评论11 

       我们不认为HPHC的定义需要做任何更新，FDA在现有的定义中描述了组成HPHC成分的准则而不会具体指出是什么化学物质构成了HPHC成分。相反，FD&C法案904章节要求FDA建立并定期审核HPHCs列表。同时针对PMTA，本法规的VIII.B.9.a.v.章节说明了并不强制要求申请者进行全HPHCs的测试，而是根据产品本身的性质设计实验，测试包括部分HPHCs在内的一系列组成成分，同时解释说明所测试成分的合理性。

       同样，由于不同烟草产品之间的差异性，我们不想给出硬性的规定必须要检测的化学成分列表。我们相信厂家比我们更了解他们的产品，更清楚他们的产品能释放出哪些化学物质。因此，在科学合理的前提我们相信给予申请者更多的自主权来决定测试项目和测试内容能帮助他们更高效的来准备PMTA的申请。

咨源解读 

       显而易见，这是FDA在为后续的HPHC列表升级做铺垫，基于对产品的理解以及未来可能的材料升级，有很大可能会引入新的有毒有害物质，因此，HPHC是一定会扩大的。然而，我们企业在做研究时，基于不同的设计以及预期的试验结果，不一定在每个试验对完整的HPHC进行考查。所以，FDA也给企业留下了足够的自主空间。

法规原文 

Comment 11: One comment stated thatFDA should either change the definition of the term “harmful or potentiallyharmful constituent” (HPHC) to include a list of all HPHCs for which testingresults must be submitted in a PMTA or include a list of all such HPHCselsewhere in the rule.

FDA Response 11: FDA declines to revisethe definition of HPHC. In defining this term, FDA is describing criteria forwhat constitutes an HPHC and is not attempting to identify specificconstituents. In contrast, section 904 of the FD&C Act requires FDA toestablish, and periodically revise, a list of HPHCs. More importantly for PMTAcontent, as discussed in section VIII.B.9.a.v. of this document, an applicationwould not be required to contain testing for all HPHCs; rather, it would berequired to contain testing for constituents, including HPHCs, that arecontained within and can be delivered by the type of product and contain adescription of why the HPHCs that were tested are appropriate for the type ofproduct.

FDA similarly declines toset forth a list of constituents that must be tested because it would be overlybroad as it pertains to most tobacco products. It is FDA’s understanding thatmanufacturers have information concerning what constituents might be emittedfrom their specific tobacco products. FDA believes that allowing applicants touse this knowledge in selecting the appropriate constituents for testing wouldresult in a more efficient process for preparing PMTAs than requiringmanufacturers to test for each constituent in a broad list, including HPHCsthat might not pertain to the applicant’s specific product.

评论18 

       有不少评论指出FDA应该标准化提交文件中所需要的数据，同时应该允许申请厂家在提交相似产品时使用同样的标准化数据，比如产品中使用了相同的成分等等，如此可以同时提高申请和审核的效率。

FDA的回复 

       如果申请厂商想要使用相同的数据库，我们鼓励大家使用共享资源，比如烟草产品主文件(TPMF)。申请者也可考虑在PMTA提交文件中交叉引用提交过的烟草产品风险改进申请（MRTPA）中的内容。对于那些想提交MRTPA但还没收到上市许可的申请厂商，建议他们可以只提交一个申请同时寻求上市许可和风险改进许可（PMTA和MRTPA结合体）。如果申请厂商决定分开提交PMTA和MRTPA，我们建议他们在PMTA中包含完整的内容（比如生产制造、产品配方等等），然后在MRTPA中交叉引用相关信息。

       在本法规中，除了subpart B中所描述的内容之外，我们不会考虑所提交文件外部的交叉引用内容。对于申请文件中重复出现的内容可以选择内容交叉引用以避免冗长的重复文件。如果申请厂商想要交叉引用已提交过的非烟草主文件或MRTPA（比如同质等同申请，或是已提交过的其它产品PMTA），他们则必须在该申请文件中包含完整的相关信息以减轻我们的审核难度并避免耽搁审核的进程。

咨源解读 

       FDA一直在提倡企业建立并使用TPMF来桥连和加速产品的认证。因此，我们有理由相信，TPMF将是未来申请的一个重要组成部分。基于烟油或开放式器具的TPMF，其临床前研究，甚至是临床研究都有可能成为下一款产品申请的主要部分，从而使后续的申报变得相对简单、便捷。

法规原文 

Comment 18: A number of commentssubmitted similar concerns about the lack of data standardization, stating thatFDA should standardize the data required to be submitted and allow companies torely on the same pool of standardized data where it applies to similar aspectsof their new tobacco product, such as submitting the same ingredients, toimprove the efficiency for both application submission and review.

FDA Response 18: When companies want torely on the same pool of data, FDA encourages the use of shared resources, suchas tobacco product master files, where appropriate. Applicants may also includecontent in a PMTA by cross-reference to a pending MRTPA for the same tobaccoproduct.14 FDA recommends that applicants seeking to market a new tobaccoproduct that has not previously received marketing authorization as a modifiedrisk tobacco product (MRTP) submit a single application to seek both amarketing granted order and a modified risk granted order (i.e., a combinedPMTA and MRTPA); however, where an applicant chooses to submit a separate PMTAand MRTPA, FDA recommends that an applicant submit the full text of any commoncontent (e.g., the manufacturing or product formulation sections) in a PMTA andinclude it in the MRTPA by cross-reference. This approach would prevent anytranscription errors and would allow for a more effective review by FDA becausethe content would only need to be reviewed once to be considered as part ofboth applications.

Under this rule, exceptas described in subpart B, FDA will not consider content included by cross-referenceto any other sources of information outside of a submission. An applicant mayuse internal cross-references for any content that would need to be referencedin multiple sections of a PMTA (i.e., include the full text of the content inone section and use cross- references to the content in other sections), ratherthan including the full text of the same information multiple times. If anapplicant wishes to include information it has previously submitted to FDAother than a master file or a pending MRTPA (e.g., portions of an SE Report orpreviously submitted PMTA for a different product), the applicant must includethe full text of such information in its PMTA. FDA is implementing thisrestriction because cross-referencing information from other types ofapplications (e.g., SE Reports, previously submitted PMTAs for differentproducts) can make review difficult and contribute to delays in the reviewprocess.

评论19 

       有评论陈述了FDA应该增补一个有关申请格式的要求，以此允许PMTA申请中交叉引用已经提交过的其它产品PMTA相关信息。

FDA的回复 

       法案§ 1114.7(b)已明确允许申请厂商在申请相同产品时可以交叉引用烟草产品主文件(TPMF)和烟草产品风险改进申请(MRTPA)。但我们不同意允许交叉使用任何已经提交的PMTA申请，因为如此会极大增加我们完成PMTA审核的工作量，同时也会增加出现错误信息的可能，降低审核效率。另外我们不认为允许交叉使用任何已经提交过的PMTA可以提高我们审核的效率。故此，我们还是鼓励申请方提交烟草产品主文件作为交叉引用的主要信息来源。

       此外即使申请厂商在一个PMTA申请文件中包含多个产品，我们在审核过程中会认为每一个产品是一个独立的PMTA申请，所以希望申请厂商在文件中针对每一个产品都做好相关的目录和内容。

咨源解读 

   FDA上述的要求并非否定TPMF，TPMF的作用和重要性毋庸置疑。只是，FDA基于实际考虑，在我们提交新产品PMTA申请时，如果更加清晰的表达相关联的内容，那么对他们的审核效率是有帮助的。从FDA的角度来说，如果只给一个TPMF编码，他们可能会花很多时间去调取档案进行查阅，而如果把这些信息直接放在申报文件里，则会更加方便他们的审核。这步操作对我们企业而言，并不费事，只是拷贝粘贴即可。但准备好一套完整的TPMF，也是轻松进行拷贝粘贴的前提。

法规原文 

Comment 19: One comment stated thatFDA should amend the application format requirements so that it allows PMTAs toinclude information by cross-reference to parts of previously filed PMTAs fordifferent products that contain studies applicable to the new tobacco product.

FDA Response 19: The format requirementsof § 1114.7(b) permit an applicant to cross- reference a tobacco product masterfile or a pending MRTPA for the same tobacco product. FDA declines to revise §1114.7(b) to broadly allow an applicant to cross-reference informationcontained in any previously filed PMTA because it could result in a process inwhich FDA would have to pull information from a variety of sources to have acomplete PMTA for review, which would increase the potential for error anddecrease the efficiency of FDA’s review.

Additionally, permittingan applicant to broadly cross-reference information presented for differentproducts would not necessarily result in a more efficient review process. FDAis limiting the ability of applicants to cross-reference content frompreviously reviewed PMTAs to specific circumstances set forth in §§ 1114.15 and1114.17 where it would facilitate application review. Where an applicantintends to submit the same information in multiple applications submitted atdifferent periods in time, FDA recommends establishing a TPMF containing theinformation so that it could be included by cross-reference in eachapplication.

An applicant may alsosubmit a single premarket submission for multiple products (i.e., a bundledPMTA) and a single, combined cover letter and table of contents across allproducts; however, when FDA receives a premarket submission that coversmultiple new tobacco products, we intend to consider information on eachproduct as a separate, individual PMTA and it is important to identify thecontent that pertains to each product.

评论20 

       有很多评论要求FDA提供更多的信息来指导如何将多个有关联的、相似的烟草产品PMTA整合到一个申请文件中。其中一个评论要求FDA澄清烟油厂商是否能绑定提交口味不同但其它成分相同的烟油产品？封闭式厂商能否绑定提交参数相似的产品？另外一个评论则要求FDA说明应该如何提交那些分开售卖但是会一起使用的产品，比如封闭式烟油、封闭式烟弹、封闭式电子烟和所使用的烟油等。

FDA的回复 

   对于同一个厂商生产的、属于相同亚类（见§ 1114.7(c)）的产品，我们建议申请方可以绑定申请PMTA。这类同属相同亚类产品绑定申请的PMTA需要使用FDA的4057b表来确认绑定申请中的所有产品。另外我们也建议将产品和相应的配件、部件一同绑定申请。针对封闭式电子烟产品，我们认为器具和所使用的烟油应该一起绑定申请PMTA；针对开放式的电子烟产品，我们不建议将器具和烟油绑定申请PMTA，除非厂商声明烟油仅仅是为该开放式器具设计和使用的。我们再次提醒申请厂商，不论申请包含单个产品还是多个产品，抑或是多个部件、配件，我们在审阅过程中都默认每一个产品都是一个单独的PMTA。所以申请文件必须清晰明确的阐明每一个产品的相关内容信息，否则我们有可能拒绝接受或是受理该申请。

法规原文

Comment 20: Multiple commentsrequested additional information regarding how they should bundle multiplePMTAs for related or similar tobacco products into a single submission. Onecomment requested that FDA formally clarify whether e-liquid manufacturers andmanufacturers of closed-system devices may bundle applications for multipleflavors of e-liquid that share common nicotine strengths, package sizes,propylene glycol/vegetable glycerin ratios, or other characteristics. Anothercomment requested information regarding how a manufacturer should submit PMTAsfor products that are used together but may be sold separately (e.g., closede-liquids, such as cartridges or pods that are not intended to be refillable,and the e-cigarette with which the e-liquids would be used).

FDA Response 20: FDA recommends that anapplicant group PMTAs for products in the same subcategory (see § 1114.7(c))that are produced by the same manufacturer into a single submission becausethey will likely share a significant amount of application content. An applicantgrouping PMTAs together by subcategory would be required to use Form FDA 4057bto identify the products that are contained in the grouped submission.Additionally, FDA recommends an applicant group PMTAs for a new tobacco productand its components or parts into a single submission where an applicant seeksto sell the components or parts separately. As discussed in section VIII.B.3.of this document, FDA generally considers an open e-cigarette, also referred toas a refillable e-cigarette, to be an e-cigarette that includes a reservoirthat a user can refill with an e-liquid of their choosing. A closed e-cigaretteis an e-cigarette that includes an e-liquid reservoir that is not refillable,such as a disposable cigalike, or that uses e-liquid contained in replaceablecartridges or pods that are not intended to be refillable. For example, if amanufacturer wanted to sell a closed e-cigarette and the closed e-liquids(e.g., nonrefillable cartridges or pods) that could be used with thee-cigarette separately, it should group a PMTA for the e-cigarette and PMTAsfor each of the e-liquids into a single submission. FDA does not recommendgrouping open e-liquids and open ENDS devices that will be sold separately in asingle submission except for instances where the applicant is seeking amarketing granted order for the e-liquids that have been designed by themanufacturer to be used solely in a particular open ENDS device. FDA remindsapplicants that we intend to consider information on each product as aseparate, individual PMTA, so it is important to identify the content thatpertains to each product. If an applicant does not clearly identify the contentin the submission that makes up the PMTA for each product, FDA may refuse toaccept or refuse to file the submission.

评论21 

       有评论提到法案§ 1114.7(c)(3)(iii)应该增补内容要求披露新型烟草产品中所使用的所有口味添加剂和溶剂的成分信息。

FDA的回复 

       我们拒绝该提议，因为相关的要求已经在法案§ 1114.7(i)(1)(ii)中做了说明，要求提供产品全套列表的成分、添加物、组成要素等。法案1114.7(c)(3)(iii)的标题是“概要信息”，目的是让我们快速判断产品是否属于烟草中心管辖以及产品的基本信息。所以不需要在这里要求提供产品完整的成分列表等详尽信息。

咨源解读 

       FDA对于申报文件的原则一直是“不要说废话！”现在很多申请人都将材料做成十万页Plus，里面充斥着大量的重复和废话，这无疑增加了FDA的工作量和审核难度；更因为重复内容过多，偶尔加一句有用的内容，反而使FDA漏掉这句关键性信息。因此，咨源科技再次强调，申请文件并非以多为美，要以逻辑清楚，内容简明额要为基础。主文档一定要条理清晰易读，所有证明性文件和数据可以做成附件。

法规原文 

Comment 21: One comment stated that§ 1114.7(c)(3)(iii) should be amended to require disclosure of all flavoringagents regardless of whether they constitute characterizing flavors and allsolvents rather than just propylene glycol and glycerin in all new tobaccoproducts.

FDA Response 21: We decline to make thisproposed edit, because such information is already required as part of the fulllisting of all of the product’s ingredients, additives, and constituents in §1114.7(i)(1)(ii). Section 1114.7(c)(3)(iii), entitled “general information,” isintended to allow FDA to quickly determine whether the product is under CTP’sjurisdiction and readily identify the specific product that is the subject ofthe application. A complete listing of all flavoring agents and solvents inthis section would not further the purpose of this section.

评论23 

       有评论认为FDA应该在法案§ 1114.7(c)(3)中删除有关识别产品类别及亚类别的要求，原因在于申请厂商应该将他们的产品与其它所有种类的烟草产品进行对比，同时FD&C法案910(b)章节也没有对产品类别分类做出考虑。该评论也指出没有证据支持产品使用者会在相同的类别下更换使用产品，相反现实世界的使用情况表明使用者会在不同类别的烟草产品之间更换使用。

FDA的回复 

   我们不同意该评论的说法，产品的类别和亚类别分类不仅能让我们识别该产品，更重要的是能提供包括与产品设计成分相关的健康风险信息、产品包装设计风险信息、操作原理、及警告信息要求等。具体来说，识别产品的类别和亚类别能确保我们区分那些相同品牌/亚品牌下但属于不同类别/亚类别的产品。举例比如一个PMTA申请中的产品与其它产品属于同一个品牌/亚品牌，但是该产品被识别为无烟烟草产品，那么我们在审核该产品的商标等信息时会确保它们符合 “Comprehensive SmokelessTobacco Health and Education”法案的要求。除此之外，理解产品的分类能让我们决定该产品的申请是否符合§ 1114.27(b)(1)(ii)(B)法案的要求，对比其与相同分类产品的健康风险差异以及与至少一种不同分类的产品健康风险差异。

法规原文 

Comment 23: One comment stated thatFDA should remove the requirement to identify the category and subcategory ofthe tobacco product in § 1114.7(c)(3), because applications should comparetheir products to all other tobacco products and product categories are notcontemplated under section 910(b) of the FD&C Act. The comment also statedthat there is no justification to support the potential for users to switchbetween products within categories when real-world evidence shows that currentusers may switch to products from different categories.

FDA Response 23: FDA declines to removethe requirement to identify a product’s category and subcategory. Not only doesthis information allow FDA to identify the product, it provides importantcontext for information contained in the application, including but not limitedto health risks associated with product design and its constituents, productand packaging design risks and misuse hazards, principles of operation, andwarning statement requirements. Specifically, identifying a product’s categoryand subcategory ensures that FDA is able to distinguish between products thathave the same brand and subbrand, but a different category or subcategory,which may be associated with different health risks, design risks or even havedifferent warning statement requirements. For example, if an applicant submitsa PMTA for a product that has the same brand and subbrand as another productbut has been identified as smokeless tobacco, FDA will review the productlabeling to ensure it complies with category specific applicable requirementssuch as the Comprehensive Smokeless Tobacco Health and Education Act.

Additionally,understanding the category will allow FDA to determine whether the applicationmeets the requirement in § 1114.27(b)(1)(ii)(B) to compare the health risks ofthe new tobacco product to the health risks of products in the same productcategory and products in at least one different product category.

评论24 

       有评论认为FDA应该将所有的PMTA申请都递送给“烟草产品科学咨询委员会”（TPSAC），同时将所有PMTA申请向社会公开征集评论。该评论也提到如果递送所有的PMTA申请给委员会不好操作的话，那么至少应该把大烟草公司的申请以及有代表性的小烟草公司的申请文件递送给委员会审查。

FDA的回复 

       我们不同意该评论的提议。FD&C法案910(b)(2)章节里提到FDA可以自主决定、或是在申请者提出要求后将PMTA申请递送给烟草产品科学咨询委员会征集意见评论等信息。但是该过程耗时长，需要的支持资源庞大，包括来来回回的文件反复编写以确保商业机密信息不被泄露等。同时将PMTA申请向社会公开征集意见信息也需要投入大量的时间和经历，操作起来并不现实。我们再次提醒大家FD&C法案的910(c)章节要求我们在收到申请的180天完成PMTA审核，所以我们必须要考虑到现实情况来决策整个审理的过程。

咨源解读 

      显然，这是申请者“反客为主”的要求，以沉重的工作压力迫使FDA放宽审核的难度，但FDA的反应是，他会采取主动权来决定此事，会否将申请递交到TPSAC进行审核，主动权永远在FDA。因此，企业在提交申请时，是否在申请中要求PMTA呈递给TPSAC已没有太大意义。

法规原文 

Comment 24: One comment stated thatFDA should refer all PMTAs to Tobacco Products Scientific Advisory Committee(TPSAC) and should make all PMTAs available for public comment. The commentstated that if referring all applications to TPSAC is unfeasible, FDA should atleast refer applications from major tobacco companies and representativeapplications from smaller companies.

FDA Response 24: We decline to take thecomment’s suggestion. Under section 910(b)(2) of the FD&C Act, FDA has thediscretion, on its own initiative or upon the request of an applicant, to refera PMTA to TPSAC for reference and for submission of a report and recommendationrespecting the application. Referring an application to TPSAC is a lengthyprocess that requires extensive time and resources, including the significantback-and-forth process with an applicant to redact trade secrets andconfidential commercial information in an application before it can be madepublicly available. Receiving and reviewing public comments also requiressignificant time and resources. It would not be feasible to redact all PMTAs,receive and consider public comments, and receive and consider TPSAC’s reportand recommendations prior to acting on the expected high volume of applicationsthe comment is suggesting go to TPSAC within the 180- day review periodrequired by section 910(c) of the FD&C Act.

评论25 

       有很多评论提到FDA应该要求申请厂商说明他们的产品是否属于被认定的烟草产品，即2016年8月8日之前在美国售卖的产品。如果是，FDA则应要求他们提供这些产品的市场信息，包括销售、商标、广告、市场策略等。其中一个评论同时提到FDA还应该要求这些申请者描述这些这产品之前存在于美国市场时是否有利于保护群体的健康，如果不是则应该拒绝此次的PMTA申请。

FDA的回复 

       我们已经在新法规中增补了内容要求PMTA申请中必须阐明产品首次在美国上市的时间。同样法案§ 1114.7(k)的内容也要求申请者提供任何已知的和应该被知道的有关认定的烟草产品之前的上市信息。虽然之前的上市信息可以帮助我们更加了解产品，但我们不要求申请厂商来描述之前的上市是否有利于保护群体的健康，也不会为此而拒绝一个PMTA申请。我们会根据所有的PMTA提交资料来评估产品的上市是否有利于保护群体的健康，此外我们也要求厂商提供上市后的监管计划来确保上市之后对群体健康的保护。

法规原文 

Comment 25: Multiple commentsstated that FDA should require applicants to specify whether the new tobaccoproduct is a deemed tobacco product that has been on the market prior to thedeadline for submitting a PMTA and, if so, require the submission ofinformation regarding the marketing of the product prior to applicationsubmission, including items such as prior sales, labeling, advertising, andmarketing strategy. One comment also requested that FDA require an applicantdescribe whether the prior marketing of its product has been APPH and denyapplications where this has not been the case.

FDA Response 25: FDA has amended therule to require a PMTA to specify the prior dates, if any, during which thetobacco product was initially marketed. Additionally, the requirement in §1114.7(k) to submit full reports of investigations that are published or knownto, or which should reasonably be known to, an applicant includes the timeperiod during which an applicant previously marketed a deemed tobacco product.While information relating to the prior marketing of a tobacco product mayinform FDA review of a PMTA, FDA declines to require an applicant to describewhether it believed its prior marketing of a product was APPH, or necessarilydeny an application where prior marketing was not APPH. FDA will make its owndetermination as to whether permitting the marketing of the new tobacco productis APPH based on all of the contents of the application. In addition, FDA hasauthority to include postmarket requirements to help ensure that marketing ofthe product after authorization continues to be APPH.

评论27 

       有评论赞同FDA所提出的有关样品准备的要求，即申请厂商在PMTA被接受之后需要准备好产品样品，以备FDA的要求。但是该评论指出FDA最好能提前告知厂商具体所需准备样品的数量和类型，这样也方便厂商提前安排好足量的样品。

FDA的回复 

       正如本法规VIII.B.5章节所描述的，我们要求厂商在提交PMTA后的30内准备好相应的样品，等待FDA的指示随时准备寄送给我们。虽然有很多诸如产品类别、产品特性等因素会影响到FDA所需要产品样品的数量和类型，我们还是想在接受产品PMTA申请之后给出一个样品数量和类型的确切决定的。但是，正如章节VIII.B.5.所描述的，申请者可以与FDA进行PMTA递交前的会议讨论是否有必要在PMTA申请过程中给FDA准备产品的样品。

法规原文 

Comment 27: One comment agreed thatrequesting samples after a PMTA submission has been accepted makes sense;however, it stated that providing information regarding the quantity and typeof samples that will be required for submission in advance is important toensure that the samples FDA requires are actually available at the time ofrequest.

FDA Response 27: As described in sectionVIII.B.5 of this document, FDA generally expects that product samples will be arequired part of a PMTA and that an applicant should be prepared to submit themin accordance with FDA instructions within 30 days after submitting a PMTA.Because the quantity and type of samples need for testing may vary based upon anumber of factors including product category and specific productcharacteristics, FDA intends to determine the quantity and type that will berequired after application acceptance. However, as noted in section VIII.B.5.,presubmission meetings with FDA may help provide additional information aboutwhether product samples will need to be included in a PMTA.

评论28 

       我们收到了很多关于在FDA接受PMTA之后再准备提交样品的相关评论。其中一个评论指出FDA的180天审核周期不能因为样品的寄送问题而被推迟，该审核周期应该从接受申请开始计算时间。另一个评论指出相较于延迟启动科学审核所带来的损失要远远大于在样品寄送问题上节省的开支。该评论还指出 FDA可以无限期的在样品需求的问题上无限期的拖延PMTA受理进度。

FDA的回复 

       我们不赞同评论中的说法。即使我们要求申请者准备样品，那也只是在我们接受申请之后而不是要求申请者将样品和申请同时提交。如此可以帮助我们有一定的时间来决定所需要的样品数量、识别申请中的所有产品、准备好接受这些样品的机构等等。另外，在我们接受申请之后再准备样品寄送可以避免申请者不必要的开支，比如申请被拒绝接受或是根本不要求提供样品。同样也减少了我们后期处理不必要的样品的工作量。

我们会在接受申请后的第一时间告知申请厂商是否需要为下一步准备样品。总的来说，我们要求申请厂商在提交申请后的30内将所需要的样品准备好，以便FDA随时提出需求。同样申请者可以与我们进行递交前的会议来讨论有关样品准备的问题。

法规原文 

Comment 28: We received multiplecomments regarding FDA’s proposal to require an applicant to submit productsamples only after an application is accepted for review. One comment statedthat the start of FDA’s 180-day review period should not be postponed untilsamples are received and should instead begin at the time the application isotherwise complete except for samples. Another comment requested that FDA amendthe rule to allow applicants to submit product samples as part of its initialPMTA to avoid delays. The comment stated that the costs of the delaying thestart of substantive review outweigh any minor savings gained by postponinginevitable product sample submission. The comment also noted that under FDA’sproposed approach, FDA could indefinitely delay filing an application forreview by not requesting product samples after application acceptance.

FDA Response 28: We decline to make therequested revisions. FDA will have applicants submit samples (if required byFDA) after acceptance of an application rather than as part of an initialsubmission. This timing will help FDA to determine the need for samples, allowthe samples to be tracked and identified as part of the correct application,and facilitate the submission of samples to testing facilities that areadequately prepared to accept them (e.g., one that has a refrigerated unit ifthe product needs to be stored at a certain temperature).

Additionally, by havingapplicants submit samples after FDA accepts an application, applicants will beable to avoid the effort and expense of submitting samples if the applicationis not accepted for review or if samples are not required. It will also allowFDA to avoid similar concerns with respect to storage and the return of samplesfor applications where FDA refuses to accept a PMTA. As described in § 1114.27,if required by FDA, product samples will be necessary for application filing andFDA intends to refuse to file a PMTA for a lack of product samples if theapplicant has not submitted samples in accordance with FDA’s instructions bythe time FDA is prepared to make its filing determination.

FDA intends to notify anapplicant if it determines after PMTA acceptance that product samples are notrequired for PMTA filing; however, even in such a situation, FDA may requestproduct samples during substantive review after an application is filed, asneeded.  FDA generally expects that,where required, samples will be requested within 30 days after applicationsubmission. Applicants may discuss the need for product samples during apresubmission meeting with FDA, which may speed up the sample submissionprocess.

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