Guidance for Industry
Modified Risk Tobacco
Product Applications
DRAFT GUIDANCE 
This guidance document is being distributed for comment purposes only. 
Written comments and suggestions regarding this draft document may be submitted 
within 60 days of publication in the Federal Register of the notice announcing the 
availability of the draft guidance.  Submit comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 
1061, (HFA-305), Rockville, MD, 20852. Alternatively, electronic comments may be 
submitted to http://www.regulations.gov.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
For questions regarding this draft guidance, contact the Center for Tobacco Products at 
(Tel) 1-877-CTP-1373 (1-877-287-1373) Monday-Friday, 9:00 a.m.  4:00 p.m. EDT. 
Additional copies are available online at 
http://www.fda.gov/TobaccoProducts/GuidanceComplianceRegulatoryInformation/defaul 
t.htm.  You may send an e-mail request to SmallBiz.Tobacco@fda.hhs.gov to receive an 
electronic copy of this guidance.  You may send a request for hard copies to U.S. Food 
and Drug Administration, Center for Tobacco Products, Attn: Office of Small Business 
Assistance, Document Control Center, Building 71, Room G335, 10903 New Hampshire 
Avenue, Silver Spring, MD 20993-0002. 
U.S. Department of Health and Human Services
 
Food and Drug Administration 

Center for Tobacco Products 

March 2012  Contains Nonbinding Recommendations
 
Draft  Not for Implementation
 
Table of Contents 
I.  Introduction................................................................................................................... 1
 
II.  Background ................................................................................................................... 2
 
III.  Definitions..................................................................................................................... 5
 
A.  Tobacco Product ........................................................................................................... 5
 
B.  New Tobacco Product................................................................................................... 6
 
C.  Modified Risk Tobacco Product ................................................................................... 6
 
D.  Risk Modification Order ............................................................................................... 7
 
E.  Exposure Modification Order ....................................................................................... 7
 
IV.  General Information...................................................................................................... 8
 
A.  Who Submits an MRTPA? ........................................................................................... 8
 
B. 	 When Should You Submit an MRTPA? ....................................................................... 8
 
C. 	 Can I Introduce or Deliver for Introduction into Interstate Commerce an MRTP 

Without an Order Under Section 911(g) in Effect? .................................................... 10
 
V.  Contents of an MRTPA .............................................................................................. 10
 
A.  Contents of an MRTPA Required Under Section 911(d) ........................................... 10
 
1.	  A Description of the Proposed Tobacco Product and Any Proposed Advertising and 

Labeling ...................................................................................................................... 11 

2.	  The Conditions for Using the Tobacco Product ......................................................... 12
 
3.	  The Formulation of the Tobacco Product ................................................................... 12
 
4.	  Sample Product Labels and Labeling ......................................................................... 13
 
5.	  All Documents Relating to Research Findings ........................................................... 13
 
6.	  Data and Information on How Consumers Actually Use the Tobacco Product ......... 14
 
B.  Other Information ....................................................................................................... 15
 
C.  Environmental Impact Considerations........................................................................ 16
 
VI.  Scientific Studies and Analyses in MRTPAs.............................................................. 16
 
A.  Key Areas of Investigation Regarding the Effect of an MRTP .................................. 16
 
1.  Health Risks of the Tobacco Product.......................................................................... 17
 
2.  Effect on Tobacco Use Behavior among Current Tobacco Users .............................. 19
 
3.  Effect on Tobacco Use Initiation among Non-Users .................................................. 20
 
4.  Effect of Marketing on Consumer Understanding and Perceptions ........................... 20
 
5.  Effect on the Population as a Whole ........................................................................... 21
 
B.  Detailed Considerations Regarding the Recommended Studies and Analyses .......... 22
 
1.  Product Analyses ........................................................................................................ 23
 
2.  Nonclinical Studies ..................................................................................................... 24
 
3.  Studies in Adult Human Subjects ............................................................................... 24
 
4.  Secondary Data Analyses and Computational Modeling ........................................... 27
 
C.  General Principles for Scientific Studies and Analyses.............................................. 27
 
VII.  Postmarket Surveillance and Studies .......................................................................... 29
 
A.  Postmarket Surveillance.............................................................................................. 30
 
B.  Postmarket Studies...................................................................................................... 31
 
C.  Outcomes Evaluated in Postmarket Surveillance and Studies.................................... 31
 
D.  Design of Postmarket Studies and Active Surveillance.............................................. 32
 
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VIII.  Submission Information.............................................................................................. 33
 
A.  Organizing Your MRTPA for Submission to FDA .................................................... 33
 
1.  Cover Letter ................................................................................................................ 33
 
2.  Table of Contents and Summary................................................................................. 34
 
3.  Descriptive Information .............................................................................................. 35
 
4.  Labels, Labeling and Advertising ............................................................................... 35
 
5.  Environmental Impact................................................................................................. 35
 
6.  Summary of All Research Findings ............................................................................ 35
 
7.  Scientific Studies and Analyses .................................................................................. 36
 
B.  Single Application ...................................................................................................... 38
 
C.  How and Where Should I Submit My MRTPA? ........................................................ 39
 
D.  What Happens After You Submit an MRTPA?.......................................................... 41
 
E.  Can I Withdraw My Pending MRTPA?...................................................................... 41
 
F.  What is FDAs Timeframe for Review of an MRTPA? ............................................. 42
 
G.  What Happens After an Order Under Section 911(g) of the FD&C Act is Issued? ... 42
 
H.  Can FDA Withdraw an Order Issued Under Section 911(g)? .................................... 43
 
I.  Can I Renew an Order Issued Under Section 911(g)? ................................................ 43
 
IX.  Investigational Use of Tobacco Products ................................................................... 43
 
A.  Exemptions for Investigational Use of Tobacco Products.......................................... 43
 
B.  Requesting a Meeting with FDA ................................................................................ 45
 
C.  Studies Conducted Outside of the United States ........................................................ 46
 
X.  Confidentiality ............................................................................................................ 46
 
ii  Contains Nonbinding Recommendations
 
Draft  Not for Implementation
 
1 
Guidance for Industry
1 
2 
Modified Risk Tobacco Product 
3 
Applications 
4 
5 
6  This draft guidance, when finalized, will represent the Food and Drug Administration's 
7  (FDA's) current thinking on this topic.  It does not create or confer any rights for or on 
8  any person and does not operate to bind FDA or the public. You can use an alternative 
9  approach if the approach satisfies the requirements of the applicable statutes and 
10  regulations.  If you want to discuss an alternative approach, contact the FDA staff 
11  responsible for implementing this guidance.  If you cannot identify the appropriate FDA 
staff, call the appropriate number listed on the title page of this guidance. 
12 
13 
14  I.  Introduction 
15 
16  This draft guidance provides information about submitting applications for modified risk 
17  tobacco products under section 911 of the Federal Food, Drug, and Cosmetic Act (the 
18  FD&C Act) (21 U.S.C. 387k), as amended by the Family Smoking Prevention and 
19  Tobacco Control Act (Tobacco Control Act) (Public Law 111-31). Congress found that 
20  [u]nless tobacco products that purport to reduce the risks to the public of tobacco use 
21  actually reduce such risks, those products can cause substantial harm to the public 
22  health . . . . Section 2(37) of the Tobacco Control Act. Furthermore, Congress noted 
23  that [t]he dangers of products sold or distributed as modified risk tobacco products that 
24  do not in fact reduce risk are so high that [FDA must] ensur[e] that statements about 
25  modified risk tobacco products are complete, accurate, and relate to the overall disease 
26  risk of the product. Section 2(40) of the Tobacco Control Act. Thus, Congress 
27  recognized that manufacturers must demonstrate that such products . . . meet a series of 
28  rigorous criteria, and will benefit the health of the population as a whole before 
29  marketing tobacco products for use to reduce harm or the risk of tobacco-related disease 
30  or to reduce exposures to harmful substances associated with tobacco products.  Section 
31  2(36) of the Tobacco Control Act. 
32 
33  The modified risk tobacco product provisions of the FD&C Act may be valuable tools in 
34  the effort to promote public health by reducing the morbidity and mortality associated 
35  with tobacco use, particularly if companies take advantage of these provisions by making 
1 This guidance was prepared by the Office of Science and Office of Regulations in the Center for Tobacco 
Products at FDA. 
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36  bold, innovative product changes that substantially reduce, or even eliminate altogether, 
37  either the toxicity or addictiveness of tobacco products, or both. 
38 
39  Section 911(l)(1) of the FD&C Act directs FDA to issue regulations or guidance (or any 
40  combination thereof) on the scientific evidence required for assessment and ongoing 
41  review of modified risk tobacco products. This draft guidance, issued pursuant to section 
42  911(l)(1), explains, among other things: 
43 
44    Who may submit a modified risk tobacco product application under section 911 of 
45  the FD&C Act; 
46    When to submit a modified risk tobacco product application; 
47    What information the FD&C Act requires you to submit in a modified risk 
48  tobacco product application; 
49    What scientific studies and analyses FDA recommends you submit in a modified 
50  risk tobacco product application; 
51    What information should be collected through postmarket surveillance and 
52  studies; and 
53    How to organize and submit a modified risk tobacco product application. 
54 
55  FDAs guidance documents, including this guidance, do not establish legally enforceable 
56  responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and 
57  should be viewed only as recommendations, unless specific regulatory or statutory 
58  requirements are cited. The use of the word should in Agency guidances means that 
59  something is suggested or recommended, but not required. 
60 
61  This document provides extensive information about the types of scientific studies and 
62  analyses FDA recommends that applicants consider conducting in order to provide the 
63  evidence needed to support issuance of an order under section 911(g) of the FD&C Act. 
64  As with all guidance, applicants can use an alternative approach if that approach would 
65  provide the evidence needed to support issuance of an order.  FDA encourages anyone 
66  who is considering development of, or preparing an application for, a modified risk 
67  tobacco product to meet with FDA to discuss what studies would be appropriate for your 
68  product, so that you can best use your resources to conduct studies that will support your 
69  application. We request comment on the extent of information needed to support FDAs 
70  decision-making process under section 911(g) of the FD&C Act. 
71  II.  Background 
72 
73  Modified risk tobacco products (MRTPs) are tobacco products that are sold or distributed 
74  for use to reduce harm or the risk of tobacco-related disease associated with 
75  commercially marketed tobacco products (see Definitions). 
76 
77  Before an MRTP can be introduced or delivered for introduction into interstate 
78  commerce, an order from FDA under section 911(g) of the FD&C Act (risk 
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79  modification order or exposure modification order  see Definitions) must be in effect 
80  with respect to the tobacco product. Section 911(a) of the FD&C Act. If the modified 
81  risk tobacco product is a new tobacco product within the meaning of section 910(a)(1), 
82  any applicable premarket review requirements under section 910 of the FD&C Act must 
83  also be satisfied.  Section 910(a)(2)(A) of the FD&C Act. 
84 
85  Section 911(g) of the FD&C Act describes the demonstrations applicants must make to 
86  obtain an order from FDA.  Sections 911(g)(1) and (2) of the FD&C Act set forth two 
87  bases for FDA to issue an order. 
88 
89  In general, FDA shall issue an order under section 911(g)(1) of the FD&C Act (risk 
90  modification order) only if it determines the applicant has demonstrated that the product, 
91  as it is actually used by consumers, will: 
92 
93     Significantly reduce harm and the risk of tobacco-related disease to individual 
94  tobacco users; and 
95     Benefit the health of the population as a whole taking into account both users of 
96  tobacco products and persons who do not currently use tobacco products. 
97 
98  Section 911(g)(1) of the FD&C Act. 
99 
100  FDA has the authority to require with respect to tobacco products for which risk 
101  modification orders are issued that the product comply with requirements relating to 
102  advertising and promotion of the tobacco product.  Section 911(h)(5) of the FD&C Act. 
103 
104  In the alternative, for products that cannot receive a risk modification order from FDA 
105  under section 911(g)(1) of the FD&C Act, FDA may issue an order under section 
106  911(g)(2) of the FD&C Act (exposure modification order) if it determines that the 
107  applicant has demonstrated that: 
108 
109     Such an order would be appropriate to promote the public health; 
110     Any aspect of the label, labeling, and advertising for the product that would cause 
111  the product to be a modified risk tobacco product is limited to an explicit or 
112  implicit representation that the tobacco product or its smoke does not contain or is 
113  free of a substance or contains a reduced level of a substance, or presents a 
114  reduced exposure to a substance in tobacco smoke; 
115     Scientific evidence is not available and, using the best available scientific 
116  methods, cannot be made available without conducting long-term epidemiological 
117  studies for an application to meet the standards for obtaining an order under 
118  section 911(g)(1); and 
119     The scientific evidence that is available without conducting long-term 
120  epidemiological studies demonstrates that a measurable and substantial reduction 
121  in morbidity or mortality among individual tobacco users is reasonably likely in 
122  subsequent studies. 
123 
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124  Section 911(g)(2)(A) of the FD&C Act. 
125 
126  Furthermore, for FDA to issue an exposure modification order, FDA must find that the 
127  applicant has demonstrated that: 
128 
129     The magnitude of overall reductions in exposure to the substance or substances 
130  which are the subject of the application is substantial, such substance or 
131  substances are harmful, and the product as actually used exposes consumers to the 
132  specified reduced level of the substance or substances; 
133     The product as actually used by consumers will not expose them to higher levels 
134  of other harmful substances compared to the similar types of tobacco products 
135  then on the market unless such increases are minimal and the reasonably likely 
136  overall impact of use of the product remains a substantial and measurable 
137  reduction in overall morbidity and mortality among individual tobacco users; 
138     Testing of actual consumer perception shows that, as the applicant proposes to 
139  label and market the product, consumers will not be misled into believing that the 
140  product is or has been demonstrated to be less harmful or presents or has been 
141  demonstrated to present less of a risk of disease than one or more other 
142  commercially marketed tobacco products; and 
143     Issuance of the exposure modification order is expected to benefit the health of 
144  the population as a whole taking into account both users of tobacco products and 
145  persons who do not currently use tobacco products. 
146 
147  Section 911(g)(2)(B) of the FD&C Act. 
148 
149  In evaluating the benefit to health of individuals and of the population as a whole under 
150  sections 911(g)(1) and (g)(2) of the FD&C Act, FDA must take into account: 
151 
152     The relative health risks the modified risk tobacco product presents to 
153  individuals; 
154     The increased or decreased likelihood that existing tobacco product users who 
155  would otherwise stop using such products will switch to using the modified risk 
156  tobacco product; 
157     The increased or decreased likelihood that persons who do not use tobacco 
158  products will start using the modified risk tobacco product; 
159     The risks and benefits to persons from the use of the modified risk tobacco 
160  product compared to the use of smoking cessation drug or device products 
161  approved by FDA to treat nicotine dependence; and 
162     Comments, data, and information submitted to FDA by interested persons. 
163 
164  Section 911(g)(4) of the FD&C Act. 
165 
166  In reviewing any MRTPA and making its determination whether to grant an order under 
167  section 911(g) of the FD&C Act, FDA will consider the scientific evidence submitted by 
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168  the applicant as well as other scientific evidence or information made available to FDA. 
169  Section 911(g)(3) of the FD&C Act. 
170 
171  Furthermore, FDA must ensure, for a risk or exposure modification order, that the 
172  advertising and labeling of the MRTP enable the public to comprehend the information 
173  concerning modified risk and to understand the relative significance of such information 
174  in the context of total health and in relation to all of the tobacco-related diseases and 
175  health conditions.  Section 911(h)(1) of the FD&C Act. 
176 
177  A risk modification order issued under section 911(g)(1) of the FD&C Act will be 
178  effective for the period of time specified in the order issued by FDA.  Section 911(h)(4) 
179  of the FD&C Act. An applicant to whom a risk modification order is issued under 
180  section 911(g)(1) must conduct postmarket surveillance and studies and submit the 
181  results of such surveillance and studies to FDA annually.  Section 911(i)(1) of the FD&C 
182  Act. 
183 
184  An exposure modification order issued under section 911(g)(2) of the FD&C Act will be 
185  effective for a term of not more than 5 years.  FDA may renew an exposure modification 
186  order if the applicant files a new application and FDA finds that the requirements for 
187  such order under section 911(g)(2) continue to be satisfied.  Section 911(g)(2)(C)(i) of 
188  the FD&C Act.  Further, an exposure modification order will be conditioned on the 
189  applicants agreement to conduct postmarket surveillance and studies and to submit the 
190  results of such surveillance and studies to FDA annually.  Section 911(g)(2)(C)(ii), (iii) 
191  of the FD&C Act. 
III.  Definitions 
192 
193 
194  This section provides definitions of certain terms used in this guidance. 
195  A.  Tobacco Product 
196 
197  Tobacco product means any product made or derived from tobacco that is intended for 
198  human consumption, including any component, part, or accessory of a tobacco product 
199  (except for raw materials other than tobacco used in manufacturing a component, part, or 
200  accessory of a tobacco product).  Section 201(rr)(1) of the FD&C Act (21 U.S.C. 
201  321(rr)(1)).  Thus, the term is not limited to products containing tobacco, but also includes 
202  components, parts, or accessories of tobacco products, whether they are sold for further 
203  manufacturing or for consumer use.  For example, cigarette rolling papers and filters are 
204  tobacco products, whether they are sold to consumers for use with roll-your- own tobacco 
205  or are sold for further manufacturing into a product sold to a consumer, such as a 
206  cigarette. This term does not include an article that is a drug, a device, or a combination 
207  product as defined in the FD&C Act. Section 201(rr)(2) of the FD&C Act (21 U.S.C. 
208  321(rr)(2)). 
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209  B.  New Tobacco Product 
210 
211  New tobacco product means any tobacco product (including those products in test 
212  markets) that was not commercially marketed in the United States as of February 15, 
213  2007; or any modification (including a change in design, any component, any part, or any 
214  constituent, including a smoke constituent, or in the content, delivery or form of nicotine, 
215  or any other additive or ingredient) of a tobacco product where the modified product was 
216  commercially marketed in the United States after February 15, 2007.  Section 910(a)(1) 
217  of the FD&C Act (21 U.S.C. 387j(a)(1)). 
218  C.  Modified Risk Tobacco Product 
219 
220  Modified risk tobacco product means any tobacco product that is sold or distributed for 
221  use to reduce harm or the risk of tobacco-related disease associated with commercially 
222  marketed tobacco products. Section 911(b)(1) of the FD&C Act.  Sold or distributed for 
223  use to reduce harm or the risk of tobacco-related disease associated with commercially 
224  marketed tobacco products means a tobacco product 
225 
226  (1) that represents in its label, labeling, or advertising, either implicitly or 
227  explicitly, that: 
228  i.   the tobacco product presents a lower risk of tobacco-related disease or 
229  is less harmful than one or more other commercially marketed tobacco 
230  products; 
231  ii.  the tobacco product or its smoke contains a reduced level of a 
232  substance or presents a reduced exposure to a substance; or 
233  iii.  the tobacco product or its smoke does not contain or is free of a 
234  substance; 
235  (2) that uses the descriptors light, mild, low, or similar descriptors in its 
236  label, labeling, or advertising;2 or 
237  (3) for which the tobacco product manufacturer has taken any action directed to 
238  consumers through the media or otherwise, other than by means of the 
239  tobacco products label, labeling, or advertising, after June 22, 2009, 
240  respecting the product that would be reasonably expected to result in 
241  consumers believing that the tobacco product or its smoke may present a 
242  lower risk of disease or is less harmful than one or more commercially 
2 While cigarettes had been marketed with such descriptors before the Tobacco Control Act was enacted, as 
of June 22, 2010, manufacturers were prohibited from manufacturing for sale or distribution any tobacco 
products for which the label, labeling, or advertising contains the descriptors light, low, or mild, or 
any similar descriptor, without an FDA order in effect under section 911(g) of the FD&C Act. Section 
911(b)(3) of the FD&C Act. Furthermore, as of July 22, 2010, manufacturers, including importers of 
finished tobacco products, were prohibited from introducing into the domestic commerce of the United 
States any tobacco product for which the label, labeling, or advertising contains the descriptors light, 
low, or mild, or any similar descriptor, irrespective of the date of manufacture, without an FDA order 
in effect under section 911(g) of the FD&C Act. Id. 
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243  marketed tobacco products, or presents a reduced exposure to, or does not 
244  contain or is free of, a substance or substances. 
245 
246  Section 911(b)(2) of the FD&C Act.3 
247 
248  A product that is intended to be used for the treatment of tobacco dependence, including 
249  smoking cessation, is not a modified risk tobacco product if it has been approved as a 
250  drug or device by FDA and is subject to the requirements of chapter V of the FD&C Act. 
251  Section 911(c) of the FD&C Act. 
252  D.  Risk Modification Order 
253 
254  A risk modification order is an order permitting the introduction or delivery for 
255  introduction into interstate commerce of a modified risk tobacco product that FDA has 
256  found meets the criteria for an order under section 911(g)(1) of the FD&C Act.  In order 
257  for FDA to issue a risk modification order under section 911(g)(1) of the FD&C Act, the 
258  applicant must demonstrate that the product, as it is actually used by consumers, will: 
259 
260    Significantly reduce harm and the risk of tobacco-related disease to individual 
261  tobacco users; and 
262    Benefit the health of the population as a whole taking into account both users of 
263  tobacco products and persons who do not currently use tobacco products. 
264 
265  FDA intends to describe in the risk modification order the claim(s) for the tobacco 
266  product covered by the order. 
267  E.  Exposure Modification Order 
268 
269  An exposure modification order is an order permitting the introduction or delivery for 
270  introduction into interstate commerce of a modified risk tobacco product that reduces or 
271  eliminates exposure to a substance and for which the available scientific evidence 
272  suggests that a measurable and substantial reduction in morbidity and mortality is 
273  reasonably likely to be demonstrated in future studies.  In order for FDA to issue an 
274  exposure modification order, the applicant must satisfy all of the criteria for issuance of 
275  an order under section 911(g)(2) of the FD&C Act.  An applicant may file an application 
276  seeking an exposure modification order only if scientific evidence is not available and, 
277  using the best available scientific methods, cannot be made available without conducting 
278  long-term epidemiological studies, for an application to meet the standards set forth in 
279  section 911(g)(1). 
3 No smokeless tobacco product shall be considered to be sold or distributed for use to reduce harm or the 
risk of tobacco-related disease solely because its label, labeling, or advertising uses the following phrases: 
smokeless tobacco, smokeless tobacco product, not consumed by smoking, does not produce 
smoke, smokefree, smoke-free, without smoke, no smoke, or not smoke. Section 911(b)(2)(C) 
of the FD&C Act. 
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280 
281  If an applicant is seeking an exposure modification order, any aspect of the label, 
282  labeling, and advertising that would cause the tobacco product to be an MRTP must be 
283  limited to an explicit or implicit representation that: 
284 
285    The tobacco product or its smoke does not contain or is free of a substance; 
286    The tobacco product or its smoke contains a reduced level of a substance; or 
287    The tobacco product presents a reduced exposure to a substance in tobacco 
288  smoke. 
289 
290  FDA intends to describe in the exposure modification order the claim(s) for the tobacco 
291  product covered by the order. 
292  IV.  General Information 
293  A.  Who Submits an MRTPA? 
294 
295  Any person may submit an application seeking an order under section 911(g) of the 
296  FD&C Act. The requirements of section 911 of the FD&C Act apply to any tobacco 
297  product subject to Chapter IX of the FD&C Act that meets the definition of an MRTP. 
298 
299  Tobacco products subject to Chapter IX of the FD&C Act include the products named in 
300  section 901(b) (i.e. cigarettes, cigarette tobacco, smokeless tobacco and roll-your-own 
301  tobacco) and tobacco products that have been or may be deemed by regulation to be 
302  subject to Chapter IX of the FD&C Act (section 901(b) of the FD&C Act), as well as the 
303  components, parts, and accessories of such products (e.g., cigarette rolling papers, filters, 
304  or filter tubes sold separately or as part of kits) sold or distributed for consumer use or for 
305  further manufacture. 
306 
307  At this time, FDA does not intend to enforce the requirements of section 911 of the 
308  FD&C Act for components, parts, or accessories of regulated tobacco products that are 
309  both (1) sold or distributed for further manufacturing into finished tobacco products, and 
310  (2) not sold or promoted to consumers. 
311  B.  When Should You Submit an MRTPA? 
312 
313  Before you may introduce or deliver for introduction into interstate commerce an MRTP, 
314  there must be in effect an order under section 911(g) of the FD&C Act.  FDA encourages 
315  persons to meet with FDA early in their process of developing an MRTP to discuss 
316  MRTPA submission and investigational requirements and recommendations.  See section 
317  IX.B. 
318 
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319  Other Required Submissions 
320 
321  If your proposed MRTP is a new tobacco product within the meaning of section 
322  910(a)(1), it is subject to any applicable premarket review requirements under section 
323  910 of the FD&C Act, in addition to any requirements under section 911 of the FD&C 
324  Act.  To introduce or deliver for introduction a new tobacco product into interstate 
325  commerce there must be: 
326 
327    A substantial equivalence order under section 910(a)(2)(i) of the FD&C Act in 
328  effect for the tobacco product; 
329    An exemption of the tobacco product from the requirement to obtain a substantial 
330  equivalence order under section 910(a)(2)(i) of the FD&C Act pursuant to a 
331  regulation issued under section 905(j)(3) of the FD&C Act; or 
332    A marketing authorization order issued by FDA for the tobacco product under 
333  section 910(c)(1)(A)(i) of the FD&C Act. 
334 
335  The label and packaging of a tobacco product are considered a part of that product. A 
336  change to any part of a tobacco product after February 15, 2007, makes that product a 
337  new tobacco product.4  Adding modified risk claims to the label or packaging of a 
338  tobacco product that is already commercially marketed makes the tobacco product a new 
339  tobacco product. Therefore, in addition to obtaining an order from FDA under section 
340  911(g) of the FD&C Act, the applicant must satisfy the applicable premarket review 
341  requirements under section 910 of the FD&C Act. 
342 
343  For details on how to submit a substantial equivalence report under section 905(j) of the 
344  FD&C Act (21 U.S.C. 387e(j)), see FDAs Guidance for Industry Section 905(j) Reports: 
345  Demonstrating Substantial Equivalence for Tobacco Products 
346  (http://www.fda.gov/downloads/TobaccoProducts/GuidanceComplianceRegulatoryInfor 
347  mation/UCM239021.pdf) and FDAs Draft Guidance for Industry Demonstrating the 
348  Substantial Equivalence of a New Tobacco Product: Responses to Frequently Asked 
349  Questions 
350  (http://www.fda.gov/downloads/TobaccoProducts/ResourcesforYou/ForIndustry/UCM27 
351  1239.pdf).  For details on how to request an exemption from the substantial equivalence 
352  requirements, see FDAs final rule  Exemptions from Substantial Equivalence 
353  Requirements for Tobacco Products (76 FR 38961; July 5, 2011) 
354  (http://www.gpo.gov/fdsys/pkg/FR-2011-07-05/pdf/2011-16766.pdf).  For details on how 
355  to submit a Premarket Tobacco Product Application (PMTA) under section 910(b) of the 
356  FD&C Act (21 U.S.C. 387j(b)), see FDAs Draft Guidance for Industry Applications for 
357  Premarket Review of New Tobacco Products 
4 See FDAs Draft Guidance for Industry Demonstrating the Substantial Equivalence of a New Tobacco 
Product: Responses to Frequently Asked Questions. As discussed in this draft guidance, however, we do 
not intend to enforce the premarket requirements of sections 905(j) and 910 of the FD&C Act for certain 
limited modifications to labels and packaging (e.g., if modifications are made to comply with warning label 
requirements of the Tobacco Control Act). 
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358  (http://www.fda.gov/downloads/TobaccoProducts/GuidanceComplianceRegulatoryInfor 
359  mation/UCM273425.pdf). 
360  C.  Can I Introduce or Deliver for Introduction into Interstate 
361  Commerce an MRTP Without an Order Under Section 911(g) in 
362  Effect? 
363 
364  No. Such activity would violate section 911 of the FD&C Act, which provides that an 
365  MRTP may not be introduced or delivered for introduction into interstate commerce 
366  without an order under section 911(g) in effect with respect to such product. Section 
367  911(a) of the FD&C Act. 
368 
369  Under section 301(pp) of the FD&C Act (21 U.S.C. 331(pp)), introduction or delivery for 
370  introduction into interstate commerce of a tobacco product in violation of section 911 is a 
371  prohibited act.  In addition, under section 902(8) of the FD&C Act (21 U.S.C. 387b(8)), a 
372  tobacco product is deemed adulterated if it is in violation of section 911 of the FD&C 
373  Act, and the introduction or delivery for introduction into interstate commerce of any 
374  adulterated tobacco product is also a prohibited act. Section 301(a) of the FD&C Act (21 
375  U.S.C. 331(a)).  Violations of the FD&C Act are subject to regulatory and enforcement 
376  action by FDA, including, but not limited to, seizure and injunction.  Note, however, that 
377  section 911 only applies to MRTPs; a responsible entity can introduce a new tobacco 
378  product without modified risk claims into interstate commerce so long as they satisfy the 
379  applicable premarket review requirements under section 910 of the FD&C Act. 
380 
381  V.  Contents of an MRTPA 
382  A.  Contents of an MRTPA Required Under Section 911(d) 
383 
384  Under section 911(d) of the FD&C Act, you must provide the following information in 
385  your MRTPA:5 
386 
387    A description of the proposed product and any proposed advertising and labeling; 
388    The conditions for using the product; 
389    The formulation of the product; 
390    Sample product labels and labeling; 
391    All documents (including underlying scientific information) relating to research 
392  findings conducted, supported, or possessed by the tobacco product manufacturer 
393  relating to the effect of the product on tobacco-related diseases and health-related 
394  conditions, including information both favorable and unfavorable to the ability of 
395  the product to reduce risk or exposure and relating to human health; and 
5 Under section 911(d)(7) of the FD&C Act, FDA has the authority to require the submission of additional 
information. 
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396    Data and information on how consumers actually use the tobacco product. 
397 
398  This subsection (V.A) describes information that the Agency recommends you submit for 
399  each category of information required by section 911(d)(1)-(6) of FD&C Act. Section 
400  VI, in contrast, describes the information that you are required to submit, or that the 
401  Agency recommends you submit, to support the scientific demonstrations necessary for 
402  the issuance of an order under section 911(g) of the FD&C Act. 
403  1.  A Description of the Proposed Tobacco Product and Any Proposed 
404  Advertising and Labeling 
405 
406  You must include in your application a description of the product and any proposed 
407  advertising and labeling.  Section 911(d)(1) of FD&C Act. 
408 
409  FDA recommends that your description of the proposed product include the following 
410  information: 
411 
412    The brand name and, if applicable, subbrand name of the proposed modified risk 
413  tobacco product; 
414    A description of the product form (e.g., traditional cigarette, shredded tobacco, 
415  inhaler, liquid, gel, dissolvable strip, stick, or tablet); 
416    A description of the product dimensions and the overall construction of the 
417  product (using a diagram or schematic drawing that clearly depicts the finished 
418  product and its components with dimensions, operating parameters, and 
419  materials); 
420    Whether the product uses a heating source and, if so, a description of the heat 
421  source (e.g., burning coal or other substance, electric, chemical reaction, carbon 
422  tip); 
423    A description of all design features of the product6 (e.g., location of ventilation 
424  holes, heat source, paper porosity, coatings, nicotine concentration gradient); and 
425    Any other information relevant to describing the tobacco product, such as whether 
426  the tobacco product requires special handling or storage. 
427 
428  FDA recommends that your description of proposed advertising and labeling include the 
429  following information, which is important in evaluating whether the product will benefit 
430  the health of the population as a whole (section 911(g)(1)(B) and (g)(2)(B)(iv) of the 
431  FD&C Act) and how consumers understand the risks posed by the product as the 
432  applicant proposes to label and market it (section 911(g)(2)(B)(iii) and (h)(1) of the 
433  FD&C Act): 
434 
435    Copies of any draft promotional materials (e.g., advertising and labeling) 
436  developed by the time of filing that the applicant expects will be used in 
437  marketing the MRTP.  FDA recognizes that some promotional materials may be 
6 Numerical levels should be supplied, where appropriate. 
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438  derivative of other materials submitted in the application, representing only minor 
439  differences in layout or format, or displaying a different health warning than 
440  material submitted in the application.  Such derivative materials may be omitted; 
441  and, 
442    A description of how you intend to communicate the proposed modified risk 
443  claim(s) to consumers, including any actions directed to consumers that the 
444  tobacco product manufacturer or distributor of the tobacco product plans to take 
445  to communicate the proposed modified risk claim(s) to consumers (other than by 
446  means of the product label, labeling, or advertising). 
447  2.  The Conditions for Using the Tobacco Product 
448 
449  You must provide as part of your application the conditions for using the product. 
450  Section 911(d)(2) of the FD&C Act.  FDA recommends that you include the following 
451  information on conditions for using the product: 
452 
453    A full narrative description of the way in which a consumer will use the tobacco 
454  product, including a description of how a consumer operates the product (e.g., 
455  whether a consumer places the tobacco product in the mouth or nose, whether a 
456  consumer ignites the tobacco product and by what means, whether the product is 
457  designed to be smoked, inhaled, swallowed, dissolved, sniffed, chewed, etc.); 
458    A description of the length of time it takes a consumer to consume a single unit of 
459  the product. The description should be quantitative in nature and include 
460  information about the pattern of use during that time (i.e., intermittent or 
461  continuous); 
462    Specific instructions on how to use and store the product to get the proposed 
463  reduction in risk or exposure; and 
464    Specific instructions on how to avoid using the product in a way that could reduce 
465  or eliminate the potential benefit or increase the risk of using the product. 
466  3.  The Formulation of the Tobacco Product 
467 
468  You must submit as part of your application, the formulation of the product. Section 
469  911(d)(3) of the FD&C Act.  In submitting the formulation of your product, FDA 
470  recommends that you include the following: 
471 
472    A complete list of uniquely identified components, ingredients, and additives by 
473  quantity in your tobacco product as well as the applicable specifications and a 
474  description of the intended function for each.7  Components, ingredients, and 
7 For guidance on uniquely identifying components, ingredients, and additives and reporting their 
quantities, refer to FDAs Guidance for Industry Listing of Ingredients in Tobacco Products 
(http://www.fda.gov/downloads/TobaccoProduct/GuidanceComplianceRegulatoryInformation/UCM19205 
3.pdf). If you have previously submitted this information under another section of the FD&C Act (e.g., a 
listing of ingredients or new tobacco product application), you can reference that submission in your 
MRTPA. 
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475  additives include anything that may reasonably be expected, directly or indirectly, 
476  to become part of, or affect the characteristics of, the finished tobacco product. 
477  This includes, but is not limited to tobacco, paper, glue, flavorings, burn-rate 
478  controllers, and pH modifiers; 
479    A description of tobacco blending, reconstitution, or manipulation; 
480    A description of manufacturing steps, including the sources of all components, 
481  and quality control measures in place.  The applicant should provide sufficient 
482  detail to assure FDA that the product meets manufacturing specifications and that 
483  it may be manufactured in a consistent manner that minimizes the variability in 
484  levels of exposures and/or risk to users/nonusers across occasions of use; 
485    A description of how the design, materials, ingredients, and heating source (if 
486  applicable) combine to produce the final product; 
487    A quantitative description of the performance criteria for the tobacco product 
488  (e.g., burn rate, ventilation criteria, dissolution rate); and 
489    Data establishing the stability of the product through the stated shelf life. 
490 
491  FDA recommends that the list of components, ingredients, and additives contain all items 
492  used in the synthesis, extraction, and/or preparation of the product, regardless of whether 
493  the items are found in the final the product.  You should list ingredients by component of 
494  the tobacco product, including: 
495 
496  Chemical Abstract Service number, where applicable; 
o 
497  Function and purpose; 
o 
498  Unit of measure; and 
o 
499  Level used in tobacco product. 
o 
500  4.  Sample Product Labels and Labeling 
501 
502  You must include in your application sample product labels and labeling.  Section 
503  911(d)(4) of the FD&C Act. You should include copies of each package label variation 
504  (including inserts and onserts) that is proposed to be used for the modified risk tobacco 
505  product, except that you may omit copies of package label variations for each health 
506  warning required by law. 
507  5.  All Documents Relating to Research Findings 
508 
509  You must include in your application all documents (including underlying scientific 
510  information) relating to research findings conducted, supported8, or possessed9, by the 
8 FDA considers a person to have supported a study if the person in any way provides assistance for the 
conduct of the study (e.g., by providing funding, personnel or other resources, protocols, product, etc.).
9 FDA considers research findings possessed to include findings from studies not conducted or supported 
by the manufacturer, but which it has received, or has reviewed to inform the development of the modified 
risk tobacco product. 
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511  tobacco product manufacturer10 relating to the effect of the product on tobacco-related 
512  diseases and health-related conditions, including information both favorable and 
513  unfavorable to the ability of the product to reduce risk or exposure and relating to human 
514  health.  Section 911(d)(5) of the FD&C Act. The documents required to be submitted 
515  under section 911(d)(5) may include documents not in the possession of the tobacco 
516  product manufacturer.  We request that you submit a description of the procedures you 
517  used to collect documents to comply with section 911(d)(5) as well as a list of the entities 
518  and individuals from whom you retrieved or attempted to retrieve documents. 
519 
520  You should submit documents relating to research findings from studies conducted both 
521  within and outside the United States.  See section IX.C for further discussion on the use 
522  of studies conducted outside the United States in support of an MRPTA. 
523 
524  In general, for guidance on what constitutes a document and otherwise submitting all 
525  documents . . . relating to research finding refer to FDAs Guidance for Industry 
526  Tobacco Health Document Submission 
527  (http://www.fda.gov/downloads/TobaccoProducts/GuidanceComplianceRegulatoryInfor 
528  mation/UCM208916.pdf). 
529 
530  FDA expects that the applicant will include, among other things, as part of its submission 
531  of relevant documents: 
532 
533     Study reports, 
534     Study protocols, and 
535     Raw data (in electronic format, where available, with instructions about its use). 
536 
537  If any of this information is not available, applicants should provide an explanation for 
538  the omission. 
539 
540  Additionally, if the applicant is aware of relevant research findings not conducted, 
541  supported, or possessed by the tobacco manufacturer, we ask that the applicant include 
542  copies of the research findings.  Alternatively, if the research findings are found in 
543  published literature, applicants can submit a bibliography. 
544 
545  Further guidance regarding how to organize your scientific studies and analyses for 
546  submission to FDA is provided in section VIII.A.7. 
 
547  6.  Data and Information on How Consumers Actually Use the Tobacco 
548  Product 
549 
10 You should include documents related to research findings conducted, supported, or possessed by entities 
that are the same, related, or affiliated with the tobacco product manufacturer, as well as any of the tobacco 
manufacturers predecessors in interest. 
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550  You must include in your application data and information on how consumers actually 
551  use the tobacco product. Section 911(d)(6) of the FD&C Act. In providing this 
552  information, FDA recommends that you include data generated from consumer use in 
553  both controlled situations in which the subjects use can be closely monitored, and natural 
554  environments in which the subjects may use the product as they would without the 
555  limitations inherent in a controlled setting.  FDA recommends that the data and 
556  information provided address: 
557 
558     Whether consumers can and are likely to comply with any instructions for 
559  product use; 
560     The number of units of the product consumed per day (e.g., cigarettes per day) 
561  and the way in which individuals consume each unit of the product (e.g., puffing 
562  profiles); and 
563     Concurrent use of multiple products containing nicotine or tobacco. 
 
564  B.  Other Information 
565 
566  FDA may request other information FDA finds it needs to determine whether a 911(g) 
567  order is appropriate. 
568 
569  For example, FDA may request: 
570 
571     Additional product analyses to verify information provided about specific 
572  components, ingredients, additives, or constituents present in the final product 
573     Data to support comparative claims, i.e., data comparing the tobacco product to a 
574  commercially available tobacco product that is representative of that type of 
575  tobacco product on the market (see, e.g., section 911(h)(2) of the FD&C Act) 
576     Samples of the tobacco product 
577     For products that have been on the market prior to the MRTPA submission, a 
578  summary of information that the manufacturer possesses regarding the product, 
579  including, but not limited to, adverse events from use of the product, levels of 
580  product use in the market, and consumer feedback regarding the product 
581     For products that have not been on the market prior to the MRTPA submission, a 
582  summary of any market research and information that was used to inform the 
583  development of the new product and its label, labeling and marketing plan 
584 
585  If you become aware of any new information relating to the effect of the proposed 
586  product on tobacco-related diseases and health-related conditions (including adverse 
587  events) while your application is pending with FDA, you should promptly provide this 
588  information to FDA. 
589 
590  Further, each applicant granted an order under section 911(g) must conduct postmarket 
591  surveillance and studies and annually submit the results of the surveillance and studies so 
592  FDA can assess, among other things, the impact of an order on consumer perception, 
593  behavior, and health.  See sections 911(g)(2)(C) and (i)(1) of the FD&C Act. FDA asks 
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594  the applicant to submit a plan for postmarket surveillance and studies.  The plan should 
595  contain sufficient detail for FDA to evaluate whether the results from surveillance and 
596  studies will give FDA the information it needs to review the accuracy of the 
597  determinations on which it based the order. Section VII, Postmarket Surveillance and 
598  Studies, below, provides information and recommendations. 
 
599  C.  Environmental Impact Considerations 
600 
601  FDAs regulation implementing the National Environmental Policy Act (NEPA) of 1969 
602  requires that [a]ll applications or petitions requesting agency action require the 
603  submission of an [environmental assessment] or a claim of categorical exclusion.  21 
604  CFR 25.15(a). 
605 
606  Currently there are no categorical exclusions in place for tobacco products; therefore, you 
607  must submit an environmental assessment as part of your MRTPA.  You should refer to 
608  21 CFR Part 25 for additional information. 
 
 
609  VI.  Scientific Studies and Analyses in MRTPAs 
610 
611  This section sets forth recommendations regarding scientific studies and analyses that 
612  should be contained in an MRTPA so that FDA can determine whether the criteria for 
613  issuance of an order under section 911(g) of the FD&C Act have been satisfied.  FDA 
614  encourages anyone who is considering development of, or preparing an application for, a 
615  modified risk tobacco product to meet with FDA to discuss what studies would be 
616  appropriate for your product, so that you can best use your resources to conduct studies 
617  that will support your application. 
 
618  A.  Key Areas of Investigation Regarding the Effect of an MRTP 
619 
620  In determining whether it can issue an order under section 911(g) of the FD&C Act for an 
621  MRTP, FDA must assess whether the applicant has demonstrated that the product will or 
622  is expected to benefit the health of individuals and the population as a whole.  In order for 
623  an applicant to demonstrate that its product meets the criteria for issuance of an order 
624  under section 911(g) of the FD&C Act, the applicants MRTPA should address the 
625  following key areas of investigation: 
626 
627     Health risks of the tobacco product; 
628     The effect the tobacco product and its marketing may have on tobacco use 
629  behavior among current tobacco users; 
630     The effect the tobacco product and its marketing may have on tobacco use 
631  initiation among non-users (both never users and former users); 
632     The effect of the tobacco products marketing on consumer understanding and 
633  perceptions; and 
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634     The effect the tobacco product and its marketing may have on the population as a 
635  whole. 
 
636  1.  Health Risks of the Tobacco Product 
637 
638  An MRTPA must provide scientific evidence regarding the effect of the product on the 
639  health of individuals so that FDA can determine whether the MRTP does, in fact, modify 
640  risk as claimed by the applicant and whether FDA can issue an order for such product 
641  under section 911(g) of the FD&C Act. 
642 
643  In the case of an application for a risk modification order, the MRTPA must provide 
644  scientific evidence to demonstrate that the product significantly reduces harm and the risk 
645  of tobacco-related disease to individual users.  See section 911(g)(1)(A) of the FD&C 
646  Act.  In the case of an application for an exposure modification order, the MRTPA must 
647  provide scientific evidence to demonstrate that: 
648 
649     The magnitude of overall reductions in exposure to the substance or substances 
650  which are the subject of the application is substantial; 
651     Such substance or substances are harmful; 
652     Consumers actually use the product in a way that exposes them to the specified 
653  reduced level of the substance or substances; 
654     Consumers are not exposed to higher levels of other harmful substances, or if they 
655  are, those increases are minimal, such that the reasonably likely overall impact of 
656  use of the product remains a substantial and measurable reduction in the overall 
657  morbidity and mortality among individual tobacco users; and 
658     The scientific evidence that is available without conducting long-term 
659  epidemiological studies demonstrates that a measureable and substantial reduction 
660  in morbidity or mortality is reasonably likely in subsequent studies. 
661 
662  See section 911(g)(2)(A)(iv) and (B)(i) & (ii) of the FD&C Act. 
663 
664  FDA must also assess whether the tobacco product will benefit (see section 911(g)(1)(B) 
665  of the FD&C Act) or is expected to benefit (see section 911(g)(2)(B)(iv)) the health of 
666  the population as a whole before an order can be issued under section 911(g) of the 
667  FD&C Act.  To make this determination, FDA must consider, among other things, the 
668  risks and benefits to all persons who may potentially use or be exposed to the tobacco 
669  product that is the subject of the application, including as compared to the use of products 
670  for smoking cessation approved to treat nicotine dependence.  Section 911(g)(4) of the 
671  FD&C Act. 
672 
673  In order to make the required demonstrations for issuance of an order, FDA recommends 
674  that applicants seeking either a risk modification order or an exposure modification order 
675  submit: 
676 
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677    Product analyses to validate information provided by the applicant regarding the 
678  formulation of the product as it relates to the risk or exposure modification; 
679    Product analyses to assess users and non-users potential exposure to harmful 
680  substances; and 
681    Human studies regarding actual use of the product to determine if users are likely 
682  to use the product in a manner that reduces their individual health risks or 
683  exposures as compared to using other commercially marketed tobacco products. 
684 
685  FDA also recommends that applicants seeking risk modification orders submit: 
686 
687    Human studies that show the products use will result in a significant reduction in 
688  harm and the risk of tobacco-related disease to individual tobacco users. 
689 
690  FDA also recommends that applicants seeking exposure modification orders submit: 
691 
692    Human studies that demonstrate that the level of exposure to harmful substances 
693  has been substantially reduced; 
694    Nonclinical and/or human studies that demonstrate that the substance(s) or 
695  exposure(s) that have been reduced are harmful; and 
696    Nonclinical and/or human studies that demonstrate that use of the product is 
697  expected to result in a measurable and substantial reduction in morbidity or 
698  mortality to individual tobacco users based on the effects of the product on an 
699  endpoint that is reasonably likely, based on epidemiological, therapeutic, 
700  pathophysiologic, or other evidence, to predict an effect on reducing harm or 
701  disease. 
702 
703  Scientific studies submitted by the applicant regarding the risk of the product should 
704  enable FDA to fully assess  whether using clinical risk endpoints in the case of a risk 
705  modification order or exposure risk endpoints in the case of an exposure modification 
706  order -the health risks of the tobacco product as compared to other consumer behaviors, 
707  including: 
708 
709    The health risks associated with use of the product as compared to using other 
710  tobacco products on the market, including tobacco products within the same class 
711  of products; 
712    The changes in health risks to users who switch from using another tobacco 
713  product to using the product, including tobacco products within the same class of 
714  products; 
715    The health risks associated with switching to the product as compared to quitting 
716  the use of tobacco products; 
717    The health risks associated with using the product in conjunction with other 
718  tobacco products; 
719    The health risks associated with switching to the product as compared to using an 
720  FDA-approved tobacco cessation medication; and 
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721    The health risks associated with initiating use of the product as compared to never 
722  using tobacco products. 
723 
724  Where a tobacco product presents novel features that may cause risks to non-users, you 
725  should also submit information regarding the health risks posed to non-users of the 
726  product. 
727  2.  Effect on Tobacco Use Behavior among Current Tobacco Users 
728 
729  In order for FDA to assess the full effect that an MRTP and its marketing may have on 
730  population health under section 911(g)(1)(B) or 911(g)(2)(B)(iv) of the FD&C Act, an 
731  MRTPA should contain scientific evidence about the effect the product may have on 
732  tobacco use behavior among current tobacco users.  This includes consideration of areas 
733  such as the expected rates of use of the tobacco product by current tobacco users, the use 
734  of the tobacco product in conjunction with other tobacco products, and the potential for 
735  abuse and misuse of the product. An application must provide evidence regarding 
736  whether the product and its marketing will increase or decrease the likelihood that 
737  existing users of tobacco products who would otherwise stop using such products would 
738  instead switch to the tobacco product that is the subject of the application.  See section 
739  911(g)(4)(B) of the FD&C Act. 
740 
741  To address the effect on behavior among current tobacco users, FDA recommends that 
742  applicants submit: 
743 
744    Nonclinical and/or human studies to assess the abuse liability and the potential for 
745  misuse of the product as compared to other tobacco products on the market;11 and 
746    Human studies regarding actual use of the product and consumer perception of the 
747  product, including its labeling, marketing and advertising. 
748 
749  The scientific studies submitted by the applicant should inform FDAs evaluation of the 
750  tobacco products impact on tobacco use behavior, including: 
751 
752    The likelihood that current tobacco product users will start using the product; 
753    The likelihood that tobacco users who adopt the product will switch to or switch 
754  back to other tobacco products that present higher levels of individual health risk; 
755    The likelihood that consumers will use the product in conjunction with other 
756  tobacco products; 
11 
Abuse liability is the likelihood that individuals will develop physical and/or psychological dependence 
on the tobacco product. Physical dependence is characterized by the development of tolerance to tobacco 
product use and/or the onset of withdrawal symptoms upon stopping use of the tobacco product. 
Psychological dependence is characterized by persistent tobacco-seeking and tobacco-use behaviors, 
impairment in behavioral control, craving, and inability to abstain consistently. 
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757    The likelihood that users who may have otherwise quit using tobacco products 
758  will instead use the product; and 
759    The likelihood that consumers will use the product as intended or designed. 
760  3.  Effect on Tobacco Use Initiation among Non-Users 
761 
762  A critical population health consideration under section 911(g)(1)(B) and 
763  911(g)(2)(B)(iv) of the FD&C Act is the effect that an MRTP and its marketing will have 
764  on tobacco use initiation among non-users (both never users and former users).  An 
765  MRTPA must contain scientific evidence regarding the effect the product and its 
766  marketing will have on increasing the likelihood that persons who do not use tobacco 
767  products will start using the tobacco product that is the subject of the application.  See 
768  section 911(g)(4)(C) of the FD&C Act. 
769 
770  To address the effect of the MRTP on tobacco use initiation, FDA recommends that 
771  applicants submit: 
772 
773    Human studies that evaluate consumer perception of the product, including its 
774  labeling, marketing and advertising. 
775 
776  These studies should be designed to provide evidence regarding the likelihood of 
777  population benefit or harm from the proposed product, including: 
778 
779    The likelihood that consumers who have never used tobacco products, particularly 
780  youth and young adults, will initiate use of the tobacco product; 
781    The likelihood that non-users who adopt the tobacco product will switch to other 
782  tobacco products that present higher levels of individual health risk; and 
783    The likelihood that former users of tobacco products will re-initiate use with the 
784  tobacco product. 
785  4.  Effect of Marketing on Consumer Understanding and Perceptions 
786 
787  Another important consideration is the effect that an MRTP and its marketing will have 
788  on consumer understanding and perceptions.  All MRTPAs must contain evidence to 
789  show that the advertising and labeling concerning modified risk products enable the 
790  public to comprehend the information concerning modified risk and to understand the 
791  relative significance of such information in the context of total health and in relation to 
792  all of the diseases and health-related conditions associated with the use of tobacco 
793  products. See section 911(h)(1) of the FD&C Act. 
794 
795  For exposure modification orders, any aspect of the products label, labeling, and 
796  advertising that would make it a modified risk tobacco product must be limited to an 
797  explicit or implicit representation that the product or its smoke does not contain or is free 
798  of a substance or contains or presents a reduced level of exposure to a substance.  See 
799  section 911(g)(2)(A)(ii) of the FD&C Act.  Applicants seeking an exposure modification 
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800  order must demonstrate through testing of actual consumer perception that the proposed 

801  labeling and marketing of the product does not mislead consumers into believing that the 

802  product is or has been demonstrated to be less harmful, or mislead consumers into 

803  believing that the product presents less of a risk of disease than one or more other 

804  commercially marketed tobacco products.  See section 911(g)(2)(B)(iii) of the FD&C 

805  Act. 

806 

807  To address the effect of marketing on consumer understanding and perception, FDA
 
808  recommends that applicants submit: 

809 

810    Human studies regarding consumer understanding of the product, including its
 
811  labeling, marketing and advertising.
 
812 

813  The scientific studies submitted by the applicant should inform FDAs evaluation of the 

814  tobacco products marketing on consumer perception and understanding, including: 

815 

816    The ability of consumers to understand the modified risk claims and the 

817  significance of the information in the context of ones health; 

818    Consumers beliefs about the health risks of using the product relative to other
 
819  tobacco products, including those within the same class of products; 

820    Consumer beliefs about the health risks of using the product relative to cessation 

821  aids; and 

822    Consumer beliefs about the risks of using the product relative to quitting all
 
823  tobacco use. 

824  5.  Effect on the Population as a Whole
 
825 

826  All applicants must demonstrate that the marketing of the tobacco product will or is 

827  expected to benefit the health of the population as a whole.  See section 911(g)(1)(B) 

828  and 911(g)(2)(B)(iv) of the FD&C Act.  Applicants seeking an exposure modification
 
829  order must further demonstrate that issuance of an exposure modification order would be
 
830  appropriate to promote the public health. Section 911(g)(2)(A)(i) of the FD&C Act.
 
831  Therefore, an MRTPA should contain an overall assessment of the potential effect that 

832  the marketing of the product as proposed may have on tobacco-related morbidity and 

833  mortality in the population as a whole. 

834 

835  To address the effect of an MRTP on the population as a whole, FDA recommends that 

836  applicants submit: 

837 

838    Quantitative estimates of the effect the marketing of the product, as proposed, 

839  may have on the health of the population as a whole. 

840 

841  The estimates should integrate all of the information regarding the marketing of the 

842  product and its potential effects on health, tobacco use behavior and tobacco use initiation 

843  to provide an overall assessment of the potential effect that the products introduction to
 
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844  the market may have on overall tobacco-related morbidity and mortality.  FDA 
845  recommends that the applicant estimate the attributable risk of all of the various health 
846  effects for various types of individuals in the U.S. population, as well as the total number 
847  of individuals of each type.  As an illustration, consider a product that an applicant 
848  maintains poses one-tenth of the risk of death from lung cancer as compared to smoking 
849  cigarettes. FDA recommends that the applicant quantify the potential changes in 
850  mortality to the various types of affected individuals in the U.S. population (see bullets 
851  below).  This would include, among other things, an estimate of the number of smokers 
852  who are likely to switch to the product and the subsequent reduction in the number of 
853  lives lost due to tobacco use, the number of smokers who may use the product in 
854  conjunction with other tobacco products or instead of quitting and the subsequent effect 
855  on the number of lives lost due to tobacco use, as well as the number of non-smokers who 
856  may initiate use of tobacco with the product and the subsequent increase in the number of 
857  lives lost to tobacco use. FDA recommends that a similar approach be used to assess the 
858  potential impact on mortality resulting from other diseases, as well as morbidity in the 
859  various types of affected individuals in the U.S. population.  The types of individuals 
860  may include, but are not limited to, the following: 
861 
862    Tobacco users who switch from other commercially marketed tobacco 
863  products to the proposed product; 
864    Tobacco users and non-users who, after adopting the proposed product, switch 
865  to or switch back to other tobacco products that may present higher levels of 
866  individual health risk; 
867    Tobacco users who opt to use the proposed product rather than cease tobacco 
868  use altogether; 
869    Tobacco users who opt to use the proposed product rather than an FDA
870  approved tobacco cessation medication; 
871    Non-users who initiate tobacco use with the proposed product, such as youth, 
872  never users, former users; 
873    Tobacco users who use the product in conjunction with other tobacco 
874  products; and 
875    Non-users who experience health risks from the product. 
876  B.  Detailed Considerations Regarding the Recommended Studies 
877  and Analyses 
878 
879  Given the breadth of evidence needed to support the issuance of an order under section 
880  911(g) of the FD&C Act, it is unlikely that a single study will provide sufficient evidence 
881  to support FDAs issuance of an order.  Furthermore, it is unlikely that a set of studies of 
882  one type will provide sufficient evidence to support the issuance of an order. Therefore, 
883  as described above in section VI.A, FDA recommends that applicants provide 
884  information from a number of studies of different types in order to address the full range 
885  of areas of investigation set forth in section 911 of the FD&C Act so that FDA can 
886  determine whether or not it can issue an order under section 911(g) for the MRTP.  These 
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887  include product analyses, nonclinical studies, studies in adult human subjects, and 
888  secondary data analyses and modeling.  Below is a more detailed description of the types 
889  of studies and analyses that FDA recommends an applicant use to address the key areas 
890  of investigation and recommendations for the conduct of these studies and analyses. 
891 
892  In general, studies should be quantitative in nature12 and designed in accordance with the 
893  principles outlined in section VI.C.  The information that follows identifies the various 
894  outcomes these studies should assess when evaluating the impact of the tobacco product. 
895  1.  Product Analyses 
896 
897  Product analyses regarding the chemistry and engineering of the product may be used to 
898  verify and validate the information submitted regarding the formulation of the product. 
899  In addition, product analyses will facilitate FDAs understanding of the product, the 
900  potential for exposure to harmful or potentially harmful constituents from use of the 
901  product, and provide context for evaluating other data submitted in an MRTPA. 
902 
903  For each product, FDA recommends that applicants conduct product analyses to 
904  determine levels of harmful and potentially harmful constituents (HPHC), including 
905  smoke constituents, as appropriate to the product.13  Applicants should test for and report 
906  on the HPHC list as established by FDA under section 904(d) of the FD&C Act.14 
907 
908  In testing your product for HPHCs, you should adhere to any rules or guidance FDA has 
909  issued in connection with section 904(a)(3) of the FD&C Act or, as applicable, under 
910  section 915.  Absent rules or guidance to the contrary, for cigarettes, applicants should 
911  determine quantitative levels in smoke using both the ISO and Canadian Intense smoking 
912  regimens.15  For other smoked tobacco products, applicants should determine quantitative 
913  levels in smoke using smoking regimens to reflect a wide range of smoking intensities 
914  that would be appropriate for the product.  Applicants should justify the use of any 
915  alternative testing methods. 
12 The results of qualitative research, e.g., interviews and focus groups, may be submitted to provide insight 
about how consumers interact with the product or why consumers hold certain beliefs about a product. 
However, qualitative research alone is not sufficient and will not enable FDA to assess the effect that the 
product may have on the population.
13 For a discussion of harmful and potentially harmful constituents, including smoke constituents, in 
tobacco products or tobacco smoke, see FDAs Guidance for Industry and FDA Staff Harmful and 
Potentially Harmful Constituents in Tobacco Products as Used in Section 904(e) of the Federal Food, 
Drug, and Cosmetic Act 
(http://www.fda.gov/downloads/TobaccoProducts/GuidanceComplianceRegulatoryInformation/UCM2413 
52.pdf). 
14 Further information about the list is available on the Internet (under the Regulatory Information heading) 
at http://www.fda.gov/TobaccoProducts/GuidanceComplianceRegulatoryInformation/default.htm. 
15 
The ISO method is available at 
http://www.iso.org/iso/iso_catalogue/catalogue_tc/catalogue_detail.htm?csnumber=28325&commid=5215 
8. The Canadian method for measuring emissions from tobacco products is available in Part 3 of SOR 
2000-273, available at http://laws-lois.justice.gc.ca/PDF/SOR-2000-273.pdf. 
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Draft    Not for Implementation  
916 
917  FDA recommends that applicants conduct product analyses on samples of the product 
918  manufactured on the same date and complete those analyses within a short timeframe. 
919  Where feasible, applicants should also provide data on multiple batches of product to 
920  provide evidence that product characteristics remain consistent across batches of 
921  production. 
 
922  2.  Nonclinical Studies 
923 
924  Nonclinical studies include in vitro, in vivo, and ex vivo studies. The results of these 
925  studies may offer useful information about the health risks and abuse liability of a 
926  tobacco product. These studies may also provide context for data obtained from other 
927  types of studies, such as product analyses and human studies. 
928 
929  FDA recommends that applicants conduct nonclinical studies to address the known 
930  clinical toxicities of tobacco products and evaluate a range of potential toxicities of the 
931  product as compared to other tobacco products on the market. Applicants should choose 
932  appropriate models for nonclinical studies that are sufficiently sensitive for the evaluation 
933  of the selected endpoint and be able to provide support for the model used, including an 
934  explanation of the sensitivity and probative value of the model chosen.  For in vivo 
935  animal studies, researchers should administer the test product to animals by a route 
936  representative of human exposure, where feasible.  Nonclinical toxicology studies should 
937  use methods that are sufficiently sensitive to assess the actual differences between use of 
938  the product and use of other tobacco products, or between use of the product and non-use 
939  of tobacco products. 
940 
941  With respect to abuse liability, nonclinical studies should address differences in the abuse 
942  liability of the product compared to other tobacco products currently on the market.  An 
943  assessment of abuse liability may rely on a battery of studies that could include animal 
944  models of conditioned place preference, drug discrimination and self-administration. 
 
945  3.  Studies in Adult Human Subjects 
946 
947  Studies in human subjects (human studies) include clinical investigations, 
948  epidemiological studies, consumer perception studies, actual use studies and other studies 
949  that involve humans actually consuming or interacting with the product, its proposed 
950  labeling and/or marketing materials.  Human studies provide FDA with information 
951  critical for determining what effect the product may have on the health of individuals and 
952  on the population as a whole if the product is commercially marketed as an MRTP. 
953 
954  Health Risks and Tobacco Use Behavior 
955 
956  The types of human studies that can be conducted to evaluate the impact of a tobacco 
957  product on health risks and tobacco use behavior include experimental studies (e.g., 
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958  randomized clinical trials); observational epidemiological studies such as cross-sectional 
959  surveys, longitudinal surveys, case-controls studies, and cohort studies; and others. 
960 
961  FDA recommends that applicants conduct human studies to assess the full range of the 
962  human health risks related to the use of the tobacco product, including exposure to 
963  tobacco-related compounds (e.g., biomarkers of exposure) and health outcomes (e.g., 
964  disease incidence or mortality), as well as tobacco use behaviors, including initiation of 
965  use of the tobacco product among never users and former users, rates that current tobacco 
966  users switch to the tobacco product, and patterns of use of the tobacco product by current 
967  tobacco users. 
968 
969  When conducting human studies in controlled settings, it is important to adhere to 
970  principles of good clinical practices, including adequate human subject protection. 
971  Further information on FDA regulations and available guidance documents on this topic 
972  can be accessed at 
973  http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm 
974 
975  When conducting observational epidemiological studies, applicants should take measures 
976  to reduce or prevent the occurrence of bias and to control for confounding factors, either 
977  by using an appropriate study design or applicable statistical methods during data 
978  analysis.  The applicant should present information on the reliability and validity of 
979  measures used to assess the various outcomes. 
980 
981  Actual use 
982 
983  Actual use studies should allow consumers to interact freely with the product in real
984  world conditions.  FDA recommends that these studies assess: 
985 
986     How the product is consumed in early stages of use; 
987     How the product is consumed during continued use; 
988     The frequency and intensity (e.g., depth of inhalation) of product use; 
989     The amount of the product typically used per occasion; 
990     The duration of use per occasion; 
991     The use of the product with other tobacco products (i.e., the use of multiple 
992  tobacco products); 
993     The possible ways that a user may consume the product; specifically those 
994  that may differ from that intended by the applicant; 
995     The likelihood that a user may consume the product in a manner that may 
996  differ from that intended by the applicant; 
997     The potential impact to individual and public health from the failure to use the 
998  product as intended; and 
999     The elements of the products design and manufacture that may lend 
1000  themselves to product misuse by users. 
1001 
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1002  Human abuse liability 
1003 
1004  FDA recommends that applicants conduct human abuse liability studies to assess the 
1005  impact of various features of the product on the speed and efficiency of nicotine delivery 
1006  and the formation of unprotonated nicotine.  These features may include: 
1007 
1008     The presence of pharmacologically active constituents (e.g., nicotine, 
1009  acetaldehyde, anabasine, and nornicotine); 
1010     Other ingredients in the product (e.g., buffering agents); and 
1011     Design features (e.g., tobacco cut size, use of reconstituted tobacco and/or filter 
1012  ventilation). 
1013 
1014  Human abuse liability studies should also assess the threshold dose(s) of nicotine for 
1015  producing reinforcing effects, discriminative stimulus effects, and physical dependence 
1016  (e.g., symptoms of withdrawal), accounting for variability of this dose across individuals. 
1017 
1018  Consumer perception and understanding 
1019 
1020  In order to assess how consumers perceive the product and its associated labels, labeling, 
1021  and/or marketing, FDA recommends that applicants conduct consumer perception 
1022  studies.  These studies should provide data regarding how consumers perceive the risks to 
1023  health from using the product, and the likelihood of trying the product. Furthermore, the 
1024  applicant should provide data regarding consumer understanding of the products 
1025  instructions for use and of the information concerning modified risk in the context of total 
1026  health.  Applicants are encouraged to use methods that assess the impact of repeated 
1027  exposure to labels and advertising on consumer perceptions. 
1028 
1029  When designing consumer perception studies, applicants should take care that the studies 
1030  themselves do not promote use of the product, particularly among vulnerable populations, 
1031  such as youth, non-users of tobacco products, and pregnant women.  FDA recommends 
1032  that applicants meet with FDA to discuss research plans before embarking on research 
1033  with vulnerable populations.  Section IX.B of this guidance provides information on 
1034  requesting a meeting with FDA. 
1035 
1036  Applicants seeking exposure modification orders must also demonstrate that testing of 
1037  actual consumer perception shows that, as the applicant proposes to label and market the 
1038  product, consumers will not be misled into believing that the product is or has been 
1039  demonstrated to be less harmful, or presents or has been demonstrated to present less of a 
1040  risk of disease than one or more other commercially marketed tobacco products. See 
1041  section 911(g)(2)(B)(iii) of the FD&C Act.  FDA acknowledges that there may be 
1042  challenges to constructing appropriate claim language that conveys the potential benefits 
1043  of the product to tobacco users and does not convey that the product is less harmful than 
1044  other tobacco products.  As such, FDA recommends, when assessing consumer 
1045  perception of the product, labeling and/or marketing, that the applicant consider testing 
1046  several variations of the proposed claim(s) on labels and/or in advertisements.  As 
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Draft  Not for Implementation
 
1047  indicated previously, the applicant must provide FDA with the results of all studies, both 
1048  favorable and unfavorable, related to the product. Section 911(d)(5) of the FD&C Act. 
 
1049  4.  Secondary Data Analyses and Computational Modeling 
1050 
1051  FDA acknowledges the difficulties inherent in making premarket assessments of the 
1052  effect that the introduction of a modified risk product would have on the population as a 
1053  whole and the public health.  FDA encourages the development and application of 
1054  innovative analytical methods to make preliminary estimates of the potential effects of 
1055  some change in the marketplace.  Methods for making similar estimates are commonly 
1056  used in the fields of economics, statistics, decision sciences, and demography, and 
1057  include secondary data analyses and computational modeling. Applicants may opt to use 
1058  currently available models in the scientific literature to forecast the harm to public health 
1059  from tobacco use.  At this time, FDA does not endorse the use of any particular model. 
1060  Applicants may also opt to conduct secondary analyses of existing data to provide further 
1061  insight on the potential effects of modified risk products. 
1062 
1063  When applying secondary data analyses and computational modeling techniques, 
1064  applicants should select appropriate techniques, use data from scientific analyses and 
1065  studies conducted in accordance with the general principles outlined below in section 
1066  VI.C, and conduct analyses of various scenarios, including worst-case scenarios. 
 
1067  C.  General Principles for Scientific Studies and Analyses 
1068 
1069  This subsection describes sound scientific principles relating to the design and conduct of 
1070  studies to support submissions to FDA, including MRTPAs.  Following these 
1071  recommendations will help to ensure that researchers and analysts conduct adequate and 
1072  well-designed studies. 
1073 
1074  Applicants should conduct well-designed studies and analyses and provide sufficient 
1075  information about those studies and analyses to allow for critical evaluation and so that 
1076  other investigators could conduct similar studies and analyses to replicate the applicants 
1077  findings.  This will help provide adequate assurance that a finding in a study can be 
1078  replicated to show that the finding is not the result of unanticipated, undetected, or 
1079  systematic biases, study site or investigator-specific factors, or chance.  It will also 
1080  provide a safeguard against instances in which the results of a study are the product of 
1081  fraudulent reporting of scientific studies because it allows for verification of study 
1082  results. 
1083 
1084  Following these recommendations will also help FDA determine whether the results of an 
1085  analysis or study can be generalized from the study population under the conditions 
1086  tested to the population who will use the proposed modified risk tobacco product (e.g., 
1087  broad segments of the U.S. population) under actual conditions of use. 
1088 
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Draft  Not for Implementation
 
1089  FDA recommends that studies and analyses conducted to support an MRTPA have the 
1090  following characteristics: 
1091 
1092    Clearly articulated objectives and hypotheses; 
1093    Protocols that employ standardized and validated methods of analysis; 
1094    Sample sizes that permit for robust statistical analyses; 
1095    Designs that permit valid comparisons with appropriate controls for the testing of 
1096  study hypotheses (selection of the control group(s) should be based on the 
1097  endpoint or effect to be evaluated16); 
1098    Procedures to minimize bias on the part of observers and analysts of the data and 
1099  prevent undue influences on the results and interpretation of the study data, such 
1100  as blinding, masking, random assignment to condition, etc.; 
1101    Procedures for the selection of human subjects to allow for generalizability of 
1102  study results to the U.S. population; 
1103    Methods for assigning subjects to different comparator groups that are appropriate 
1104  for making comparisons between groups with respect to pertinent variables; 
1105    Oversampling of populations that are particularly likely to be affected, positively 
1106  or negatively, by the marketing of the product; 
1107    Protocols that allow for conditions of use of the product that are reflective of how 
1108  the product will actually be used by consumers when it is marketed; 
1109    A study duration to allow for adequate assessment of selected endpoint(s) and/or 
1110  effects;17 and 
1111    Analyses that adequately address the effects of the product on the study measures, 
1112  endpoints or outcomes. 
1113 
1114  In order to assure the quality and integrity of the data from studies and analyses relied on 
1115  or referenced in an MRTPA, the studies or analyses should, as applicable: 
1116 
1117    Be conducted in laboratories accredited by a nationally or internationally 
1118  recognized external accreditation organization; 
1119    Use appropriate animal models and adhere to the best practices of refinement, 
1120  reduction, and replacement of animals in research and to applicable laws, 
1121  regulations, and policies governing animal testing, for example, the Animal 
1122  Welfare Act (7 U.S.C. 2131 et seq.) and the Public Health Service Policy of 
1123  Humane Care and Use of Laboratory Animals (available at 
1124  http://grants.nih.gov/grants/olaw/references/phspol.htm); 
16 For example, in a study designed to assess the effect of a modified risk tobacco product on disease risk 
compared to a commercially marketed tobacco product, it would be appropriate to include multiple 
comparator groups of both the product and the commercially marketed tobacco product based on tobacco 
use levels (e.g., smokers of less than 10 cigarettes per day, smokers of 10 or more cigarettes per day). In a 
study designed to assess the impact of a products labeling on consumer perception of risk, the study may 
include comparator groups that view product labels that bear alternate versions of the proposed claim(s) or 
do not bear modified risk claims at all. 
17 For example, a study of the products effect on cessation from tobacco use would likely require greater 
duration than a study to assess the topography of product use or consumer perception of the product. 
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1125     Implement good laboratory practices, for example, as specified in 21 CFR Part 
1126  58; 
1127     Be conducted by qualified and appropriately trained investigators; 
1128     Accurately account for and document the receipt, use, and disposition of all 
1129  investigational product(s); 
1130     Ensure the protection of human subjects by, for example: 
1131  Implementing procedures for informed consent, such as those found in 21 
o 
1132  CFR Part 50, and 
1133  Ensuring study oversight by an Institutional Review Board, governed by 
o 
1134  21 CFR Part 56. 
1135     Be conducted in accordance with study protocols and implementation procedures 
1136  that ensure that all study subjects receiving tobacco products are current daily 
1137  tobacco product users at least 21 years of age. 
 
 
1138  VII.  Postmarket Surveillance and Studies 
1139 
1140  Each applicant who receives a risk modification or exposure modification order must 
1141  conduct postmarket surveillance and studies.  See section 911(g)(2)(C)(ii) and (i)(1) of 
1142  the FD&C Act.  For the purposes of implementing section 911 of the FD&C Act, 
1143  postmarket surveillance involves the identification and collection of unanticipated and 
1144  undesired events related to the tobacco product once it is introduced to the market; 
1145  postmarket studies generally are prospective, have well-defined study objectives and 
1146  require active recruitment compared to surveillance.18 
1147 
1148  These postmarket surveillance and studies allow for evaluation of the effect of issuance of 
1149  an order on consumer perception, behavior, and health, and enable FDA to review the 
1150  accuracy of the determinations upon which the order was based.  Id.  An applicant who 
1151  receives a risk modification order must also conduct postmarket surveillance and studies 
1152  that provide information that FDA determines is otherwise necessary regarding the use or 
1153  health risks involving the tobacco product.  See section 911(i)(1) of the FD&C Act. 
1154 
1155  Applicants granted a risk modification order must submit protocols for required 
1156  postmarket surveillance for FDA concurrence within 30 days after receiving notice that 
1157  they are required to conduct such surveillance.  Within 60 days of receipt of the protocol, 
1158  FDA must determine whether: 
1159 
18 We recognize that section 505(o) of the FD&C Act regarding postmarket review of new drugs and the 
related guidance document (see Guidance for Industry Postmarketing Studies and Clinical Trials 
Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act, available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulator yInformation/Guidances/UCM17200 
1.pdf) make distinctions between the postmarket studies and postmarket clinical trials. No such 
distinctions are made in section 911 of the FD&C Act and we do not make such distinctions in this 
guidance. 
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Draft  Not for Implementation
 
1160     The principal investigator responsible for the surveillance has sufficient 
1161  qualifications and experience to conduct such surveillance; and 
1162     The protocol will result in collection of the data or other information FDA 
1163  determines is necessary to protect the public health, including data and 
1164  information that the MRTP continues to satisfy the requirements for the issuance 
1165  of an order under section 911(g)(1). 
1166 
1167  Applicants who receive an exposure modification order must agree to conduct postmarket 
1168  surveillance and studies in accordance with a protocol approved by FDA.  See section 
1169  911(g)(2)(C)(ii) of the FD&C Act.  FDA recommends that these applicants follow the 
1170  same timelines that apply to the approval of protocols relating to risk modification orders. 
1171 
1172  All applicants must submit the results of postmarket surveillance and studies annually. 
1173  See sections 911(g)(2)(C)(iii) and 911(i)(1).  Failure to conduct or submit the required 
1174  postmarket surveillance and studies is a basis for withdrawal of an applicants order. See 
1175  section 911(j)(4) of the FD&C Act.  Furthermore, any applicant who fails to conduct or 
1176  submit the required postmarket surveillance and studies would be liable for civil 
1177  monetary penalties under section 303(f)(9)(B)(ii) of the FD&C Act (21 U.S.C. 
1178  333(f)(9)(B)(ii)), and may be subject to other regulatory and enforcement action by FDA. 
1179 
1180  In order to ensure that applicants are prepared to satisfy the post-market review 
1181  requirements in section 911 of the FD&C Act, FDA encourages applicants to submit with 
1182  their MRTPAs draft protocols and/or detailed outlines of the postmarket surveillance and 
1183  studies they plan to conduct.  FDA will review and comment on these materials and work 
1184  with applicants in developing appropriate protocols during the MRTPA review process so 
1185  that a final version of the protocols can be timely completed and approved if an order 
1186  under section 911(g) is issued. 
 
1187  A.  Postmarket Surveillance 
1188 
1189  In order to grant a risk modification or exposure modification order, the Agency must 
1190  have sufficient evidence at the time of issuance of the order that marketing of the MRTP 
1191  will or is expected to benefit the health of individuals and of the population as a whole, 
1192  taking into account both users and non-users of tobacco products. See section 
1193  911(g)(1)(B) and (g)(2)(B)(iv) of the FD&C Act. The knowledge related to the effect of 
1194  the MRTP on individuals and the population as a whole can change over time due to a 
1195  variety of factors, including changes in tobacco use behavior, consumer perceptions, and 
1196  changes in the tobacco product marketplace.  During the postmarket period, the MRTP 
1197  will be used in settings different from studies in human subjects conducted during the 
1198  development of the MRTP, and a much larger population may be exposed to the product 
1199  for a much longer term. Therefore, postmarket surveillance is a very important tool for 
1200  monitoring the effects of the MRTP on individual and population health. 
1201 
1202  For the purposes of this draft guidance, we identify two types of postmarket surveillance: 
1203 
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Draft  Not for Implementation
 
1204     Passive surveillance, which relies on spontaneous reports submitted by tobacco 
1205  product manufacturers, health care professionals, or consumers; and 
1206     Active surveillance, which relies on an active collection of data. Data may be 
1207  collected by local agencies (e.g., city, state, American Indian tribal) or through 
1208  registries established by tobacco product manufacturers, published literature or 
1209  other sources. 
 
1210  B.  Postmarket Studies 
1211 
1212  The objective of conducting postmarket studies is to gather and assess information about 
1213  the product after introduction into the marketplace, including but not limited to: 
1214 
1215     Data on real world use of the MRTP in a general population of tobacco users; 
1216     Tobacco-related adverse events; 
1217     Longer-term assessment of exposure and health outcomes, including intermediate 
1218  clinical outcomes and mortality; and 
1219     Ongoing assessment of consumer perception and tobacco use behavior (e.g., 
1220  initiation, cessation, frequency of use). 
 
1221  C.  Outcomes Evaluated in Postmarket Surveillance and Studies 
1222 
1223  The outcomes evaluated in postmarket surveillance and studies should focus on the effect 
1224  of the MRTP on consumer perception, behavior and health under real world conditions of 
1225  use. 
1226 
1227  Postmarket surveillance and studies of consumer perception should provide data 
1228  regarding how consumers perceive the risks to health from using the marketed product, 
1229  and the likelihood they will try the product. These studies should also provide 
1230  information concerning consumers understanding of the marketed products instructions 
1231  for use and its modified risk claims. 
1232 
1233  Postmarket surveillance and studies of consumer behavior should provide data with 
1234  respect to the effect the products marketing has on whether current tobacco users switch 
1235  to the product from their usual product, whether current tobacco users continue using the 
1236  product, whether current tobacco users who would otherwise cease all tobacco use switch 
1237  to the product instead, and whether non-users start using the product. 
1238 
1239  Postmarket surveillance and studies of consumer health should provide data with respect 
1240  to the health risks of the MRTP, including the effect the product has on tobacco-related 
1241  morbidity and mortality.  Surveillance and studies should measure the health risks to 
1242  individuals from using the product as compared to using other tobacco products or 
1243  quitting use of tobacco products.  Specific health outcomes to consider may include, but 
1244  are not limited to: 
1245 
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1246     New diagnosis or worsening diagnosis by health care providers of particular 
1247  disease risks that may be associated with the use of the MRTP, including the risk 
1248  of development of cancers, stroke, cardiovascular diseases, non-malignant 
1249  respiratory diseases, fetal toxicity, oral/dental diseases, etc. 
1250     Occurrence of emergency room visits or hospitalizations for illnesses associated 
1251  with the use of the MRTP (e.g., rate of hospitalization and the proportion of 
1252  subjects with hospitalizations for tobacco-related illness). 
1253     Physiologic or blood chemistry parameters of MRTP users such as HPHC levels, 
1254  measures of biomarkers of exposure, measures of biomarkers of disease, ECG, 
1255  and pulmonary function testing. 
1256 
1257  Adverse Events19 
1258 
1259  An important component of postmarket surveillance and studies is to collect information 
1260  on adverse events that occur in relation to a product.  For purposes of this draft guidance, 
1261  an adverse event (AE) is any health-related event associated with the use of a tobacco 
1262  product in humans that is adverse or unfavorable, whether or not it is considered tobacco
1263  product related.20  An AE can arise from any use of the product (including use in 
1264  combination with other products and overdose). 
1265 
1266  Postmarket surveillance and studies should identify adverse events and provide data on 
1267  their nature, frequency, and potential risk factors so that informed decisions on risk 
1268  minimization can be made.  A serious AE is an AE that results in any of the following: 
1269 
1270  Death; 
o 
1271  A life-threatening condition or event; 
o 
1272  Persistent or substantial disability or incapacitation; 
o 
1273  Hospitalization or prolonged hospitalization; or 
o 
1274  A congenital anomaly or birth defect. 
o 
1275 
1276  You should report all adverse events that occur during surveillance or while monitoring 
1277  studies.  Non-serious AEs should be reported as part of your annual submission of the 
1278  results of postmarket studies and surveillance.  FDA requests that serious AEs be 
1279  reported to CTPs Office of Science within 15 business days after the report is received 
1280  by the applicant. 
 
1281  D.  Design of Postmarket Studies and Active Surveillance 
1282 
1283  Depending on the study objectives, the study design used for postmarket studies could 
1284  include observational epidemiological studies, interventional studies, such as randomized 
19 Section 909(a) of the FD&C Act directs FDA to issue regulations requiring the reporting of adverse 

events for tobacco products. FDA has not yet issued such regulations.

20 Your submission will not be construed by FDA as an admission that the tobacco product involved caused 

or contributed to the adverse event being reported. See section 756 of the FD&C Act (21 U.S.C. 379v).
 
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1285  clinical trials, or studies of other design.  For all studies and active surveillance, the draft 

1286  protocol or the outline submitted to FDA with your MRTPA should include the following 

1287  elements: 

1288 

1289    Objective(s);
 
1290    Hypotheses; 

1291    Background information (e.g., a critical review of the literature, brief description 

1292  of the new tobacco product and any regulatory history, the significance of the 

1293  study to be conducted);
 
1294    Design and setting (e.g., clinic, community) of the study; 

1295    Sample size and power calculation (please specify strata and clustering as 

1296  appropriate); 

1297    Relative standard errors for subgroups (if appropriate);
 
1298    Study population (selection of study population, number of subjects to be 

1299  enrolled, inclusion/exclusion criteria, comparison group(s));
 
1300    Primary and secondary endpoints (definition and success criteria); 

1301    Statistical analysis plan (description of the statistical methods to be employed, the 

1302  reason for your choice of sample size, including calculations of the power of each 

1303  study, and the level of significance and/or confidence level to be used); 

1304    Data collection procedures and instruments; 

1305    Baseline and follow-up assessments and duration of follow-up;
 
1306    Case report forms;
 
1307    Documentation describing steps to be taken to ensure the protection of human 

1308  subjects, for example, proposed informed consent and IRB approval forms; and 

1309    Study milestone and timeline elements, including study initiation, annual
 
1310  enrollment goals, completion of enrollment, completion of follow-up, and 

1311  submission of final report.
 
VIII. Submission Information 
1312 
1313  A.  Organizing Your MRTPA for Submission to FDA
 
1314 

1315  You should organize your MRTPA into the following distinct sections:
 
1316  1.  Cover Letter 

1317 

1318  The cover letter should contain: 

1319 

1320    The name and address of your company; 

1321    An authorized contacts name, title, address, phone number, fax number, and 

1322  email address;
 
1323    The brand name and, if applicable, subbrand name of the proposed modified 

1324  risk tobacco product; 

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1325    The name of the manufacturer; 

1326    A list of all previous submissions to CTP for the proposed MRTP product or
 
1327  any product that is the same except for the claims that are the subject of your 

1328  application, e.g., a submission of listing of ingredients in tobacco products 

1329  submitted pursuant to section 904 of the FD&C Act, a substantial equivalence 

1330  report, a request for an exemption from substantial equivalence, or a 

1331  premarket tobacco product application, or a previous MRTPA, and what 

1332  action FDA took as a result of any such submission;
 
1333    A statement regarding how you have satisfied, or intend to satisfy, any 

1334  applicable premarket review requirements under section 910 of the FD&C
 
1335  Act; 

1336    A list of dates of any prior meetings with FDA about the tobacco product that 

1337  is the subject of the MRTPA; 

1338    A statement whether you are seeking a risk modification order or an exposure 

1339  modification order; and 

1340    A description or listing of the specific portions of the application you believe
 
1341  constitute trade secret or confidential commercial information that is exempt
 
1342  from disclosure.  In the alternative, you may submit a second version of the 

1343  application with transparent highlights of proposed redactions.  (See section 

1344  X, Confidentiality, for more information). 

1345  2.  Table of Contents and Summary
 
1346 

1347  A comprehensive table of contents should precede a summary of the application and all 

1348  other sections of the application. 

1349 

1350  The application should contain a summary of the application in enough detail that the 

1351  reader may gain a good general understanding of the data and information in the 

1352  application, including the quantitative aspects of the data. The summary should discuss
 
1353  all aspects of the application, and synthesize the information into a well-structured and 

1354  unified document. The summary should be written at approximately the level of detail 

1355  required for publication in, and meet the editorial standards generally applied by, 

1356  refereed scientific journals. To the extent possible, data in the summary should be 

1357  presented in tabular and graphic forms. The summary should contain the following 

1358  information: 

1359 

1360    The proposed modified risk claims;
 
1361    A statement briefly describing the type of tobacco product and providing the
 
1362  scientific rationale for the potential benefits of the tobacco product;
 
1363    A summary of the information and scientific data submitted in the application;
 
1364  and 

1365    A concluding discussion describing how you have met each of the relevant 

1366  statutory requirements for the type of order you are seeking under section 911(g) 

1367  of the FD&C Act. 

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1368  3.  Descriptive Information
 
1369 

1370  The application should contain a section that includes the following descriptive 

1371  subsections: 

1372 

1373    A subsection describing the proposed product;
 
1374    A subsection describing the formulation of the product;
 
1375    A subsection describing the conditions for using the product; and
 
1376    A subsection describing how consumers actually use the product. 21
 
1377 

1378  See section V for guidance about the information that should be contained in each of 

1379  these descriptive subsections. 

1380  4.  Labels, Labeling and Advertising 
1381 
1382  The application should contain a section describing how the applicant intends to 
1383  communicate the proposed modified risk claim(s) to the public and including copies of 
1384  proposed advertising and labeling and sample product labels and labeling as described 
1385  above in section V.A.1 and 4. 
1386  5.  Environmental Impact 
1387 
1388  The application should contain an environmental assessment under 21 CFR Part 25. 
1389  6.  Summary of All Research Findings 
1390 
1391  The application should contain a section summarizing all of the research findings related 
1392  to the product, both favorable and unfavorable.  FDA recommends that this portion of the 
1393  application be organized according to the key areas described in section VI.A: 

1394 

1395    Health Risks of the Tobacco Product.
 
1396    Effect on Tobacco Use Behavior among Current Users.
 
1397    Effect on Tobacco Use Initiation among Non-Users.
 
1398    Effect of Marketing on Consumer Understanding and Perceptions.
 
1399    Effect on the Population as a Whole.
 
1400 
1401  We also recommend that applicants include a tabulated index of all studies and analyses 
1402  organized by the key areas above.  This index should also be organized by study type 
1403  (product analyses, nonclinical studies, studies in adult human subjects, secondary data 
1404  analyses and modeling) and identify each study and analysis by name, section and page 
1405  numbers.  For electronic submissions, the index should also include a hypertext link to 
21 Findings from actual use studies should be submitted as part of your summary of all research findings. 
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1406  each study and analysis.  If any of the documents provided appear in peer-reviewed 

1407  literature, please provide a citation. 

 
1408  7.  Scientific Studies and Analyses
 
1409 

1410  This section should include the documents relating to the research referenced elsewhere 

1411  in the MRTPA as well as any other documents related to research findings conducted, 

1412  supported, or possessed by the tobacco product manufacturer.  See section V.A.5.  To 

1413  facilitate review, the documents relating to research findings should be complete and 

1414  well-organized. 

1415 

1416  Applicants should organize studies by study type (i.e., product analyses, non-clinical 

1417  studies, human studies, and secondary analyses and modeling) and follow the submission
 
1418  recommendations below for each study type. 

1419 

1420  Product Analyses 

1421 

1422  FDA recommends reporting HPHC information in a tabular format using separate 

1423  columns, in the order listed below (from left to right) for each of the following: 

1424 

1425     The constituent name;
 
1426     The constituents common name(s); 

1427     The corresponding Chemical Abstract Services (CAS) number; 

1428     The unit of measure;
 
1429     The level measured for the proposed product (with 95% confidence intervals);
 
1430     The sample size; and 

1431     The method of measuring and reference quotes. 

1432 

1433  FDA recommends separate tables for results generated using the ISO and Canadian 

1434  Intense smoking regimens, when applicable.  Documentation of laboratory accreditation 

1435  should be included in the MRTPA. 

1436 

1437  FDA recommends reporting information related to other product features (e.g., total 

1438  particulate matter, packaging, shelf life, etc.) as follows: 

1439 

1440     Mean level measured for the product (with 95% confidence intervals);
 
1441     Unit of measure; 

1442     Sample size; 

1443     Test method, linked to method defined within design specifications;
 
1444     Test date and location; and 

1445     Product lot number or the date of manufacture. 

1446 

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1447  Nonclinical and Human Studies
 
1448 

1449  For individual study reports, the applicant should submit descriptions of: 

1450     The study objective; 

1451     The hypotheses tested; 

1452     The study design; 

1453     The study population, animals, bacteria strain, or cell line; including sample 

1454  size, and comparator groups; 

1455     The methods of data collection and analysis; and 

1456     The findings, key limitations, and conclusions.
 
1457 

1458  In addition, the following information should be included, where applicable: 

1459 

1460     The original study protocol(s) used;
 
1461     Any amendments (which should be dated) to the study protocol;
 
1462     The final study protocol;
 
1463     A justification for the method selected, i.e. appropriateness for the evaluation 

1464  of the selected endpoint; 

1465     All raw data and data files used to generate the results;
 
1466     The questionnaires used; 

1467     Any transcripts or recordings of interviews and focus groups, where
 
1468  applicable;
 
1469     Case report forms;
 
1470     For nonclinical studies, documentation describing the actions taken to ensure 

1471  reliability and validity of the study (for example, documentation of good 

1472  laboratory practices as specified in 21 CFR Part 58);
 
1473     Documentation describing the actions taken to ensure the protection of human 

1474  subjects (for example, documentation of study oversight by a qualified 

1475  Institutional Review Board duly constituted and operating under 21 CFR Part 

1476  56, and documentation of informed consent procedures such as those 

1477  described in 21 CFR Part 50);
 
1478     A detailed description of the statistical analyses employed, including all 

1479  variables, confounders, and subgroup analyses, and a full report of the 

1480  findings; 

1481     Information on Data Monitoring Committee members; 

1482     Information on any contract research organization if obligations were 

1483  transferred for the conduct of any study; and 

1484     Investigator expertise and credentials.
 
1485 

1486  For each study, the report should also identify whether the study was conducted by or on
 
1487  the applicants behalf. 

1488 

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1489  Secondary Data Analyses and Modeling 
1490 
1491  For other analyses and modeling, the applicant should provide: 
1492 
1493     Explanations and justification of the technique used; 
1494     Assumptions used in the development of any models and parameters; 
1495     A listing of the parameters used in the analyses and/or models; 
1496     Data used to derive parameters or estimates and a rationale for the 
1497  applicability of the data for the given parameter; and 
1498     The results of various scenarios, including worst-case scenarios. 
1499 
1500  Applicants should also address the inherent uncertainty in these approaches as they 
1501  discuss the results derived from available secondary data and use of computational 
1502  models. 
 
1503  B.  Single Application 
1504 
1505  Section 911(l)(4) of the FD&C Act requires FDA to permit the filing of a single 
1506  application for any tobacco product that is a new tobacco product under section 910 of 
1507  the FD&C Act and which the applicant seeks to commercially market with modified risk 
1508  claims.  Accordingly, if the tobacco product for which you are seeking an order under 
1509  section 911(g) of the FD&C Act is a new tobacco product for which you must also satisfy 
1510  applicable premarket review requirements under section 910 of the FD&C Act, you may 
1511  file a single application.  The single application must include the information required for 
1512  the applicable premarket review (i.e., a substantial equivalence report, request for 
1513  exemption from substantial equivalence requirements, or the information required for 
1514  premarket review under section 910(b) of the FD&C Act), as well as the information 
1515  required to support issuance of an order under section 911(g) of the FD&C Act. 
1516 
1517  If you file a single application, it should be organized as follows: 
1518 
1519    Cover letter. The cover letter should include: 
1520  Identification of the submission as a single application permitted under 
o 
1521  section 911(l)(4) of the FD&C Act; 
1522  The name and address of your company; 
o 
1523  An authorized contacts name, title, address, phone number, fax number, 
o 
1524  and email address; 
1525  The brand name and, if applicable, subbrand name of the tobacco product; 
o 
1526  The name of the manufacturer; 
o 
1527  A list of all previous submissions to CTP for the proposed MRTP product 
o 
1528  or any product that is the same except for the claims that are the subject of 
1529  your application, e.g., a submission of listing of ingredients in tobacco 
1530  products submitted pursuant to section 904 of the FD&C Act or a previous 
1531  MRTPA, and what action FDA took as a result of any such submission; 
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1532  A statement regarding what type of premarket review you are seeking (a 
o 
1533  substantial equivalence determination, an exemption from substantial 
1534  equivalence requirements, or a marketing authorization order under 
1535  section 910(c)(1)((A)(i)); 
1536  A list of dates of any prior meetings with FDA about the tobacco product 
o 
1537  that is the subject of the MRTPA; 
1538  A statement whether you are seeking a risk modification order or an 
o 
1539  exposure modification order; and 
1540  A description or listing of the specific portions of the application you 
o 
1541  believe constitute trade secret or confidential commercial information that 
1542  is exempt from disclosure.  In the alternative, you may submit a second 
1543  version of the application with transparent highlights of proposed 
1544  redactions.  (See section X, Confidentiality, for more information). 
1545     Premarket review information.  Your application must contain all the information 
1546  required for a substantial equivalence report, request for exemption from 
1547  substantial equivalence requirements, or for premarket review under section 
1548  910(b) of the FD&C Act.  For details on how to submit a substantial equivalence 
1549  report under section 905(j) (21 U.S.C. 387e(j)), see FDAs Guidance for Industry 
1550  Section 905(j) Reports: Demonstrating Substantial Equivalence for Tobacco 
1551  Products and FDAs Draft Guidance for Industry Demonstrating the Substantial 
1552  Equivalence of a New Tobacco Product: Responses to Frequently Asked 
1553  Questions.  For details on how to request exemptions from the substantial 
1554  evidence requirements, see FDAs final rule  Exemptions from Substantial 
1555  Equivalence Requirements for Tobacco Products (76 FR 38961; July 5, 2011). 
1556  For details on how to submit a Premarket Tobacco Product Application (PMTA) 
1557  under section 910(b) (21 U.S.C. 387j(b)), see FDAs Draft Guidance for Industry 
1558  Applications for Premarket Review of New Tobacco Products. 
1559     Modified risk information.  Your application must also contain all the information 
1560  required for issuance of a modified risk order under section 911(g) of the FD&C 
1561  Act.  To the extent data or information contained in the premarket review portion 
1562  of the application is also relevant to or required for the modified risk 
1563  determination, you may cross-reference that data or information rather than 
1564  duplicating it in the modified risk portion of the application. 
 
1565  C.  How and Where Should I Submit My MRTPA? 
1566 
1567  In order to ensure the accessibility of documents and facilitate more effective and 
1568  efficient communication between you and FDA regarding your submission, FDA 
1569  recommends that you do the following: 
1570 
1571     Uniquely number all pages of your submission using continuous pagination; 
1572     Provide English translations for any foreign language documents.  Applicants 
1573  should also provide the original foreign language document and certification that 
1574  the translation into English is accurate; and 
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Draft  Not for Implementation
 
1575     Create and submit a glossary or explanation of any abbreviations, acronyms, or 
1576  industry-specific terminology or codes. 
1577 
1578  There are three ways to submit your MRTPA: 
1579 
1580 
1581     Electronic format submitted via the FDA Electronic Submission Gateway; 
1582     Electronic format submitted on physical media (e.g., CD or DVD); or 
1583     Paper format. 
1584 
1585  FDA strongly encourages you to submit your MRTPA in an electronic format to 
1586  facilitate efficiency and timeliness of data submission and processing.  You can securely 
1587  submit your application via the FDA Electronic Submissions Gateway (ESG).  To 
1588  prepare for this capability, please refer to the ESG website instructions for setting up a 
1589  WebTrader account at 
1590   http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/ucm114831.htm. 
1591 
1592  MRTPAs submitted in paper or on electronic media should be sent to: 
 
1593  Food and Drug Administration 
1594  Center for Tobacco Products 
1595  Document Control Center 
1596  Building 71, Room G335 
1597  10903 New Hampshire Avenue 
1598  Silver Spring, MD 20993-0002 
1599 
1600  Physical Electronic Media 
1601 
1602  Files submitted on electronic media should be stored on a CD/DVD or flash drive media. 
1603  Electronic media should be labeled with your company name, a contact phone number, 
1604  Modified Risk Tobacco Product Application - name of proposed modified risk tobacco 
1605  product, submission date, and series number (e.g., disc 1 of 2). The files should 
1606  include a signed cover letter prominently identified as a Modified Risk Tobacco Product 
1607  Application, and should also identify the software (name, version, and company) that 
1608  you used to confirm the submission is free of viruses or other malware.  In case we have 
1609  difficulty accessing the digital media, we recommend that you also include a paper copy 
1610  of the cover letter that prominently identifies the submission as a Modified Risk 
1611  Tobacco Product Application  name of proposed modified risk tobacco product and 
1612  includes the manufacturers name, address and phone number. 
 
1613  Electronic Submission Formats 
1614 
1615  For MRTPAs submitted in electronic format, we recommend that all content (including 
1616  the cover letter), except raw data, be in Portable Document Format (PDF) files 
1617  compatible with Adobe Acrobat 6.0 or higher.  Files should not be password protected or 
1618  encrypted.  In preparing your submission in PDF format, we recommend that you: 
 
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Draft  Not for Implementation 
 
1619     Create PDF files directly from an electronic source such as a word processing file 
1620  or excel; 
1621     Avoid image-only based PDF files whenever possible because scanned images are 
1622  more difficult to read and search.  If you scan a document to create a PDF file, we 
1623  recommend that you capture text by optical character recognition (OCR) software 
1624  so that the text of the resulting electronic documents is reasonably accessible and 
1625  searchable; 
     Create a submission table of contents and format it using bookmarks designed to 
1626  help the reader navigate through the document efficiently. 
1627 
  Any raw data submitted with an MRTPA should be submitted in an electronic source file 
1628  format such as Microsoft Excel or SAS transport file. 
1629 
D.  What Happens After You Submit an MRTPA? 
1630 
1631 
1632  FDA will first conduct an administrative review of your MRTPA for completeness. 
1633  Applicants should prepare complete, high quality submissions that facilitate FDAs 
1634  complete and timely review.  If FDA finds that your MRTPA does not contain 
1635  information required by section 911 of the FD&C Act for a risk modification order or 
1636  exposure modification order,22 FDA may refuse to file your application. 
1637 
1638  FDA may request additional information to clarify issues, ask questions that arise during 
1639  the review process, and ask for updates on ongoing studies. 
1640 
1641  As required by section 911(f) of the FD&C Act, FDA will refer your application to the 
1642  Tobacco Products Scientific Advisory Committee (TPSAC) and ask TPSAC to report its 
1643  recommendations on the application to FDA within 60 days.  FDA will also make the 
1644  application available to the public (except for matters in the application that are trade 
1645  secrets or otherwise confidential commercial information) and request comments 
1646  pursuant to section 911(e) of the FD&C Act. FDA intends to make the application 
  available to the public through FDAs Center for Tobacco Products website: 
1647  http://www.fda.gov/TobaccoProducts/default.htm. 
1648 
E.  Can I Withdraw My Pending MRTPA? 
1649 
1650 
1651  You may withdraw your pending MRTPA at any time.  You should promptly notify FDA 
1652  in writing of your decision to withdraw your application.  Withdrawal of an MRTPA 
1653  does not prevent you from submitting a subsequent MRTPA for the same tobacco 
1654  product in the future. However, any subsequent MRTPA should be complete without 
referencing data or any other information in the original MRTPA.  FDA intends to act 
upon any subsequent MRTPA no later than 360 days after its receipt. 
22 For example, FDA may refuse to file your application if you do not provide sample product labels and 
labeling required by section 911(d)(4), or for an exposure modification order, you do not provide results 
from testing of actual consumer perception required by section 911(g)(2)(b)(iii). 
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1655  F.  What is FDAs Timeframe for Review of an MRTPA? 
1656 
1657  FDA intends to act upon your MRTPA no later than 360 days after the receipt of an 
1658  application that contains the information required by section 911 of the FD&C Act.23 
1659 
1660  Similarly, if you choose to file a single application seeking authorization to market your 
1661  new tobacco product under section 910 of the FD&C Act and an order under section 
1662  911(g) of the FD&C Act, FDA intends to act upon your single application no later than 
1663  360 days after its receipt. 
 
1664  G.  What Happens After an Order Under Section 911(g) of the FD&C 
1665  Act is Issued? 
1666 
1667  An applicant granted an order under section 911(g) of the FD&C Act may commercially 
1668  market the tobacco product as described in the order issued by FDA.  Note that an order 
1669  under section 911(g) is issued for specific modified risk claims.  Introducing or delivering 
1670  for introduction into interstate commerce a tobacco product the label, labeling, or 
1671  advertising of which makes modified risk claims other than those described in the 
1672  products order is a violation of section 911 of the FD&C Act. 
1673 
1674  Furthermore, the 911(g) order is issued for the product that is the subject of the MRTPA. 
1675  Introducing or delivering for introduction into interstate commerce a tobacco product 
1676  other than that described in an order issued under section 911(g) of the FD&C Act may 
1677  cause the tobacco product to be in violation of section 911 of the FD&C Act.  If an 
1678  applicant makes changes to the product that would trigger the premarket requirements of 
1679  section 905(j) or 910 of the FD&C Act,24 the applicant must (in addition to satisfying any 
1680  applicable premarket review requirements under section 910 of the FD&C Act) submit an 
1681  MRTPA and FDA must issue an order under section 911(g) of the FD&C Act for the new 
1682  tobacco product.  Note that FDAs Guidances for Industry Section 905(j) Reports: 
1683  Demonstrating Substantial Equivalence for Tobacco Product and Demonstrating the 
1684  Substantial Equivalence of a New Tobacco Product: Responses to Frequently Asked 
1685  Questions describe changes that can be made to tobacco products for which FDA does not 
1686  intend to enforce the premarket review requirements of section 905(j) and 910 of the 
1687  FD&C Act. In such situations, FDA also does not intend to enforce the premarket review 
1688  requirements of section 911. 
23 For additional information regarding timing of FDAs review of MRTPAs refer to FDAs Draft 
Guidance for Industry, Preliminary Timetable for the Review of Applications for Modified Risk Tobacco 
Products under the Federal Food, Drug, and Cosmetic Act 
(http://www.fda.gov/downloads/TobaccoProducts/GuidanceComplianceRegulatoryInformation/UCM1919 
15.pdf).
24 FDAs Guidance for Industry Section 905(j) Reports: Demonstrating Substantial Equivalence for 
Tobacco Products and FDAs Draft Guidance for Industry Demonstrating the Substantial Equivalence of a 
New Tobacco Product: Responses to Frequently Asked Questions provide further guidance on the changes 
to a tobacco product that make it a new tobacco product. 
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1689  H.  Can FDA Withdraw an Order Issued Under Section 911(g)? 

1690 

1691  Yes.  The grounds for withdrawal of an order issued under section 911(g) are set forth in 

1692  section 911(j) of the FD&C Act. 

 
1693  I.  Can I Renew an Order Issued Under Section 911(g)?
 
1694 

1695  An exposure modification order issued under section 911(g)(2) of the FD&C Act will be 

1696  effective for a term of not more than 5 years.  FDA may renew an exposure modification
 
1697  order if the applicant files a new application and FDA finds that the requirements for 

1698  such order under section 911(g)(2) continue to be satisfied.  Section 911(g)(2)(C)(i) of
 
1699  the FD&C Act. 

1700 

1701  A risk modification order issued under section 911(g)(1) of FD&C Act will be effective 

1702  for the period of time specified in the order issued by FDA.  Section 911(h)(4) of the
 
1703  FD&C Act.  FDA may renew a risk modification order if the applicant files a new 

1704  application and FDA finds that the requirements for such order under section 911(g)(1)
 
1705  continue to be satisfied. 

1706 

1707  When submitting an application for renewal of an order issued under section 911(g), you 

1708  should ensure that you have complied with applicable requirements to provide results
 
1709  from the required postmarket surveillance and studies conducted pursuant to your order.
 
1710  Section 911(g)(2)(C)(iii) and 911(i)(1) of the FD&C Act.  You should also submit with 

1711  your application any updated study results from and all data collected in the required 

1712  postmarket surveillance and studies.  See section 911(l)(1)(E) and 911(d)(5) of the FD&C
 
1713  Act. 

 
 
1714  IX.  Investigational Use of Tobacco Products 
 
1715  A.  Exemptions for Investigational Use of Tobacco Products 
1716 
1717  You must file an MRTPA and obtain an order from FDA under section 911(g) of the 
1718  FD&C Act before you can introduce or deliver for introduction into interstate commerce 
1719  a modified risk tobacco product.  Section 911(a) of the FD&C Act. FDA plans to issue 
1720  regulations pursuant to section 910(g) of the FD&C Act (21 U.S.C. 387j(g)) providing 
1721  conditions under which modified risk tobacco products may be exempted from the 
1722  requirements of section 911 of the FD&C Act when used for investigational purposes. 
1723  Until these regulations are issued, FDA will consider exercising discretion in enforcing 
1724  the requirements of section 911 of the FD&C Act, in some circumstances, for the 
1725  purposes of allowing investigational use of proposed modified risk tobacco products. 
1726 
1727  Specifically, at this time, FDA does not intend to enforce the requirements of section 911 
1728  of the FD&C Act with respect to the use of proposed modified risk tobacco products in 
1729  studies that follow the specifications listed below that will help ensure that the studies are 
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1730  well-controlled, data derived from such studies are reliable, and study subjects are 
1731  adequately protected. 
1732 
1733  For all studies (both human and nonclinical), you should: 
1734 
1735     Limit direct distribution of the proposed modified risk tobacco product to 
1736  qualified and appropriately trained investigators; 
1737     Not promote for commercial distribution or test market the proposed modified 
1738  risk tobacco product; 
1739     Account for receipt, use, and disposition of all investigational product(s), and 
1740     Label the product for investigational use only. 
1741 
1742  For human studies, you should: 
1743 
1744     Take measures to ensure the reliability and validity of the study, for example, 
1745  through sound study design and adherence to study protocol.  In addition, you 
1746  should ensure that all studies are conducted such that the rights, safety, and 
1747  welfare of human subjects have been protected in accordance with ethical 
1748  principles acceptable to the world community and that the data are scientifically 
1749  valid.  One approach to implementing such measures would be to conduct the 
1750  study in accordance with appropriate provisions found in 21 CFR Part 50 
1751  (informed consent of human subjects) and ensure that the IRB oversight is 
1752  governed by 21 CFR Part 56 (IRB review and approval of clinical investigations). 
1753  Additional information about informed consent and IRBs can be found in FDAs 
1754  guidance documents.  Applicants with specific questions about human subject 
1755  protections are encouraged to contact the Center for Tobacco Products. 
1756     Ensure that all study subjects receiving product be current daily tobacco product 
1757  users at least 21 years of age. 
1758 
1759  For nonclinical studies, you should: 
1760 
1761     Take measures to ensure the reliability and validity of the study.  One approach to 
1762  implementing such measures would be to follow good laboratory practices as 
1763  specified in 21 CFR Part 58. Additional information about good laboratory 
1764  practice regulations can be found in FDAs guidance documents.  Applicants with 
1765  specific questions about good laboratory practice regulations are encouraged to 
1766  contact the Center for Tobacco Products. 
1767 
1768  Applicants who would like to conduct research using their modified risk tobacco products 
1769  should contact the Office of Science at the Center for Tobacco Products to discuss the 
1770  submission of a study protocol and/or study endpoints for investigations intended to 
1771  support an MRTPA. 
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Draft  Not for Implementation
 
1772  B.  Requesting a Meeting with FDA 
1773 
1774  You should send your request for a meeting in writing to the Director of CTPs Office of 
1775  Science at the following address: 
1776 
1777  Food and Drug Administration 
1778  Center for Tobacco Products 

1779  Document Control Center 

1780  Building 71, Room G335
 
1781  10903 New Hampshire Avenue
 
1782  Silver Spring, MD 20993-0002 

1783 
1784  The meeting request should include adequate information for FDA to assess the potential 
1785  utility of the meeting and to identify FDA staff necessary to discuss the proposed agenda 
1786  items, including the following: 
1787 
1788  	  A brief statement of the purpose of the meeting, including the name of your new 
1789  tobacco product, a brief description of the product, and the role of your planned 
study(s) in overall product development plans; 
1790 
1791  	   A list of your specific questions grouped by discipline; 
1792  	   A proposed agenda, including objectives and outcomes expected from the 

1793  meeting; 

1794  	   A list of all individuals (including titles) expected to attend the meeting on your 
1795  behalf; and 
1796  	   An investigational plan to support the demonstrations required for issuance of an 
1797  order under section 911(g) of the FD&C Act. 
1798 
1799  We recommend that the summary of your proposed study protocol(s) include the 
1800  following information: 
1801 
	  Study objective(s); 
1802 
1803  	  Study hypotheses; 
1804  	  Background information (a brief description of the modified risk tobacco product 
and any regulatory history); 
1805 
	  Study design; 
1806 
1807  	  Study population (number of subjects to be enrolled, inclusion/exclusion criteria, 
comparison group(s)); 
1808 
	  Human subject protection information, including IRB information; 
1809 
1810  	  Primary and secondary endpoints (definition and success criteria); 
1811  	  Statistical analysis plan (description of the statistical methods to be employed, the 
1812  reason for your choice of sample size, including calculations of the power of each 
study and the level of significance and/or confidence level to be used); 
1813 
	  Data collection procedures; and 
1814 
	  Baseline and follow-up assessments and duration of follow-up. 
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Draft  Not for Implementation
 
 
1815  Pre-meeting preparation is critical for achieving a productive discussion or exchange of 
1816  information.  After FDA schedules a meeting, we request that you submit a fully 
1817  paginated meeting package, organized according to the final agenda, containing a 
1818  detailed description of your product, the status of product development, an investigational 
1819  plan for evaluating whether the product meets the criteria for issuance of an order under 
1820  section 911(g) of the FD&C Act (including a summary of your proposed study 
1821  protocols), the specific questions to be discussed, and background information relevant to 
1822  those questions. 
1823 
1824  FDAs receipt of a complete meeting package, including clearly articulated questions for 
1825  FDA, well in advance of a meeting will enable FDA staff to review the information 
1826  adequately and is therefore important to achieving a productive meeting. 
 
1827  C.  Studies Conducted Outside of the United States 
1828 
1829  You may submit studies of your product conducted outside the United States as part of 
1830  your MRTPA.  You should follow the general principles for scientific studies and 
1831  analyses described in section VI.C. All human studies conducted outside the United 
1832  States should be conducted to ensure that the rights, safety, and welfare of human 
1833  subjects have been protected in accordance with ethical principles acceptable to the world 
1834  community and that the data are scientifically valid and applicable to the U.S. population. 
1835  The investigator should conduct these studies in conformance with international 
1836  standards for good clinical practices or obey the laws and regulations of the country in 
1837  which the research is conducted, whichever affords the greater protection of human 
1838  subjects.  These patient protection and data integrity measures ensure that data from 
1839  studies conducted outside the United States are from adequate and well-designed studies 
1840  and provide reliable information to FDA. 
 
 
1841  X.  Confidentiality 
1842 
1843  Information submitted under section 911 of the FD&C Act may include, but is not 
1844  limited to, a companys non-public, trade secret, or confidential commercial information. 
1845 
1846  Several laws govern the confidentiality of tobacco product information submitted under 
1847  section 911 of the FD&C Act, including sections 301(j) and 906(c) of the FD&C Act (21 
1848  U.S.C. 331(j) and 387f(c)), the Trade Secrets Act (18 U.S.C. 1905), and the Freedom of 
1849  Information Act (FOIA) (5 U.S.C. 552) as well as FDAs implementing regulations. 
1850 
1851  FDAs general regulations concerning the public availability of FDA records are 
1852  contained in 21 CFR Part 20. 
1853 
1854  Section 911(e) of the FD&C Act requires FDA to make an MRTPA publicly available 
1855  except matters in the application, which are trade secrets or otherwise confidential, 
1856  commercial information.  In order to facilitate FDAs publication of the disclosable 
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Draft  Not for Implementation 
 
1857  portions of your MRTPA under section 911(e) for public comment, FDA recommends 
1858  that you identify the portions of the application you believe constitute trade secret or 
1859  confidential commercial information that is exempt from disclosure by either: 
1860 
1861     Including in your cover letter a description or listing of such information; or 
1862     Submitting two versions of your application  a complete, unredacted version 
1863  and a second version with transparent highlights of the information you believe is 
1864  exempt from disclosure. 
1865 
1866  FDA will make the final evaluation regarding what information can be made publicly 
1867  available under section 911(e) of the FD&C Act. 
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