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DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments regarding this draft guidance may be submitted within 60 days of publication in the 

Federal Register of the notice announcing the availability of the draft guidance.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For questions regarding this draft guidance, contact the Center for Tobacco Products at (Tel) 1-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
i

Table of Contents

Guidance for Industry and Investigators.....................................................................1

I. INTRODUCTION............................................................................................ 1

II. BACKGROUND .............................................................................................. 2

III. PURPOSE......................................................................................................... 5

IV. FDA’S 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
Contains Nonbinding Recommendations

Draft – Not for Implementation

1

1

2 Use of Investigational Tobacco 

3 Products

4

5

Guidance for Industry and Investigators16

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 FDA’s 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 FDA’s guidance documents, including this guidance, do not establish legally enforceable 

30 responsibilities. Instead, guidances describe the Agency’s 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.
Contains Nonbinding Recommendations

Draft – Not for Implementation

2

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 

commercially marketed in the United States as of February 15, 2007;253 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 

product under section 910(c)(1)(A)(i) of the FD&C Act362 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 

FD&C Act;

4

67

 

2 FDA’s 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 FDA’s 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 FDA’s current thinking on this topic. 

4 FDA’s guidance for industry Section 905(j) Reports: Demonstrating Substantial Equivalence for Tobacco 

Products, dated January 2011, and FDA’s guidance for industry Demonstrating the Substantial 
Contains Nonbinding Recommendations

Draft – Not for Implementation

3

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 

tobacco product is not substantially equivalent (NSE).575

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 

marketed tobacco products”680 (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 

FD&C Act.

7

84 

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 FDA’s 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 FDA’s current thinking on this topic. 
Contains Nonbinding Recommendations

Draft – Not for Implementation

4

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 

tobacco products are not commercialized.8 120 

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 FDA’s 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 FDA’s guidance for industry Extension of Certain Tobacco Product Compliance Deadlines 

Related to the Final Deeming Rule dated November 2018 (Revised).
Contains Nonbinding Recommendations

Draft – Not for Implementation

5

138 III. PURPOSE

139

140 This guidance describes FDA’s 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 

who conduct investigations using investigational tobacco products.9 146 Such persons may 

147 include sponsors, investigators, sponsor-investigators, and contract research organizations

(CROs).10 148 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” (82 FR 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 contract research organization (CRO), as used in this 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).
Contains Nonbinding Recommendations

Draft – Not for Implementation

6

165 IV. FDA’S 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 

investigators.

11 179

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 

accordance with 21 CFR part 56 (Institutional Review Boards).12 204 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. 
Contains Nonbinding Recommendations

Draft – Not for Implementation

7

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 

Practice for Nonclinical Laboratory Studies).

13 236

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 FDA’s 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. 
Contains Nonbinding Recommendations

Draft – Not for Implementation

8

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 sponsor’s 

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 FDA evaluate 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;
Contains Nonbinding Recommendations

Draft – Not for Implementation

9

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 

file could help facilitate FDA review.14 310

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 manufacturer’s complete list of, 

components or parts,15 ingredients, and additives16 318 by 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 product’s 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, additive is 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 

or on raw tobacco or a pesticide chemical (section 900(1) of the FD&C Act (21 U.S.C. 387(1))).
Contains Nonbinding Recommendations

Draft – Not for Implementation

10

or potentially harmful constituents,17 320 as 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 Investigator’s 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 FDA’s 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. 
Contains Nonbinding Recommendations

Draft – Not for Implementation

11

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
Contains Nonbinding Recommendations

Draft – Not for Implementation

12

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 sponsor’s 

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. 

o If you are notified a study subject has a serious and unexpected18 429 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. 
Contains Nonbinding Recommendations

Draft – Not for Implementation

13

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 

Reporting Portal for Researchers.19 445

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.

.
Contains Nonbinding Recommendations

Draft – Not for Implementation

14

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;

· Correspondence with another sponsor, a monitor,20 502 a clinical investigator, the 

503 committee or group formally designated to oversee research involving human 

504 subjects, or FDA;

· Signed investigator agreements, including financial disclosure information;21 505

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).
Contains Nonbinding Recommendations

Draft – Not for Implementation

15

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 FDA’s 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 subject’s 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
Contains Nonbinding Recommendations

Draft – Not for Implementation

16

527

528 VIII. HOW TO SUBMIT INFORMATION REGARDING PROPOSED USE OF 

529 AN INVESTIGATIONAL TOBACCO PRODUCT

530

531 For sponsors who would like FDA’s 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

· Electronic format submitted via the CTP Portal;22 535

· Electronic format submitted via the FDA Electronic Submissions Gateway;23 536

537 · Electronic format submitted on physical media (e.g., CD, DVD); or

· Paper format.24 538

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 FDA’s

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 FDA’s 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.
Contains Nonbinding Recommendations

Draft – Not for Implementation

17

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 FDA’s guidance 

589 Meetings with Industry and Investigators on the Research and Development of Tobacco 

Products, dated July 2016 (Revised).

25 590

591

592

 

25 This guidance is available on the CTP guidance Web page at 

https://www.fda.gov/TobaccoProducts/Labeling/RulesRegulationsGuidance/ucm281147.htm.
Contains Nonbinding Recommendations

Draft – Not for Implementation

18

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 

 Click here to enter text

2. Date of Submission 

Click here to enter text

3. Sponsor Address and Contact Information

Physical Address 

Click here to enter text

City

Click here to enter text

State/Province/Region

Click here to enter text

Mailing Address (if different)

Click here to enter text

City

Click here to enter text

State/Province/Region

Click here to enter text

Telephone Number

Click here to enter text

Country

Click here to enter text

ZIP or Postal Code

Click here to enter text

Email Address

Click here to enter text

Facsimile Number

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 

Click here to enter text

City

Click here to enter text

State/Province/Region

Click here to enter text

Mailing Address (if different)

Click here to enter text

City

Click here to enter text

State/Province/Region

Click here to enter text

Telephone Number

Click here to enter text

Country

Click here to enter text

ZIP or Postal Code

Click here to enter text

Email Address

Click here to enter text

Facsimile Number

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

Choose an item

8. Product Sub-Category

 Choose an item

FDA Use Only

CTP/DCC Receipt Stamp STN #
Contains Nonbinding Recommendations

Draft – Not for Implementation

19

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 

☐New Protocol 

Protocol Amendments (check all that apply)

☐Change in Protocol (include P#####)

☐Response to [DATE] FDA Request for Information

☐New Investigator (include P#####)

☐Other

Information Amendments 

☐Additional Product Information

☐Other (e.g., final study report)

Administrative Amendments 

☐Change in Sponsor or POC

☐Change in Address

☐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
Contains Nonbinding Recommendations

Draft – Not for Implementation

20

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 Investigator’s 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.
Contains Nonbinding Recommendations

Draft – Not for Implementation

21

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