FDA于2021年1月27日发布PremarketTobacco Product Applications and Recordkeeping Requirements意见反馈版，相较于2020年9月25日发布的征询意见版，该版文件不仅对新型烟草产品PMTA认证提出了一些新的要求，同时也对各种反馈意见进行了回复或解释。我们将文件中FDA针对各项意见的解释与回复做以整理，选取与电子烟相关的评论话题，逐一翻译，并且针对其中一些话题给出我们的解读，仅供业内朋友参考交流。每段问答我们都将文件的原文附于其后，如有歧义，请以原文为准。
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.
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.
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.
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.
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.
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。
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.
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.
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.
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.
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.