply to only those applications filed in cohort years 3 through 5. In other words, the amendment performance metric goals described in this guidance do not apply to an amendment submitted in FY 2015, 2016, or 2017 if the original ANDA or PAS was submitted before FY 2015.
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原始ANDA或者PAS在哪年递交将决定随后修订的绩效指标.只有在第三年和第五年期间(即财政年2015,2016和2017)申请的ANDAs和PASs才指定目标日期。因此，修订的目标日期也只适用于在第三年至第五年期间提交的申请。换而言之，在财政年2015，,2016和2017递交的修订，如果其原始ANDA和PAS在财政年2015年之前递交,本指南中的修订的绩效指标将不适用。
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Example: An original application is filed on September 1, 2014. On September 1, 2015, the applicant submits an unsolicited amendment to its pending application. Neither the application nor the amendment has goal dates.
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例如：一份原始申请在2014年9月1日递交。在2015年9月1日，申请人针对这份待批准的申请递交了一份主动修订。这份申请和其修订均没有目标期限。
2 y0 `# v1 o" v D3 eExample: An original application is filed on September 1, 2014. On September 1, 2015, FDA issues a CR letter. On March 1, 2016, the applicant submits a CR amendment to the application. No goal date is assigned to this amendment.
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例如：一份原始申请在2014年9月1日递交。在2015年9月1日，FDA发布了一份CR不足信。在2016年3月1日，申请人递交了CR不足信的修订。该修订将不会指定目标日期。
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Performance metric goals apply only to amendments submitted electronically.[2]
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绩效指标仅适用于电子递交的修订。
, U: R: z, u6 p3 a& r4 ]! G2. For purposes of applying the GDUFA performance metric goals, are cohort years assigned by date of submission of the ANDA or the most recent amendment to the ANDA?为了应用GDUFA绩效指标，年份应该按照ANDA递交日期来指定还是按照最新修订递交的日期来指定？
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9 z+ L2 I% G5 L0 n: RCohort years are assigned by date of submission of the original ANDA. Once an ANDA is submitted and designated a particular cohort year, the submission of a subsequent amendment does not change the cohort year.[3] Any additional review times resulting from the submission of amendments may be added to the original goal date. In no case, does the submission of an amendment shorten the goal date for that ANDA.
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年份是按照原始ANDA递交的日期来指定的.ANDA一旦递交并被指定了具体的年份，随后递交的修订不会改变该年份。任何因为递交修订增加的审核时间可能会累积到原来的目标审核日期。但是递交修订不会缩短ANDA的目标审核日期。
* A _ `1 p" e- l9 k! JBecause amendment performance goals are incremental and may extend the original goal date, and because submission of multiple amendments may result in a Tier 3 classification with no GDUFA metric goals, FDA strongly encourages applicants to submit complete applications, making later amendments unnecessary.
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由于修订的绩效目标是增长的并且可能延迟原来的目标日期，同时由于多个修订的递交可能导致修订被划分为层次3,进而失去GDUFA指标，FDA强烈建议申请人递交完整的申请，以避免后期修订。
: H3 W# G" [$ q C. n( c3. When will an application lose its goal date?一份申请何时会失去它的目标日期？
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8 \5 A/ S; c+ bIf an applicant submits an amendment and that amendment is classified as a Tier 3 amendment (e.g., the 2nd major amendment or 6th minor amendment), the ANDA will lose its goal date.
5 \* t- N X7 ~2 i1 t+ ~* ~如果一份申请递交了一份修订，该修订被划分为层次3的修订（例如，第二个重大的修订或者第六个次要的修订），该ANDA将失去它的目标日期。
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Example: In response to a CR letter, an applicant submits an amendment (CR amendment) that is classified as a Tier 1 solicited major amendment. FDA reviews the amendment and, in a second CR letter, identifies major deficiencies that must be corrected before approval. When the applicant submits a second major amendment in response to the second CR letter, the application loses its goal date.
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例如：为了回复CR不足信，申请者递交了一份修订（CR修订）被划分为层次1的被动的重大修订。FDA审核了该修订并且在下一封CR不足信中指出了在批准前必须改正的重要缺陷项。当申请人针对这封CR不足信再次递交重大修订时，该申请就失去了它的目标日期。
/ [4 }7 W% J0 U m$ ~# |. |Example: In response to a CR letter, an applicant submits an amendment that is classified as a Tier 1 solicited minor amendment. FDA reviews the amendment and, in a second CR letter, identifies major deficiencies that must be corrected before the application may be approved. The applicant submits a second CR amendment that is classified as a Tier 1 solicited major amendment. FDA reviews the amendment and, in a third CR letter, identifies major deficiencies that remain uncorrected. When the applicant submits the second major amendment in response to the third CR letter, the application loses its goal date.
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例如：为了回复CR不足信，申请人递交了一份修订，被划分为层次1的被动的次要修订。FDA审核了该修订并且发布了另一封CR不足信，指出该申请批准前必须改正的重大缺陷项。申请人递交了第二份CR不足信的修订,被划分为层次1的被动的重大修订。FDA审核了该修订，并且发布了第三封CR不足信，指出仍未改正的重大缺陷项。当申请人针对第三封CR不足信再一次递交重大修订时，该申请就失去了它的目标日期。
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4. How are goal dates calculated when an amendment is submitted before a CR letter is issued?修订在CR不足信发布前递交，如何计算目标日期？/ k* D6 j* l5 Q6 J7 N
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An amendment submitted before a CR letter is issued adjusts the goal date for the original application and is additive. Subsequent amendments submitted before a CR letter is issued also adjust the goal date for the application and are additive.[4] FDA has discretion to accept an unsolicited amendment submitted during the review cycle and adjust the goal date for the application. In the alternative, FDA may defer review of the unsolicited amendment, issue the CR letter, and review the unsolicited amendment when the applicant submits the CR amendment. If review of a Tier 2 unsolicited amendment is deferred, the goal date is adjusted to 12 months from the date of submission of the CR amendment.
. U4 L' P& b( |6 {CR不足信发布前递交的修订将调整原始申请的目标日期[url=]并且是增加日期[/url]。随后在CR不足信发布之前递交的修订也将调整申请的目标日期并且是增加日期。FDA有权在审核周期内接收主动修订并调整申请的目标日期。另外的情况下，FDA可能会延迟审核主动修订，先发布CR不足信，当申请人递交CR不足信的修订时再审核该主动修订。如果归属为层次2的主动修订被推迟审核，目标日期将被调整至自递交CR不足信修订之日起的12个月内。
" e! M' e4 x( \) m3 x/ ]Example: An unsolicited amendment with a 12-month review metric submitted 4 months prior to the original goal date adds 8 months to the review clock.
& b) g3 g- L0 ` _$ A( k& ]例如：一份12个月审核指标的主动修订，在原始目标日期前4个月递交，将增加8个月的审核时间。
3 z. a! E) P7 b) fExample: A delaying amendment with a 3-month review metric submitted 4 months prior to the original goal date does not alter the review clock.
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例如：一个3个月审核指标的延迟修订，在原始目标日期前4个月递交，将不会改变审核日期。
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Example: An unsolicited amendment with a 12-month review metric submitted 1 month prior to the original goal date is deferred until after FDA issues the CR letter and the applicant submits the corresponding CR amendment. The new goal date for the CR amendment and the unsolicited amendment is 12 months from the date of the CR amendment.
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例如：12个月审核指标的一个主动修订，在原始目标日期前1个月递交，但是审核被FDA推迟至发布CR不足信且申请人递交该不足信的修订之后。该CR不足信的修订新的目标日期以及主动修订的目标日期将是自CR不足信递交之日起的12个月。
2 y( ]/ v) r) p2 wExample: A delaying amendment with a 3-month review metric is submitted 1 month prior to the original goal date. FDA adds 2 months to the review clock and reviews the delaying amendment before taking action on the application.
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例如：3个月审核指标的延迟修订，在原始目标日期前1个月递交。FDA将增加2个月的审核期并且将在处理该申请之前审核延迟的修订。
- a; L& ]7 n8 |. D5. How are goal dates calculated when an amendment is submitted in response to a CR letter?如果递交的修订是用于回复CR不足信，将如何计算目标日期？
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Generally, an amendment submitted after a CR letter is issued sets a new goal date for the application and subsequent amendments submitted after the CR letter is issued also adjust the goal date for the application and are additive.[5]
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一般情况下，CR不足信发布之后递交的修订，为原申请建立了新的目标审核日期。随后在CR不足信发布后递交的修订也将调整申请的目标审核日期并且是累加的。
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Example: A CR amendment is submitted in response to minor deficiencies identified in a CR letter. It is the application’s second solicited minor amendment. That amendment has a 3-month metric from the date of submission.
/ t: W+ f# h K, I" U& N0 @, {例如：一份递交的CR不足信的修订，用以回复CR不足信中指出的次要缺陷项。该修订属于申请的第二个被动的次要修订。这样的修订自递交日起有3个月的指标。
) R5 v7 e6 K1 ]( S3 {Example: An applicant submits a CR major amendment, which has a 10-month review metric. In month 4 of FDA’s review of the major CR amendment, the applicant submits an unsolicited amendment; that amendment has a 12-month metric that is added to the date of submission, adding 6 months to the original goal date.
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例如：申请人递交了一份CR不足信的重大修订，有10个月的审核指标。在这份修订审核的第四个月，申请人递交了一份主动修订自递交之日起有12个月的指标,该主动修订使得原来的目标日期增加了6个月。
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6. What happens when there are multiple factors affecting the goal date calculation?当存在多个影响因素时，如何计算目标日期？
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If an amendment contains multiple elements, the longest goal date applies to the review goal.[6]
5 I, m# P0 g8 V2 K7 D. D1 E如果一份修订包含了多个因素，取其中最长的目标期限作为审核目标。
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7. How are goal dates calculated when an applicant submits an amendment to an original ANDA before the ANDA has been received?在ANDA接收之前递交了该原始ANDA的修订，应如何计算目标日期？
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Amendments submitted during filing review of the ANDA are classified as Tier 2 unsolicited amendments. If the ANDA is submitted in the year-3 or year-4 cohort[7] and is received, review of the ANDA and the unsolicited amendment will have a 15-month goal date because the longest goal date applies (in this case, the goal date for the ANDA). If the ANDA is submitted in the year-5 cohort and is received, review of the ANDA and the unsolicited amendment will have a 12-month goal date from the date of submission of the unsolicited amendment.
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在ANDA归档审核期间递交的修订被划分为层次2的主动修订.如果ANDA是在第三年或者第四年递交并被接收,ANDA和主动修订的审核将有15个月的目标期限,因为15个月是最长的目标期限(在本例中,最长的期限是ANDA的目标期限).如果ANDA在第五年递交并且被接收,ANDA和主动修订的审核自修订递交之日起有12个月的目标期限.
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Example: An applicant submits an original ANDA on October 1, 2016 (year-5 cohort). On November 1, 2016, during filing review of the ANDA, the applicant submits an unsolicited amendment to the ANDA. The goal date for that ANDA is adjusted from July 31, 2017 (10-month review metric for year-5 cohort ANDAs), to October 31, 2017, which is 12 months from the date of submission of the unsolicited amendment.
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例如:申请人在2016年10月1日(第五年)递交了一份原始的ANDA,.在2016年11月1日,ANDA归档审核期间,申请人递交了一份主动修订.该ANDA的目标日期从2017年7月31日(第五年递交的ANDA审核指标为10个月)调整为2017年10月31日,自主动修订递交之日起12个月.
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8. How are goal dates calculated when an applicant submits an unsolicited amendment after a CR letter is issued but before the applicant responds to the CR letter?申请人在CR不足信发布之后,回复CR不足信之前递交的修订,应如何计算审核的目标期限?7 j) {% |$ A: U
; j3 n9 p7 @! L) SReview of any Tier 2 unsolicited amendments received in the period between FDA’s issuance of a CR letter and the applicant’s submission of its CR amendment is deferred until the CR amendment is received. The application will be assigned a 12-month metric calculated from the date of submission of the CR amendment.
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在FDA发布不足信到申请人递交不足信回复期间,收到的所有层次2的主动修订均被推迟到收到CR不足信的回复之后.申请将被指定12个月的指标,自接收到CR不足信的递交日期算起.
7 R4 `: b0 P- M8 KExample: An applicant receives a CR letter identifying several minor deficiencies. Before submitting the CR amendment, the applicant submits an unsolicited non-delaying amendment. FDA will defer review of the unsolicited non-delaying amendment until the applicant submits a CR amendment that responds to the deficiencies identified in the CR letter. The CR amendment is considered the applicant’s second minor amendment and is subject to a 3-month review metric. However, based on the unsolicited non-delaying amendment, the goal date is adjusted to 12 months calculated from the date of submission of the CR amendment, because the longest applicable goal date applies.
: g* ^; v7 J' u* d4 ?! p例如:申请人收到CR不足信,不足信指出若干次要缺陷.在递交CR不足信的修订之前,申请人递交了一份主动的非延迟性修订.FDA将推迟审核该修订,直到申请人递交CR不足信的修订回复缺陷项.该CR不足信的修订是申请人递交的第二份次要修订,有3个月的审核指标.但是,按照最长期限的原则,基于主动的非延迟修订,该审核目标期限被调整为12个月,自接收到CR不足信的修订之日算起.
$ t5 v: {4 l! A, _. C2 w1 V9. How are goal dates calculated for amendments to tentatively approved applications?对于临时批准申请的修订,如何计算目标日期?
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According to the Commitment Letter, a request for final approval is an example of an administrative amendment.[8] If an applicant has made no changes to product or process since the tentative approval was granted, FDA would not need to dedicate a significant amount of resources to ensure the product is eligible for final approval and would not set a new goal date for review. Most standard requests for final approval, in which few or no changes have been made to the application since the tentative approval, including acceptable compliance (good manufacturing practices (GMP)) status of applicable facilities, will be reviewed in approximately 3 months. However, if, in the time between tentative approval and the request for final approval, the applicant has made changes to product or process (i.e., change in validation procedures, change in manufacturing facilities), this information may warrant a more thorough review. Thus, if an applicant with a tentatively approved application requests final approval, but includes information in the amendment that would cause the amendment to meet the definition of an unsolicited non-delaying amendment, FDA will consider the amendment to be both a request for final approval and an unsolicited non-delaying amendment, which would set a goal of 12 months. As explained in the Commitment Letter[9] and question 6 of this section, the longest applicable review date will apply to amendments with multiple elements.
' C+ z* n" U) O# T. Z2 B b) D根据承诺书的描述,申请ANDA最终批准是行政修订的一个例子.如果申请在被临时批准之后，申请人没有对产品或者工艺进行变更,FDA就没有必要将大量的资源花费在确认产品符合最终批准的工作上,将不会设定新的目标审核日期.大部分标准的最终批准的申请,自临时批准后少有或者没有变更,并且拥有合适的符合可接受状态(符合良好的生产管理规范)的生产设施,该申请将在大约3个月的时间内被审核.此外,如果在临时批准到申请最终批准期间,申请人对产品或者工艺进行了变更(例如验证程序的变更,生产设施的变更),该变更信息需要保证更周密的审核.因此对于已经得到临时批准的申请，如果申请人申请最终批准,但是修订中包含的信息使该修订符合主动的非延迟修订的定义,FDA认为该修订既是一份最终批准的申请,同时也是一份主动的非延迟的修订,这份修订将被设定12个月的目标期限.按照承诺信的描述,以及本部分问题6,对于多个因素的修订目标日期将取其中最长的.
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OGD staff will review the content of the request for final approval to determine whether the submission is classified as an administrative amendment or as a Tier 2 unsolicited non-delaying amendment. If the amendment is classified as a Tier 2 unsolicited non-delaying amendment, OGD will act upon the amendment within 12 months from receipt.
J" C. Y1 ?6 i% |+ L% eOGD的员工将审核最终批准的申请,判断该申请属于行政修订还是层次2的主动的非延迟性修订.如果该修订被划分为层次2的主动的非延迟修订,OGD将自接收之日起在12个月内进行处理.
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Example: An applicant was granted tentative approval to an original application submitted after October 1, 2014, and submits on August 1, 2017, a request for final approval that identifies a change in the manufacturing facility. FDA will have until July 31, 2018, to review the request for final approval.
( t6 a6 R& X% t& x) Z9 G$ _例如,一份2014年10月1日之后递交的原始申请获得了临时批准,申请人在2017年8月1日递交了一份最终批准的申请,申请表明有一个生产设施的变更.FDA直到2018年7月31日才会审核该申请.
% r) ?- u3 _8 U C$ G3 z) E+ cExample: An applicant was granted tentative approval to an original application submitted after October 1, 2014, and submits on August 1, 2017, a request for final approval that includes a Tier 1 delaying amendment (e.g., RLD labeling update). FDA will have until October 31, 2017, to review the delaying amendment and the request for final approval.
6 ^( P% J. Z. D$ o例如:一份2014年10月1日之后递交的原始申请获得了临时批准,申请人在2017年8月1日递交了一份最终批准的申请,申请包含了一份层次1的延迟性申请(例如RLD标签的升级).FDA直到2017年10月31日才会审核该申请.
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10. If my application qualifies for expedited review, what is the impact of that expedited status on the GDUFA metric goals for any subsequent amendments?如果我的申请获得加速审核的资格,对随后修订的GDUFA的审核指标的目标有什么影响?
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As stated in the Commitment Letter, certain submissions may be granted expedited review. Amendments to expedited applications are subject to GDUFA performance metric goals in the same way as amendments to nonexpedited applications. If a submission has been granted expedited status, review may be completed before the applicable GDUFA goal date.
) Y5 I3 x0 ~3 V9 p( w3 x' C按照承诺信的说明,某些递交可能被授予加速审核.该类申请的修订GDUFA的绩效指标与未被批准加速审核申请的修订是一样的.如果递交的申请已经被授予加速状态,审核可能在应用GDUFA目标日期前就完成审核.
2 U! a" T. Y$ f- _* ~8 C% S11. Under what circumstances can FDA change the classification of an applicant’s CR amendment?何种情况下FDA可能变更CR不足信修订的分类?
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* ^( S' D3 C; q" D# c X! s2 QThe type, quantity, or complexity of data submitted in an amendment may prompt a change in classification of the amendment to ensure appropriate allocation of FDA resources for review. All initial classifications and changes to classifications will be made at FDA’s discretion. A CR letter will advise the applicant whether the CR amendment will be classified as a major or minor amendment. However, if the applicant submits a CR amendment that contains additional information or data beyond what was identified in the CR letter as necessary to correct the deficiency or deficiencies identified in the CR letter, FDA will change the classification of the amendment from a Tier 1 solicited major or minor amendment to a Tier 2 unsolicited amendment.
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修订中递交的数据的类型,数量和复杂程度可能促使修订分类的变更,以确保合理分配FDA的审核资源.FDA将自行决定所有最初的分类以及分类的变更.CR不足信将告知申请人该不足信的修订将被划分为重大还是次要修订. 但是,如果申请人递交的CR不足信的修订包含了额外的信息或者数据,这些信息或者数据超出了CR不足信中改正缺陷项或者不足所需要的信息或者数据,FDA将变更该修订的分类,从层次1的被动的重大或者次要修订变更为层次2的主要修订.
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Example: An applicant receives a CR letter identifying certain deficiencies in an application. The CR letter states that the CR amendment will be considered a minor amendment with a 3-month review metric (Tier 1). The applicant submits an amendment and identifies it as a minor CR amendment. However, in lieu of correcting a deficiency using the strength of the drug product that is the subject of the application, the applicant elects to use a new strength. Data supporting the new strength are included in the CR amendment. FDA changes the classification of this amendment from Tier 1 minor amendment to a Tier 2 unsolicited amendment with a 12-month review metric.
2 N# i4 \; C! \ V' O例如:申请人接收到CR不足信,不足信指出了某些申请中的不足.CR不足信中声明该不足信的修订将被分类为次要修订,有3个月的审核指标(层次1).申请人递交了一份修订且确认这是一份次要的CR不足信的修订. 但是,申请人为了改正缺陷项,使用了一个新的产品规格,代替原来申请中的产品规格.CR不足信中包含的数据是针对该新规格的.FDA将变更改修订的类型,从层次1的次要修订变更为层次2的主动修订,将拥有12个月的审核指标.
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FDA’s reclassification of a minor or major CR amendment to an unsolicited amendment will not affect the amendment count that would have applied to the amendment if the sponsor had not submitted additional information. For example, if the CR letter advises a sponsor that the responsive amendment will be classified as a minor amendment, and the sponsor submits an amendment with additional elements that FDA reclassifies as a Tier 2 unsolicited amendment, the amendment will still count toward the sponsor’s total minor amendment count.
P; m( G7 O2 a* [3 k3 A | ^如果申请人没有递交额外的信息,FDA将次要或者主要的CR不足信的修订再次分类为未被要求的修订不会影响修订的数量.例如,CR不足信通知申请人回复该不足信的修订将被分类为次要修订申请人递交了额外的信息,FDA将修订重新分类为层次2的未被要求的修订,该修订仍会被计入申请人总的次要修订数量中.
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12. Under what circumstances can FDA change the classification of an applicant’s ECD response?在何种情况下,FDA可能变更ECD修订的分类?0 x3 ~; @, W6 h! m
: V# }$ v7 V1 i1 a% eIf a response to an ECD is not provided within 10 business days from the request, FDA may reissue the ECD as a minor deficiency in the CR letter upon completion of the current review cycle. Furthermore, if the response to an ECD was filed within 10 business days but contains information requiring more extensive review than is typically required of ECDs, the amendment will be classified as a minor amendment and the goal date adjusted accordingly.
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Example: An applicant fails to submit their ECD response within 10 business days from the request. In its discretion, FDA may defer review of the submission and add the request as a minor amendment to the next CR letter.
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如果ECD的回复自通知之日起,没有在10个工作日内提供,FDA在结束现阶段的审核周期后,会再次发布该ECD，此时的ECD将作为CR不足信的一个次要缺陷项.此外,如果ECD在10个工作日被回复,但是包含的信息,相比较通常的ECDs,需要更多的审核,修订将被归类为次要修订并且相应的目标审核日期将被调整.
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Example: An applicant submits a response to the ECD and that submission contains unsolicited information. FDA will change the classification of the ECD response to a Tier 2 unsolicited non-delaying amendment subject to a 12-month metric, calculated from the date of the newly classified submission.
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例如:申请人递交了一份ECD的回复,该回复包含未被要求的信息.FDA将变更ECD的回复的分类,划分为层次2的主动的非延迟修订,该修订自递交之日起将有12个月的审核目标.
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Example: An applicant submits a response to an ECD within 10 business days from the request. The submission directly responds to the ECD request but does so with information requiring a more extensive review than is typically required of ECDs. FDA may change the classification of the submission to a minor amendment and set the appropriate goal date based on the amendment count.
7 n! ^7 Q& w! o7 d' s2 t2 C例如:申请人在10个工作日内递交了一份ECD的回复.该递交直接回应了这份ECD,但是回复的信息相对于通常的ECD回复需要更多的审核.FDA可能会变更递交的分类为次要修订,并且将基于修订的数量设定合适的目标日期.
0 M5 v$ m/ k0 b# r13. If an applicant provides a minor CR amendment in response to a CR letter within 10 business days, can FDA classify the submission as an ECD? 如果申请人在10个工作日内提供了一个次要的修订回复CR不足信,FDA可能将递交分类为ECD吗?
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& u6 V% H. }9 W5 d) @3 S. IAs stated earlier, whether a submission is classified as a minor amendment or an ECD depends on the extensiveness of FDA resources required to review the submission. Appendix B provides examples of deficiencies listed by discipline that would generally result in a minor amendment. The information or data necessary to correct these deficiencies require more FDA resources to review than an ECD, so the classification as a minor amendment will not change. We also note that a solicited amendment in response to a CR letter sets a new goal date for that application. Submission of an ECD would not set or adjust the goal date for an application, and in no case can the submission of an amendment shorten the goal date.
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如先前所说,递交被划分为次要修订还是ECD取决于审核需要多少FDA的资源支出.附件B提供了一份通常需要次要修订的缺陷项的例子,按照学科进行分类.改正这些缺陷项所需的信息或者数据相对于ECD的审核需要更多的FDA资源,因此划分为次要修订的分类将不会变更.我们同时注意到回复CR不足信的被动修订将给原来申请的审核期限设定一个新的目标时间.ECD的递交不会设置新的或者调整申请的目标日期,并且修订的递交不会缩短目标日期.
+ k" f; E# _# j& T# |& ]Example: An applicant receives a CR letter noting minor deficiencies that must be addressed. Within 10 business days of receipt of the CR letter, the applicant submits a CR amendment and requests that the submission be classified as an ECD. Because the CR amendment was classified as a minor amendment in consideration of the FDA resources required to review the submission, FDA will not change the classification of the minor CR amendment.[10]
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例如:申请人收到一份CR不足信,不足信指出必须整改的次要的缺陷项.自接收CR不足信10个工作日内,申请人递交了一份CR不足信的修订并且申请将该修订分类为ECD的修订.由于考虑到审核该修订需要的FDA资源量,该CR不足信被分类为次要修订,FDA不会变更此次要的CR不足信修订的分类.
* n! w2 ?6 p$ k14. What process will FDA use when changing the classification of amendments?FDA变更修订的分类FDA会走怎样的程序?3 o4 N7 x0 @; ?3 l/ h
( {) B+ q/ O1 G* N# ]The decision to change the classification of an amendment will be made by the regulatory project manager (RPM) and the ANDA review team in consultation with the appropriate division director. Notification of a change in classification will be provided in writing as soon as is practicable after FDA determines that the change is appropriate. Reconsideration of a decision to change the classification of an amendment may be requested using the process described in section VI of this guidance.
* t* I: N( g0 |8 p$ n W! K修订分类的变更是由管理的项目经理(RPM),ANDA审核小组协同相关部门主管磋商之后决定的.FDA判断该变更可行之后,将尽快以书面形式通知该变更的分类.修订类型变更再议的流程将在本指南VI部分进行描述.
7 a, p) _" a; L* p15. How will FDA handle amendments to applications that are of overall poor quality and amendments of overall poor quality? FDA将如何处理整体质量差的申请的修订以及整体质量差的修订?$ b3 O7 g/ f" _) O. P. \4 K# \
# y# d1 {: d! a, k+ B' IAs stated earlier, an amendment responding to multiple deficiencies that, in the aggregate, requires a substantial expenditure of FDA resources to review will be classified as a solicited major amendment. Such classification will occur if an application is of such overall poor quality that a substantive review cannot be performed with the information or data provided — and the type, quantity, or complexity of the information or data required to correct the identified deficiencies will require extensive review by FDA. Similarly, if an applicant’s amendment responding to minor deficiencies is so poorly crafted that substantive review will require, in FDA’s judgment, a greater expenditure of resources than is traditionally required for review of a minor amendment, FDA will change the classification of the amendment from minor to major.
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如之前所说,一份针对多个缺陷项的修订,总体来说,需要花费大量的FDA资源来进行审核,将被划分为被动的重大修订.如果一份申请整体质量较差不能根据其中的数据和信息进行实质性的审核,并且纠正缺陷项所需的信息或者数据的类型,数量和复杂程度需要FDA更广泛的审核，将会进行上述分类.同样地,如果申请人回复次要缺陷项的修订质量较差, ,按照FDA的判断,实质性的审核相比较传统的次要修订的审核需要花费更多资源.FDA将变更修订的分类,从次要变更为重大修订.
8 d7 e7 O0 Q( ~+ ^8 }FDA may, in its discretion, decide not to change the classification of a minor amendment of overall poor quality if the minor amendment causes the application to lose its goal date.
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FDA可能自主决定不变更一份整体质量较差的次要修订的分类,如果该次要修订使申请失去目标审核日期.
# B& @% t" X# g: E1 DExample: An applicant receives a CR letter from FDA identifying multiple deficiencies in the application. Although each deficiency, by itself, may not require a substantial expenditure of FDA resources to review, the application is of such overall poor quality that FDA determines that review of the CR amendment will require extensive FDA resources. Assuming this will be the applicant’s first major amendment, FDA classifies this CR amendment as a Tier 1 solicited major amendment with a 10-month review metric.
3 o* q3 `8 R( I2 t例如:申请人接收到一封CR不足信,FDA指出了多个申请中的缺陷项.尽管每个缺陷项本身不需要花费FDA大量资源去审核,但是由于这份申请质量如此之差,FDA判断不足信的修订需要花费大量FDA资源去审核. 假设这将是申请人的第一个重大修订,FDA将把该CR不足信的修订划分为层次1的被动的重大修订,有10个月的审核指标.
/ }7 M& _3 [: i. b' Y1 pExample: An applicant receives a CR letter from FDA indicating that the amendment should be classified as a minor amendment. Upon review of the CR amendment, FDA finds that the submission is poorly organized, difficult to navigate, and with data not clearly presented. FDA determines that review of this submission will require a significant expenditure of FDA resources. FDA will change the classification of the CR amendment from minor to major and notify the applicant of the change in classification and goal date.
/ i& h+ N1 Z7 m4 b' B. p; M4 O例如:申请人收到一封CR不足信,FDA指出修订将被划分为次要修订.在审核CR不足信修订的过程中,FDA发现递交的修订组织差,难以处理,并且没有清楚地提供数据.FDA判断该审核将需要花费大量的FDA资源.FDA将变更该CR不足信的分类,次要修订变更为重大修订,并且通知申请人分类的变更及目标日期.
$ @- r3 K, b3 P1 ZExample: An applicant submits the 6th minor amendment to its original ANDA. Upon review, FDA determines that the amendment is such overall poor quality, that FDA would normally change the classification to a major amendment. FDA will not change the classification to a major amendment because the application has already lost its goal date.
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例如:申请人递交了第6个原始ANDA的次要修订.审核过程中,FDA判断该修订质量较差,FDA通常会变更分类为重大修订.本例中,FDA不会将分类变更为重大修订,因为该申请已经失去了目标审核期限.
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16. Which submission types are excepted from the amendment/Tier classification system?哪一些类型的修订不参与修订分层系统?
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: ^$ _ c" C& Z |) a" zBecause positron emission tomography (PET) applications are not subject to the fee collecting provisions of GDUFA,[11] the Tier review classifications and performance metric goals do not apply to amendments submitted to PET applications. Similarly, the performance metric goals do not apply to changes being effected (CBE) supplements, which do not require the payment of a fee under GDUFA.
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由于正电子成像术（PET）的申请不受GDUFA收费规定的约束,34因此分层审核分类和绩效指标的目标不适用于PET申请的修订.同样地,绩效指标也不适用于待批准变更(CBE)的修订,CBE的修订不需要按照GDUFA支付费用.
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17. How will FDA determine if an inspection is necessary? FDA如何判断检查是否必要?! d' H2 c% h9 _4 ~
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If an applicant submits a Tier 1 amendment that includes information on a new facility or a facility that is being used for a new purpose, the amendment will be assigned a 10-month metric to allow time for an inspection. If an applicant submits a Tier 2 amendment that includes information on a new facility or a facility that is being used for a new purpose, the amendment will be assigned a 12-month metric, as the longest goal date applies.
r0 {9 V( a1 o6 r3 u5 K0 A1 Y4 d如果申请人递交了一份层次1的修订,包含新设施的信息,或者原来的设施用于新的使用目的,该修订将被指定10个月的指标确保有时间视察.如果申请人递交了一份层次2的修订，包含新设施的信息,或者原来的设施用于新的使用目的,该修订将被指定12个月的指标，,12个月是最长的目标期限。
/ i3 y4 _5 z2 x* \' zExample: An applicant submits its first minor (Tier 1) amendment in response to a CR letter (3-month goal) but the manufacturing site requires an inspection (10- month goal). The amendment will have a 10-month review metric.
( Q/ E, }7 x( X) [( o; F- ]例如:申请人递交了第一个次要修订(层次1)回复CR不足信(3个月的审核目标),但是生产场地需要视察(10个月的目标).该修订将拥有10个月的审核指标.
+ D: m6 B0 Q* d& z5 U2 L* ZExample: An applicant submits a Tier 1 solicited minor amendment. However, in response to the CR letter, the CR amendment contains information on a facility that is being used for a new packaging line. If the facility requires an inspection, a 10-month review metric will be assigned.
6 Z+ ~! B9 L: @7 `% X+ ^例如:申请人递交了一个层次1的被动的次要修订.但是,回复CR不足信的修订中包含了设施的信息,该设施将被用于一条新的包装线.如果设施需要视察,修订将被指定10个月的审核指标.
6 v1 |3 E/ t' V: K: E! Z; uExample: An applicant submits a Tier 2 nondelaying amendment that contains information on a new manufacturing site. The amendment will have a 12-month review metric.
4 v5 y) k4 H2 n3 `例如:申请人递交了一个层次2的非延迟申请,包含了新生产设施的信息.该修订将会拥有12个月的审核指标.
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/ p& p K3 H* x+ H; y( `) n[1] Id. at 10
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) N }! Y3 ?5 `4 [3 U[2] Commitment Letter at 7.
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[3] Id. at 10..
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[4] Id. at 10.
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[5] Id. at 10.
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8 i( M/ P7 C4 v: W" R[6] Commitment Letter at 10.
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[7] As stated in the Commitment Letter at page 9: FDA will review and act on 60%t of original ANDA submissions within 15 months from the date of submission for the year-3 cohort. FDA will review and act on 75% of original ANDA submissions within 15 months from the date of submission of the year-4 cohort. FDA will review and act on 90% of original ANDA submissions within 10 months from the date of submission for the year-5 cohort.
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[8] Commitment Letter at 10.
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+ a, b& Q& V& y i# A7 K[9] Commitment Letter at 10.
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[10] In this guidance, FDA describes the process for requesting reconsideration of amendment classification. Applicants can only request reconsideration of a major amendment. It is not possible to change the classification of a minor amendment to an ECD because an ECD is not part of the amendment Tier structure under GDUFA and, furthermore, because the review cycle has been closed by FDA by taking the action of issuing the complete response letter.
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[11] FD&C Act at section 744B(l) (21 U.S.C. 379j–42(l)).
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