Use of Investigational Tobacco 
Products 
Guidance for Industry and Investigators 
DRAFT GUIDANCE 
This guidance document is being distributed for comment purposes only. 
Comments regarding this draft guidance may be submitted within 60 days of publication in the 
Federal Register of the notice announcing the availability of the draft guidance.  Electronic 
comments may be submitted to https://www.regulations.gov.  Alternatively, submit written 
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Room 1061, Rockville, MD, 20852.  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For questions regarding this draft guidance, contact the Center for Tobacco Products at (Tel) 1-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 a.m.  4 p.m. EDT. 
Additional copies are available online at 
https://www.fda.gov/TobaccoProducts/Labeling/RulesRegulationsGuidance/default.htm.  You 
may send an email 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, Bldg. 71, Rm. G335, 10903 New Hampshire Ave., Silver Spring, MD 20993-2000. 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Tobacco Products 
February 2019  Table of Contents 
Guidance for Industry and Investigators .....................................................................1 
I.  INTRODUCTION ............................................................................................ 1 
II.  BACKGROUND .............................................................................................. 2 
III.  PURPOSE ......................................................................................................... 5 
IV.  FDAS ENFORCEMENT POLICY FOR INVESTIGATIONAL 
TOBACCO PRODUCTS ............................................................................. 6 
V.  INFORMATION REGARDING PROPOSED USE OF AN 
INVESTIGATIONAL TOBACCO PRODUCT IN A CLINICAL 
INVESTIGATION ........................................................................................ 7 
VI.  STUDIES OF TOBACCO PRODUCTS CONDUCTED OUTSIDE THE 
UNITED STATES ...................................................................................... 13 
VII.  PREPARATION AND MAINTENANCE OF STUDY RECORDS ......... 14 
VIII.  HOW TO SUBMIT INFORMATION REGARDING PROPOSED USE 
OF AN INVESTIGATIONAL TOBACCO PRODUCT ......................... 16 
IX.  REQUESTING A MEETING WITH FDA ................................................. 17 
Appendix A: Form - Proposed Use of an Investigational Tobacco Product .......... 18 
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1
Use of Investigational Tobacco 
2 
Products
3
4
5
Guidance for Industry and Investigators1
6
7
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is 
10  not binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements 
11  of the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
12 responsible for this guidance as listed on the title page.
13
14 I.  INTRODUCTION 
15
16  Section 910(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 
17  387j(g)) gives FDA the authority to issue regulations to exempt tobacco products 
18  intended for investigational use from the requirements of chapter IX of the FD&C Act, 
19  including premarket submission requirements.  To date, FDA has not issued such 
20  regulations; consequently, investigational tobacco products are not exempt from FD&C 
21  Act requirements, including premarket submission requirements.  This draft guidance 
22  supersedes the draft guidance of the same title dated September 2015 and, when final, 
23  will describe FDAs current thinking regarding the definition of investigational tobacco 
24  product and discuss the kind of information FDA intends to consider in making 
25  enforcement decisions regarding the use of investigational tobacco products until 
26  regulations are issued and become effective or FDA provides written notice of its intent 
27 to change its enforcement policy.   
28
29  FDAs guidance documents, including this guidance, do not establish legally enforceable 
30  responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and 
31  should be viewed only as recommendations, unless specific regulatory or statutory 
32  requirements are cited.  The use of the word should in Agency guidances means that 
33 something is suggested or recommended, but not required.  
34
                                                          
1 This guidance was prepared by the Office of Science and Office of Regulations in the Center for Tobacco 
Products (CTP) at FDA. 
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35 II.  BACKGROUND 
36
37 Section 910(g) of the FD&C Act states:
38
39  The Secretary may exempt tobacco products intended for investigational use 
40  from the provisions of this chapter under such conditions as the Secretary may by 
41 regulation prescribe.
42
43  FDA intends to propose regulations establishing conditions for exempting investigational 
44  tobacco products from certain FD&C Act requirements.  Until then, investigational 
45  tobacco products are not exempt from applicable FD&C Act requirements, including 
46 premarket submission requirements and tobacco product standards.  
47
48  Tobacco products intended for investigational use would be considered new tobacco 
49  products if they meet the definition in section 910(a)(1) (21 U.S.C. 387j(a)(1)).  The 
50 term new tobacco product means:   
51
52    Any tobacco product (including those products in test markets) that was not 
53 commercially marketed in the United States as of February 15, 2007;2 or 
54    Any modification (including a change in design, any component, any part, or any 
55  constituent, including a smoke constituent, or in the content, delivery or form of 
56  nicotine, or any other additive or ingredient) of a tobacco product where the 
57  modified product was commercially marketed in the United States after February 
58 15, 2007. 
59
60  To introduce, or deliver for introduction into interstate commerce, a new tobacco product, 
61  there must be in effect a marketing authorization order issued by FDA for the tobacco 
62 product under section 910(c)(1)(A)(i) of the FD&C Act3 unless: 
63
64    the manufacturer has submitted a substantial equivalence report for the tobacco 
65  product under section 905(j) of the FD&C Act (21 U.S.C. 387e(j)) and obtained 
66  from FDA a substantial equivalence order under section 910(a)(2)(A)(i) of the 
67 FD&C Act; 4
                                                          
2 FDAs guidance for industry Establishing That a Tobacco Product Was Commercially Marketed in the 
United States as of February 15, 2007, dated September 2014, provides information on how a manufacturer 
may establish that a tobacco product was commercially marketed in the United States as of February 15, 
2007.  For the most recent version of a guidance, check the CTP guidance Web page at 
https://www.fda.gov/TobaccoProducts/Labeling/RulesRegulationsGuidance/ucm281147.htm.  
3 FDAs draft guidance for industry Applications for Premarket Review of New Tobacco Products, dated 
September 2011, discusses the general procedure for submitting a premarket tobacco product application 
(PMTA), including who can submit a PMTA and when and how PMTAs can be submitted.  When 
finalized, this guidance will represent FDAs current thinking on this topic. 
4 FDAs guidance for industry Section 905(j) Reports: Demonstrating Substantial Equivalence for Tobacco 
Products, dated January 2011, and FDAs guidance for industry Demonstrating the Substantial 
 
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68    the manufacturer has submitted under 21 CFR 1107.1 a request for an exemption 
69  of the tobacco product from the requirement to obtain a substantial equivalence 
70  order, FDA has granted the exemption request, and the manufacturer has made the 
71  required submission under section 905(j)(1)(A)(ii) of the FD&C Act and waited 
72 90 days before introducing its product to the market; or
73    the manufacturer has submitted a substantial equivalence report in accordance 
74  with section 910(a)(2)(B) of the FD&C Act and there is no order finding that the 
75 tobacco product is not substantially equivalent (NSE).5
76
77  Modified risk tobacco products also require premarket review by FDA.  A modified risk 
78  tobacco product (MRTP) is any tobacco product that is sold or distributed for use to 
79  reduce harm or the risk of tobacco-related disease associated with commercially 
80 marketed tobacco products6 (section 911(b)(1) of the FD&C Act (21 U.S.C. 387k(b)(1)).  
81 Specifically, to introduce or deliver for introduction into interstate commerce an MRTP, 
82 there must be in effect an order under section 911(g) of the FD&C Act and the applicant 
83 must satisfy any applicable premarket review requirements under section 910 of the 
84 FD&C Act.7  
85
86  Any tobacco product, including a tobacco product intended for investigational use, is 
87  deemed adulterated if it is required by section 910(a) of the FD&C Act to have premarket 
88  review and it does not have an order in effect under section 910(c)(1)(A)(i).  See sections 
89  902(6)(A) and 910(a) of the FD&C Act (21 U.S.C. 387b(6)(A) and 387j(a)).  Similarly, 
90  any tobacco product, including a tobacco product intended for investigational use, is 
91  deemed adulterated if it is a modified risk tobacco product and it does not have in effect 
92  an order under section 911(g) of the FD&C Act.  See sections 902(8) and 911(a) of the 
93 FD&C Act.
94
95  Further, tobacco products must conform in all respects with any applicable tobacco 
96  product standards issued under section 907 of the FD&C Act (21 U.S.C. 387g).  See 
97  section 301(q)(1)(A) of the FD&C Act (21 U.S.C. 331(q)(1)(A)).  Any tobacco product, 
98  including a tobacco product intended for investigational use, is deemed adulterated if it is 
                                                          
Equivalence of a New Tobacco Product: Responses to Frequently Asked Questions(Edition 3), dated 
December 2016,discuss the submission process for substantial equivalence reports. 
5 New tobacco products that are the subjects of provisional substantial equivalence applications may be 
legally sold and distributed, unless FDA finds the product is NSE to a predicate product.  A provisional 
substantial equivalence application is one that was submitted before March 23, 2011, for a new tobacco 
product that was first commercially marketed between February 15, 2007, and March 22, 2011. 
6 A tobacco product is a modified risk tobacco product if, for example, the label, labeling, or advertising 
explicitly or implicitly represents that the tobacco product presents a lower risk of tobacco-related disease 
or is less harmful than one or more other commercially marketed tobacco products or the tobacco product 
or its smoke contains a reduced level of a substance or presents a reduced exposure to a substance. 
7 FDAs draft guidance for industry Modified Risk Tobacco Product Applications, dated April 2012, 
provides information about submitting applications for modified risk tobacco products.  When finalized, 
this guidance will represent FDAs current thinking on this topic. 
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99 subject to a tobacco product standard established under section 907 of the FD&C Act and 
100  does not in all respects conform with such standard.  See sections 902(5) and 907 of the 
101  FD&C Act. 
102   
103  This guidance document is intended to help researchers who may seek to study tobacco 
104  products that do not have marketing authorization or that do not comply with an 
105  applicable tobacco product standard.  Until regulations governing the use of 
106  investigational tobacco products are issued and finalized, FDA intends to evaluate 
107  specific uses of investigational tobacco products on a case-by-case basis according to 
108 potential human subject protection concerns or other impacts on public health.  
109
110  In making enforcement decisions, FDA generally intends to consider, among other 
111 things:
112
113    Whether there are controls on how and to whom investigational tobacco products 
114 are distributed;  
115    Whether the protocol for the clinical investigation or the procedures used during 
116 the clinical investigation adequately provide for the protection of human subjects;
117    Whether the study is designed to ensure the quality and integrity of the study data 
118 and permit other investigators to replicate the findings; and 
119    Whether there are adequate procedures in place to ensure that investigational 
120 tobacco products are not commercialized.8  
121
122  FDA recognizes that it may be difficult to assess a difference in risk between the use of 
123  an investigational product and the participants use of their usual tobacco product.  
124  Nonetheless, when designing the conditions of use in a study, investigators should 
125  carefully consider the risk implications for study participants and any nonusers (for 
126  example, friends, family, and colleagues) who may be exposed to the investigational 
127 tobacco product.  
128
129 As used in this guidance document: 
130
131  An investigational tobacco product means a tobacco product that is intended for 
132 investigational use and is:  
133 (1) a new tobacco product; or 
134  (2) a tobacco product that is required to comply with a tobacco product 
135  standard and that does not conform in all respects to the applicable 
136 tobacco product standard. 
137
                                                          
8 With respect to the investigational use of deemed, finished tobacco products that were on the U.S. market 
on August 8, 2016, we refer you to FDAs guidance for industry Investigational Use of Deemed, Finished 
Tobacco Products That Were on the U.S. Market on August 8, 2016, During the Deeming Compliance 
Periods, dated October 2016.  Note that the compliance timelines related to the deeming rule have been 
updated; see FDAs guidance for industry Extension of Certain Tobacco Product Compliance Deadlines 
Related to the Final Deeming Rule dated November 2018 (Revised). 
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138 III.  PURPOSE 
139
140  This guidance describes FDAs current thinking regarding the definition of 
141  investigational tobacco product and discusses the kind of information FDA intends to 
142  consider in making enforcement decisions regarding the use of investigational tobacco 
143  products in the United States until regulations become effective or FDA provides written 
144  notice of its intent to change its enforcement policy.  It is intended to assist persons who 
145  currently intend to submit study information on tobacco products to FDA and persons 
146  who conduct investigations using investigational tobacco products.9  Such persons may 
147  include sponsors, investigators, sponsor-investigators, and contract research organizations 
148  (CROs).10 This guidance also is intended to assist committees or groups formally 
149  designated to oversee human subject research (e.g., institutional review boards (IRBs)) 
150 involving investigational tobacco products.
151
152  For purposes of this guidance, a clinical investigation means an experiment or study in 
153  which an investigational tobacco product is administered to, dispensed to, or used by one 
154 or more human subjects.  
155
156  As used in this guidance document, an investigator is the individual who conducts the 
157  investigation (e.g., under whose immediate direction the tobacco product is administered 
158  or dispensed to a subject).  If an investigation is conducted by a team of individuals, the 
159  leader of the team is the lead investigator and is responsible for directing the 
160  investigation.  A sponsor means a person who takes responsibility for or initiates an 
161  investigation (e.g., a tobacco product manufacturer or an academic institution).  In those 
162  instances, in which an individual both initiates and conducts an investigation, the 
163 individual is a sponsor-investigator.   
164
                                                          
9 To provide clarity regarding our interpretation of the drug and device definitions in the FD&C Act with 
respect to products made or derived from tobacco, FDA issued a final rule entitled Clarification of When 
Products Made or Derived From Tobacco Are Regulated as Drugs, Devices, or Combination Products; 
Amendments to Regulations Regarding Intended Uses(82FR 2193,Jan. 9, 2017).  FDA notes that the 
portions of the final rule that describe the circumstances in which a product made or derived from tobacco 
that is intended for human consumption will be subject to regulation as a drug, device, or combination 
product under the FD&C Act are in effect.  The effective date, however, of the amendments to the existing 
medical product intended use regulations is delayed indefinitely.  (83 FR 11639, March 16, 2018).   
10 The term contractresearch organization(CRO),as used inthis guidance document, means a person who
assumes, as an independent contractor with the sponsor, one or more of the obligations of the sponsor (e.g., 
design of a protocol).
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165  IV.  FDAS ENFORCEMENT POLICY FOR INVESTIGATIONAL TOBACCO 
166 PRODUCTS
167
168 A. Use of Investigational Tobacco Products in Clinical Investigations 
169
170  Clinical investigations are likely to raise concerns about human subject protection, public 
171  health, or both.  FDA intends to consider the following factors, among others, in making 
172  enforcement decisions with respect to the use of an investigational tobacco product in a 
173 clinical investigation:
174
175    Whether there are controls on how and to whom investigational tobacco products 
176  for use in a clinical investigation are distributed.  For example, whether 
177  investigational tobacco products are distributed with labeling indicating that they 
178  are limited to investigational use only and are only distributed to qualified 
179 investigators.11
180    Whether the protocol for a clinical investigation and procedures used during the 
181  clinical investigation adequately provide for the protection of human subjects.  
182  For example, FDA intends to consider the proposed study population of a clinical 
183  investigation (e.g., whether the subjects are youth or women who are pregnant or 
184  nursing) and whether the protocol for the clinical investigation and procedures 
185  used during the investigation adequately provide for the protection of the 
186 population to be enrolled in the study.
187  o  While we consider each protocol on its own merits, some of the issues we 
188  would consider include assessing whether the trial participants currently 
189  are nicotine-using subjects and what is the risk to them in light of the route 
190  of administration of the investigational product.  We also would consider 
191 the adequacy of the study settings, including monitoring and stopping 
192 criteria.  
193    Whether a study is designed to ensure the quality and integrity of the study data 
194 and permit other investigators to replicate the findings. 
195    Whether there are adequate procedures in place to ensure that investigational 
196 tobacco products are not commercialized.  
197
198  Adequate procedures for human subject protection ensure that the rights, safety, and 
199  welfare of human subjects are protected in accordance with ethical principles acceptable 
200  to the research and health care communities and that the data are scientifically valid.  One 
201  approach to implementing such procedures would be to conduct the study in accordance 
202  with the appropriate provisions found in 21 CFR part 50 (Protection of Human Subjects) 
203  and ensure study oversight by a qualified IRB duly constituted and operating in 
204 accordance with 21 CFR part 56 (Institutional Review Boards).12  Sponsors with specific 
                                                          
11 The term qualified investigators, as used throughout this guidance, means experts qualified by scientific 
training and experience to evaluate tobacco products. 
12 For additional, general information on clinical trials and human subject protection, go to: 
https://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm.  
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205 questions about human subject protection are encouraged to contact FDA at 
206 AskCTP@fda.hhs.gov.
207
208  B. Use of Investigational Tobacco Products in Nonclinical Laboratory 
209 Studies 
210
211  For purposes of this guidance, nonclinical laboratory study means in vivo or in vitro 
212  experiments in which investigational tobacco products are studied prospectively in test 
213  systems under laboratory conditions.  We note that, for tobacco products, the data 
214  generated from nonclinical laboratory studies may provide important information 
215 regarding the relative toxicities of new or modified risk tobacco products.   
216
217  Generally, FDA does not recommend that investigators correspond with us about the use 
218  of investigational tobacco products in nonclinical studies.  However, sponsors of 
219  nonclinical studies may elect to meet with FDA early in the development process to 
220  discuss what, if any, animal testing is appropriate and the suitability and acceptability of 
221  non-animal tests for a particular tobacco product.  FDA supports reducing the reliance on 
222 animal testing where adequate and scientifically valid non-animal alternatives can be 
223 substituted.  
224
225  When animal-based nonclinical laboratory studies are conducted, we encourage 
226  investigators to use appropriate animal models and adhere to the best practices of 
227  refinement, reduction, and replacement of animals in research and to applicable laws, 
228  regulations, and policies governing animal testing, such as the Animal Welfare Act (7 
229  U.S.C. 2131 et seq.) and the Public Health Service Policy on Humane Care and Use of 
230 Laboratory Animals (available at 
231 https://grants.nih.gov/grants/olaw/references/phspol.htm).   
232
233  FDA encourages investigators to take measures to ensure the reliability and validity of 
234  nonclinical laboratory studies.  One approach to implementing such measures would be 
235  to follow good laboratory practices as specified in 21 CFR part 58 (Good Laboratory 
236 Practice for Nonclinical Laboratory Studies).13
237
238  V.  INFORMATION REGARDING PROPOSED USE OF AN 
239  INVESTIGATIONAL TOBACCO PRODUCT IN A CLINICAL 
240 INVESTIGATION 
241
242  This section of the guidance provides examples of the kinds of information that is likely 
243  to be relevant to FDAs consideration of the factors described above.  We encourage 
244  sponsors to meet with FDA to discuss their specific proposed uses of investigational 
                                                          
13 In the Federal Register of August 24, 2016, FDA published a proposed rule entitled Good Laboratory 
Practice for Nonclinical Laboratory Studies to amend the regulations for good laboratory practices for 
nonclinical studies (81 FR 58342).  Among other proposed modifications, FDA proposed to expand the 
scope of these regulations to include tobacco products as appropriate under the FD&C Act.  
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245  tobacco products.  Information on how to request a meeting with FDA is found in section 
246 IX of this guidance. 
247
248  A sponsor may also submit information regarding the proposed use of an investigational 
249  tobacco product to FDA for review prior to enrolling subjects in the planned 
250  investigation.  We encourage this voluntary type of submission because it will help FDA 
251  in determining whether to exercise enforcement discretion based on the sponsors 
252 investigational plan, including helping FDA assess the factors described above: e.g., that 
253 there are controls on how and to whom the investigational tobacco products for use in a 
254 clinical investigation are distributed; that clinical investigations provide adequate 
255 procedures for human subject protection and are designed to ensure the quality and 
256 integrity of the study data and permit other investigators to replicate the findings; and that 
257 there are adequate procedures in place to ensure that investigational tobacco products are 
258 not commercialized. 
259
260 A. Recommendations on Information to Include in Voluntary Submissions 
261
262  A sponsor may seek feedback from FDA by submitting information regarding its 
263  proposed use of an investigational tobacco product in a clinical investigation.  The 
264  amount of information that will assist FDA with providing the most informative feedback 
265  generally depends on the scope of the investigation.  For example, for studies involving 
266  the use of legally marketed products that are subsequently modified, the information 
267 provided may be limited to the modification(s). Generally, FDA expects to consider and 
268 respond to these submissions within 60 calendar days.
269
270 The following information (or where applicable, an explanation of why such information 
271 is unavailable or not relevant) would generally help FDAevaluate the specific proposed 
272 use of an investigational tobacco product in a clinical investigation:
273
274   Administrative information that: 
275  o  Identifies the submission as information regarding the proposed use of an 
276  investigational tobacco product in a clinical investigation (or the addition 
277 of information to an existing submission); 
278  o  Contains the name, address (physical and mailing address (if these 
279  addresses are different) along with an email address), telephone number 
280  and facsimile number of the sponsor; name, title, physical address, mailing 
281  address, email, telephone number and facsimile number of an individual 
282  who resides or maintains a place of business in the United States and is 
283 designated to act as the authorized representative for the sponsor; 
284  o  Provides the name, including brand name/sub-brand name or product 
285 code, if available, of the investigational tobacco product; 
286  o  Identifies the product, such as by category (e.g., cigarette, smokeless 
287  tobacco) and product subcategory (e.g., unfiltered cigarette or portioned 
288 snus);
289  o  Lists cross-references by FDA submission tracking number for previous 
290 submissions referenced in the submission; 
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291  o  Contains the name(s) and title(s) of the person(s) responsible for 
292 monitoring the conduct and progress of the clinical investigation;
293  o  Contains the name(s) and title(s) of the person(s) responsible for review 
294  and evaluation of information relevant to the effects of the investigational 
295 tobacco product;
296  o  If the sponsor has transferred any responsibilities for the conduct of any 
297  clinical investigation (or part of a clinical investigation) to a CRO, the 
298  information should also contain the name and address of each CRO, 
299  identify the clinical investigation it is involved in conducting, and describe 
300  the responsibilities transferred.  If all responsibilities governing the 
301  conduct of an investigation have been transferred, a general statement that 
302 all responsibilities have been transferred is acceptable; and 
303 o  Contains the signature of the sponsor or the authorized representative. 
304   A description of the investigational tobacco product.  For studies involving the 
305  use of legally marketed products that are subsequently modified, it would be 
306 helpful to receive only that information that relates to the modification.  
307  o  It also will facilitate our review if we receive product information in a 
308 table format.  
309  o  Alternatively, if appropriate, your reference to a tobacco product master 
310 file could help facilitate FDA review.14
311   FDA recommends that the description of the investigational tobacco product 
312 include, as appropriate:  
313  o  A description of the product design with schematics of the complete 
314  product and product components, a description of the design features 
315  (e.g., location of ventilation holes, heat source, paper porosity, coatings, 
316 nicotine concentration gradient), and performance specifications;
317  o  A complete list of, or a reference to the manufacturers complete list of, 
318  components or parts,15ingredients, and additives16by quantity in the 
319  tobacco product, including product chemistry and a table of any harmful 
                                                          
14 For more information on the use of master files, please see the guidance Tobacco Product Master Files, 
dated May 2016.  This guidance is available on the CTP guidance Web page at 
https://www.fda.gov/TobaccoProducts/Labeling/RulesRegulationsGuidance/ucm281147.htm. 
15 In 21 CFR 1100.3, component or part is defined as any software or assembly of materials intended or 
reasonably expected (1) to alter or affect the tobacco products performance, composition, constituents, or 
characteristics; or (2) to be used with or for the human consumption of a tobacco product.  The term does 
not include anything that is an accessory of a tobacco product. 
16 In section 900(1) of the FD&C Act, additiveis defined as any substance the intended use of which 
results or may reasonably be expected to result, directly or indirectly, in its becoming a component or 
otherwise affecting the characteristic of any tobacco product (including any substances intended for use as 
a flavoring or coloring or in producing,manufacturing, packing, processing, preparing, treating, packaging, 
transporting, or holding), except that such term does not include tobacco or a pesticide chemical residue in 
oron raw tobacco or a pesticide chemical (section 900(1) of the FD&C Act(21 U.S.C. 387(1))).
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320  or potentially harmful constituents,17as well as the applicable 
321 specifications and a description of the intended function of each; 
322  o  The name and address of the manufacturer(s) of the tobacco product and 
323 components or parts;
324  o  A description of the methods, facilities, and controls used for the 
325  manufacture, processing, packing, and storage of the investigational 
326 tobacco product; and 
327  o  Data and information sufficient to demonstrate the investigational tobacco 
328 product will be stable during the conduct of the study.  
329    Any known or reasonably known information, both favorable and 
330  unfavorable, about the investigational tobacco product, such as results of 
331  product testing, nonclinical laboratory studies, and clinical investigations, and 
332  information on marketed tobacco products similar to the investigational 
333 tobacco product (if available);
334   A study protocol; 
335   Identification of the study sites; 
336    Identification of the lead investigator(s) and a statement of his/her 
337 qualifications;
338    Copies of all packaging and labeling to be provided to clinical investigators or 
339 study subjects;
340   A copy of the Investigators Brochure, if applicable; 
341    A copy of the informed consent form and a summary of the informed consent 
342 procedures to be followed; 
343    A copy of recruitment materials and any other information to be provided to 
344 participants, such as a debriefing script; and
345    Information about the oversight committee or group (e.g., IRB) that has been 
346 formally designated to oversee the clinical investigation.
347
348 Study Protocols 
349
350  Generally, FDA recommends that your study protocol include the following information, 
351  which may be considered should FDA assess the enforcement priority of a particular 
352 investigation: 
353
354   Protocol title; 
                                                          
17 See FDAs guidance Harmful and Potentially Harmful Constituents in Tobacco Products as Used in 
Section 904(e) of the Federal Food, Drug, and Cosmetic Act, dated August 2016 (Revised), for information 
on our current thinking on the meaning of harmful and potentially harmful constituent.  This guidance is 
available on the CTP guidance Web page at 
https://www.fda.gov/TobaccoProducts/Labeling/RulesRegulationsGuidance/ucm281147.htm. 
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355    A statement of the study objective(s), hypotheses, study endpoints, 
356 definitions, and success criteria;
357    Background information, such as a brief description of the investigational 
358  tobacco product, a summary of relevant literature, the significance of the 
359  study to be conducted, and a summary of information relevant to the health 
360  risks of the investigational tobacco product.  Such a summary could consist of 
361  available information on a marketed product that is similar to the 
362 investigational tobacco product;
363    A description of the design and setting (e.g., clinical, community) for the 
364  study, including the type of control group, if any, to be used and a description 
365 of methods to be used to minimize bias and confounding;
366    A description of the study population, including the methods used for 
367  recruitment, number of subjects to be enrolled, inclusion/exclusion criteria, 
368 and comparison group(s);
369    A description of the dosing/exposure plan that describes the manner, quantity, 
370  and frequency for administration of the investigational tobacco product(s), 
371  including the principles of operation for the investigational tobacco product(s) 
372  (e.g., whether the tobacco product is administered via the mouth or nose and 
373  whether the tobacco product is ignited and, if so, by what means).  In addition, 
374  the description should explain how the product is designed to be smoked, 
375  inhaled, swallowed, dissolved, sniffed, chewed, or otherwise ingested or 
376 absorbed into the body.
377    A copy of data collection procedures and samples of data collection 
378 instruments; 
379    The timing for baseline and follow-up assessments, including assessment of 
380 adverse experiences, and duration of follow-up;
381    A risk assessment, including a description of clinical procedures, laboratory 
382  tests, criteria for stopping the study, criteria for withdrawing a study 
383  participant, or other measures to be taken to monitor the effects of the product 
384 in human subjects and to minimize risk;
385   A sample case report form; 
386    A description of the steps that will be taken to protect human subjects 
387  (including any plans to report adverse experiences and to debrief subjects, if 
388 appropriate); and
389    The name and address of any facility where laboratory testing will be 
390 performed. 
391
392 We also recommend that the protocol include a statistical analysis plan that includes: 
393
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394    A description of the statistical method(s) to be used and the reason for 
395 choosing this method(s);
396    A discussion of sample size, including calculations of the power of the study 
397 and the level of significance or confidence level to be used;
398    A description of the study design with appropriate controls for the testing of 
399  study hypotheses (selection of the controls should be based on the endpoint or 
400  effect to be evaluated).  The study duration should allow for adequate 
401 assessment of selected endpoint(s) and/or effects; and
402    The procedures that will be employed to minimize bias on the part of 
403  observers, researchers, participants, and analysts of the data and prevent 
404  undue influences on the results and interpretation of the study data, such as 
405  blinding, masking, random assignment to condition, etc.  Procedures for the 
406  selection of human subjects should allow for generalizability of study results 
407 to the U.S. population, as appropriate.
408
409 B. Additional Recommendations Regarding Human Subject Protection 
410
411  To help ensure that studies are conducted in a manner that protects human subjects, FDA 
412  recommends that sponsors have procedures to keep the Agency and the sponsors 
413  oversight committee or group formally designated to oversee research involving human 
414  subjects informed about any changes relating to the conduct of, and issues that arise 
415  during, the study (e.g., changes to current investigational use or adverse experiences).  
416  Relatedly, ensuring that clinical investigators maintain complete and accurate records to 
417  account for receipt, use, and disposition of investigational tobacco products generally 
418 also helps to protect human subjects.
419
420  Furthermore, FDA recommends that sponsors keep records of the following information, 
421 which FDA will generally consider in determining its enforcement priorities:
422
423   Protocol amendments; 
424    Names of the clinical investigators, including any clinical investigators who 
425 have been replaced for cause (e.g., due to fraud or other misconduct);
426    A description of any changes made to the investigational tobacco product or 
427 its conditions of use; and 
428   Adverse experience reports.  
429  o  If you are notified a study subject has a serious and unexpected18 adverse 
430  experience (for example, burns resulting from an exploding battery in an 
                                                          
18 For purposes of this guidance, an adverse experience would be unexpected if, for example, the nature, 
severity, or frequency of an effect of using an investigational tobacco product was not consistent with 
known or foreseeable risks associated with such product or the research procedures. 
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431  electronic nicotine delivery system (ENDS)), we recommend that you 
432  inform FDA, all participating clinical investigators, and any committee or 
433  group formally designated to oversee the study within a few days after 
434  initial receipt of the notification, and that you supply FDA with a 
435 completed case report form for the adverse experience.  
436  o  In addition, we recommend that you notify FDA, all participating clinical 
437  investigators, and any committee or group formally designated to oversee 
438  the study of any serious or unexpected adverse experience associated with 
439  the tobacco product you are investigating within a few weeks after initial 
440  notification, and that you supply FDA with a completed case report form 
441 for the adverse experience.
442
443  We encourage the reporting of adverse experiences associated with a clinical 
444  investigation of an investigational tobacco product to FDA through the FDA CTP Safety 
445 Reporting Portal for Researchers.19
446
447  If you choose to terminate a study, withdraw or inactivate a protocol, or want to withdraw 
448  studies of a product before completion, we recommend you notify FDA within a few 
449  weeks of such action and include in the notification the reason(s) for discontinuation.  
450  This information is relevant for FDA to consider in making decisions relating to future 
451  investigations involving the tobacco product that was the subject of the terminated study.  
452  You should provide, as appropriate, plans for continued monitoring of subjects or others 
453  exposed to the tobacco product during the clinical investigation.  If there is a reasonable 
454  possibility that exposure to the investigational tobacco product is directly related to a 
455  serious and unexpected adverse experience, you should inform any clinical investigators 
456  who participated in the investigation of the reason(s) for discontinuing the clinical 
457 investigation.
458
459  VI.  STUDIES OF TOBACCO PRODUCTS CONDUCTED OUTSIDE THE 
460 UNITED STATES 
461
462  For clinical investigations of tobacco products conducted outside the United States, but 
463  intended for submission to FDA, we recommend that clinical investigators conduct such 
464  studies so that the rights, safety, and welfare of human subjects have been protected in 
465  accordance with ethical principles acceptable to the international community (e.g., as 
466  reflected in International Council for Harmonisation (ICH) guidelines such as Guideline 
467  for Good Clinical Practice (ICH E6(R2))) and that the data are scientifically valid and 
468  applicable to the U.S. population.  The clinical investigator should conduct these studies 
469  in conformance with international standards for good clinical practices or obey the laws 
470  and regulations of the country in which the research is conducted, whichever affords the 
471  greater protection of human subjects.  For nonclinical laboratory studies of 
                                                          
19 The researcher pathway for the FDA CTP safety reporting portal may be accessed at 
https://www.safetyreporting.hhs.gov. 
. 
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472  investigational tobacco products conducted outside of the United States, investigators 
473  should take measures to help ensure the reliability and validity of the studies as discussed 
474 in section IV.B of this guidance.  
475
476  If you intend to export a tobacco product, including for investigational use, you should 
477 refer to section 801(e) of the FD&C Act (21 U.S.C. 381(e)).
478
479  FDA recommends that sponsors prepare and maintain records and reports, as described in 
480  section VII of this guidance, for studies conducted outside of the United States but 
481  intended for submission to FDA to permit FDA to evaluate the conduct of a clinical 
482  investigation, including assessing the quality and integrity of the study data and the 
483 protection of human subjects.
484 VII.  PREPARATION AND MAINTENANCE OF STUDY RECORDS 
485
486  FDA recommends that sponsors, CROs, sponsor-investigators, and clinical investigators 
487  maintain documentation to permit evaluation of the conduct of a clinical investigation, 
488  including assessing the quality and integrity of the study data and the protection of human 
489  subjects.  FDA may seek to review records, and thus recommends that records be 
490  maintained and available to FDA for a period of at least 4 years after the date on which 
491  the investigation is terminated or completed or the date that the records are no longer 
492  considered necessary for supporting marketing of a product or the later of the two dates if 
493  both apply.  However, in no instance is a tobacco product manufacturer of a regulated 
494  tobacco product relieved of its obligation to comply with the requirements of section 
495  904(b) of the FD&C Act (21 U.S.C. 387d(b)) or any other applicable recordkeeping or 
496 submission requirements.
497
498 FDA believes that records that would permit the evaluation described above include: 
499
500    Records showing the receipt, shipment, or other disposition of the 
501 investigational tobacco product;
502    Correspondence with another sponsor, a monitor,20 a clinical investigator, the 
503  committee or group formally designated to oversee research involving human 
504 subjects, or FDA; 
505   Signed investigator agreements, including financial disclosure information;21
506 and 
507   Adverse experience reports. 
508
                                                          
20 For purposes of this guidance, the term monitor means a qualified individual designated by a sponsor or 
CRO to oversee the progress of an investigation. 
21 One approach to determine what type of financial disclosure information to gather would be to consider 
the appropriate provisions found in 21 CFR part 54 (Financial Disclosure by Clinical Investigators). 
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509  In addition, FDA recommends that sponsors provide a copy of this guidance to clinical 
510  investigators to assist them in preparing and maintaining records.  Generally, records that 
511 would assist FDAs evaluation include:
512
513    Records of the receipt, use, and disposition of the investigational tobacco 
514 product, including dates, quantity, and use by subjects;
515    Correspondence with another investigator, the oversight committee or group 
516  formally designated to oversee research involving human subjects, the 
517 sponsor, a monitor, or FDA;
518   Signed consent forms; 
519    Records of each subjects case history and exposure to tobacco products used 
520  in the investigation.  Case histories should include the case report forms, 
521 progress notes, and medical records;
522    All relevant observations, including records concerning adverse experiences; 
523 and
524    The protocol, protocol amendments, and documents showing the dates of and 
525 reasons for each deviation from the protocol. 
526
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527
528  VIII.  HOW TO SUBMIT INFORMATION REGARDING PROPOSED USE OF 
529 AN INVESTIGATIONAL TOBACCO PRODUCT
530
531  For sponsors who would like FDAs feedback on a particular proposed use of an 
532  investigational tobacco product, there are four ways to submit information regarding a 
533 proposed use of an investigational tobacco product:
534
535   Electronic format submitted via the CTP Portal;22
536   Electronic format submitted via the FDA Electronic Submissions Gateway;23
537   Electronic format submitted on physical media (e.g., CD, DVD); or 
538   Paper format.24
539
540  FDA strongly encourages you to submit the information regarding your proposed use in 
541  an electronic format to facilitate efficiency and timeliness of data submission and 
542  processing.  For the same reason, we also encourage you to provide us with a table of 
543 contents as to your submission.
544
545  Files submitted on physical media should be stored on a CD/DVD or flash drive.  
546  Physical media should be labeled with your company name, a contact phone number, 
547  Proposed Use of an Investigational Tobacco Product  Name of the tobacco product 
548  under investigation, submission date, and series number (e.g., Disc 1 of 2).  The files 
549  should include a signed cover letter prominently identified as a Proposed Use of an 
550  Investigational Tobacco Product and should also identify the software (name, version, 
551  and company) that you used to confirm the submission is free of viruses or other 
552  malware.  We recommend that you also include a paper copy of the cover letter in case 
553 we have difficulty accessing the physical media.
554
555  Should you choose to submit information to FDA regarding the use of an investigational 
556  tobacco product, FDA has created a form to assist you.  Although use of the form is 
557  voluntary, it will help ensure that you are providing useful information for FDAs 
558  consideration and will facilitate processing and review by FDA.  A copy of the form is 
559  attached to this guidance (Appendix A) and, when this guidance is final, will be available 
560  on FDAs Web site.  For ease of processing, FDA suggests that you use this form 
561  whenever you submit information to FDA regarding a clinical investigation, for example, 
562  in response to an FDA request for information regarding your investigation or to submit a 
                                                          
22 For information, go to: 
https://www.fda.gov/TobaccoProducts/GuidanceComplianceRegulatoryInformation/Manufacturing/ucm51
5047.htm.  
23 For information, go to: https://www.fda.gov/forindustry/electronicsubmissionsgateway/default.htm. 
24 Physical media and paper submissions may be sent via U.S. Mail or courier using the address on our 
Web site: https://www.fda.gov/tobaccoproducts/default.htm. 
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563  revised protocol.  The form is not intended for use in submitting adverse experience 
564 reports.  
565
566 Electronic Submission Formats 
567  For clinical investigation information submitted in electronic format, we recommend that 
568  all content (including the cover letter), except raw data, be in Portable Document Format 
569  (PDF) files compatible with Adobe Acrobat 6.0 or higher without the use of additional 
570  plug-ins other than those provided by Adobe as part of Acrobat.  For data files, we 
571  recommend that either Microsoft Excel (.xls, .csv) or SAS transport (.xpt) files be used, 
572  and be accompanied by instructions for use and your statistical program code.  Data 
573  contained in Excel files should be actual values and not calculated values from a cell 
574  formula.  Files should not be password-protected or encrypted.  In preparing your 
575 submission of PDF files, we recommend that you:
576   Create PDF files directly from an electronic source such as a word processing file 
577 or Excel file;
578    Avoid image-based PDF files whenever possible because scanned images are 
579  more difficult to read and search.  If you scan a paper document to create a PDF 
580 file, we recommend that you capture text by optical character recognition (OCR) 
581 software so that the text of the resulting electronic document is reasonably
582 accessible and searchable; and
583   Create a submission table of contents and format it using bookmarks designed to 
584 help the reader navigate through the document efficiently.
585 IX.  REQUESTING A MEETING WITH FDA 
586
587  If a sponsor or investigator wishes to discuss the study of an investigational tobacco 
588  product with FDA, you may request a meeting with FDA as discussed in FDAs guidance 
589  Meetings with Industry and Investigators on the Research and Development of Tobacco 
590 Products, dated July 2016 (Revised).25
591
592
                                                          
25 This guidance is available on the CTP guidance Web page at 
https://www.fda.gov/TobaccoProducts/Labeling/RulesRegulationsGuidance/ucm281147.htm. 
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593
594 Appendix A: Form - Proposed Use of an Investigational Tobacco Product 
Form Approval OMB Control No. XXXX-XXXX 
Expiration Date xx/xx/xxxx 
See PRA Statement on page X 
DEPARTMENT OF HEALTH AND HUMAN SERVICES 
Food and Drug Administration 
PROPOSED USE OF AN INVESTIGATIONAL TOBACCO PRODUCT 
Note: FDA recommends submitting information only if this investigation involves an experiment or study in 
which an investigational tobacco product is administered to, dispensed to, or used by one or more human 
subjects.  The time it takes to complete the form may vary  depending on the information you wish (or are 
able) to provide.  For more information, please see the guidance Use of Investigational Tobacco Products 
on our website. 
Sponsor Information 
1.  Name of Sponsor  2.  Date of Submission                 
       Click here to enter text  Click here to enter text 
3.  Sponsor Address and Contact Information 
Physical Address  City  State/Province/Region 
Click here to enter text  Click here to enter text  Click here to enter text 
Mailing Address (if different)  City  State/Province/Region 
Click here to enter text  Click here to enter text  Click here to enter text 
Telephone Number  Country  ZIP or Postal Code 
Click here to enter text  Click here to enter text  Click here to enter text 
Email Address  Facsimile Number 
Click here to enter text  Click here to enter text 
Authorized Representative Information (individual residing or maintaining a place of business within the 
United States who is designated by the sponsor to receive communication from the FDA) 
4.  Name of Authorized Representative 
Click here to enter text 
5.  Authorized Representative Address and Contact Information 
Physical Address  City  State/Province/Region 
Click here to enter text  Click here to enter text  Click here to enter text 
Mailing Address (if different)  City  State/Province/Region 
Click here to enter text  Click here to enter text  Click here to enter text 
Telephone Number  Country  ZIP or Postal Code 
Click here to enter text  Click here to enter text  Click here to enter text 
Email Address  Facsimile Number 
Click here to enter text  Click here to enter text 
Investigational Tobacco Product Information 
6. Name of Tobacco Product (include brand name/sub-brand name or product code, if available) 
Click here to enter text 
7.    Product Category  8.  Product Sub-Category 
Choose an item         Choose an item 
FDA Use Only 
CTP/DCC Receipt Stamp  STN # 
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9. Is the tobacco product intended for investigational use a tobacco product that is a modification of a 
legally marketed tobacco product? (select applicable) 
 Yes, and the legally marketed tobacco product that was modified has grandfathered status.  
Please provide GF#######, if available. 
 Yes, and the legally marketed tobacco product that was modified has a marketing order.  
Please provide STN (SE/EX/PM#######).
 Yes, and the legally marketed tobacco product that was modified has provisional status.  
Please provide STN (SE#######).                  
 No 
10.  Related Submissions: Please list the FDA submission tracking numbers (STNs, IUXXXXXXX, etc.) for 
previous submissions to CTP in connection with this investigational tobacco product. 
Click here to enter text 
Submission Information  
11.  This submission contains the following 
 New Proposal (i.e., your first communication regarding the proposed investigational use of this product) 
or    
 Additional Information IU#######; IU#######; IU####### (list all applicable IUs)   
Protocol  Information Amendments 
New Protocol  Additional Product Information 
Other (e.g., final study report) 
Protocol Amendments (check all that apply) 
Change in Protocol (include P#####)  Administrative Amendments 
Response to [DATE] FDA Request for Information  Change in Sponsor or POC 
New Investigator (include P#####)  Change in Address 
Other  Notification to Withdraw Protocol [P#####] 
Notification to Inactivate Protocol [P#####] 
Notification to Withdraw All Studies of 
Product(s) [IU#######] 
12.  Is any part of the clinical study to be conducted by (transferred to) a contract research organization 
(CRO)? 
Yes No 
If yes, please provide the name and address of the CRO, identification of the clinical study, and a 
description of the specific responsibilities being assumed by the CRO. 
Click here to enter text 
13.  Are you referencing information in a tobacco product master file? 
Yes   No 
If yes, please attach a copy of the letter of authorization from the master file owner that permits FDA to 
reference such file on your behalf.  
14.  Name and title of the person responsible for monitoring the conduct and progress of the clinical 
investigations (i.e., study monitor). 
Click here to enter text 
15.  Name(s) and title(s) of the person(s) responsible for review and evaluation of information relevant to 
the effects of the investigational tobacco product (e.g., investigator, lead investigator, sponsor-investigator) 
Click here to enter text 
Signature of Sponsor/Authorized Representative  Type Name, Title, and Date 
595
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A.  Recommended Administrative Information for Submission of New Protocols, Amended 
Protocols, and Information Amendments for Investigational Tobacco Product(s) (unless 
previously provided in a related submission and the information is still accurate) 
1.  Identifying information that describes contents of the submission (i.e., cover letter) 
2.  Table of Contents 
3.  Description of the investigational tobacco product and any comparator or placebo to be used in the 
study 
4.  A description of the way the investigational tobacco product will be used by study participants 
5.  Any known or reasonably known information, both favorable and unfavorable, about the 
investigational tobacco product or similar marketed tobacco products 
6.  A new or amended study protocol 
7.  Identification of the study sites 
8.  Identification of the lead investigator(s) and a statement of his/her qualifications 
9.  Copies of all packaging and labeling to be provided to clinical investigators or study participants 
10. A copy of the Investigators Brochure, if applicable 
11. A summary of the informed consent procedures to be followed and a copy of the informed consent 
form 
12. A copy of recruitment materials and any other information to be provided to study participants (e.g., 
debriefing script) 
13. Information about the oversight committee or group (e.g., IRB) formally designated to oversee the 
clinical investigation 
B.  In addition to items listed in section A, for a New Protocol, please also include the following: 
1.  Protocol title 
2.  Background information (include as applicable): 
a.  summary of known or reasonably known results of any product testing and nonclinical 
studies that have been conducted previously on the specific investigational tobacco product  
b.  summary of known or reasonably known results of any clinical studies (both favorable and 
unfavorable) 
c.  summary of information relevant to the health risks of the investigational tobacco product 
(e.g., available information on a marketed product that is similar to the investigational 
tobacco product) 
3.  A statement of the study objectives, hypotheses, endpoints, definitions, and success criteria 
4.  A description of the study design, including duration and extent of tobacco product exposure 
5.  A description of the study setting (e.g., clinical, community) and study population, including 
recruitment methods, inclusion/exclusion criteria, number of planned participants, and any planned 
comparator and/or control groups 
6.  A copy of data collection procedures and samples of data collection instruments 
7.  The timing for baseline and follow-up assessments and duration of follow-up 
8.  A risk assessment, including a description of clinical procedures, laboratory tests, and criteria for 
stopping the study or withdrawing a study participant 
9.  A sample case report form 
10. A description of the plan to solicit and report adverse experiences and debrief subjects 
11. The name and address of any test facility(ies) 
C.  In addition to items listed in section A, for a Protocol Amendment, please also include the following: 
1.  Revised protocol with the proposed changes clearly documented (i.e., track changes or red line).  
Include all information from the list under section B of this form that is applicable to the amendment. 
2.  Clean version of revised protocol 
D.  In addition to items listed in section A, for an Information Amendment, please also include the 
following: 
1. Additional information related to the amendment.  Include the information from the list under section 
B of this form directly above that is applicable to the amendment. 
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E.  For an Administrative Amendment, please attach a cover letter including details of the 
administrative change (e.g., change in sponsor or address) 
F. For any Other Information, please attach document(s) that include the additional detailed 
information 
596
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