Smoking Cessation and 
Related Indications: 
Developing Nicotine 
Replacement Therapy 
Drug Products 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2023 
Clinical/Medical
   
Smoking Cessation and 
Related Indications: 
Developing Nicotine 
Replacement Therapy 
Drug Products 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2023 
Clinical/Medical
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEVELOPMENT PROGRAM ....................................................................................... 3 
A.  Recommended Studies and Application Type to Support Approval......................................... 5 
1. Investigational NRT Drug Products That Rely on an Approved NRT Drug Product ...................... 5 
a.  Generic versions of approved NRT drug products .................................................................... 5 
b.  Drug product modifications that alter the delivery of nicotine ................................................... 6 
c.  Different instructions for use ..................................................................................................... 7 
2. NRT Drug Products That Are Significantly Different From Approved NRT Drug  Products .......... 8 
a.  New route of administration ...................................................................................................... 8 
b.  New indication .......................................................................................................................... 8 
3. Secondary Endpoints ........................................................................................................................ 8 
B.  General Considerations: Early Phase Clinical Development ..................................................... 9 
C.  General Considerations: Efficacy Trials .................................................................................... 10 
1. General Efficacy Trial Design for All NRT Drug Products ........................................................... 10 
2. Sequential Approach for Development of Nonprescription Drug Products ................................... 11 
3. Study Population ............................................................................................................................ 12 
4. Cessation Efficacy Endpoints ......................................................................................................... 12 
5. Other Efficacy Endpoints ............................................................................................................... 13 
a.  Reduction in risk of relapse ..................................................................................................... 13 
b.  Reduction in urge to smoke and relief of cue-induced craving in former smokers ................ 14 
c.  Relief of withdrawal symptoms not associated with a cessation attempt ................................ 14 
6. New Regimens for Cessation and Reduction in Risk of Relapse .................................................... 14 
D.  Other Considerations ................................................................................................................... 15 
1. Pediatric Populations ..................................................................................................................... 15 
2. Behavioral Counseling ................................................................................................................... 16 
3. Statistical Considerations .............................................................................................................. 17 
a.  Analysis populations ............................................................................................................... 17 
b.  Missing efficacy data .............................................................................................................. 17 
4. Clinical Benefit of Smoking Cessation ........................................................................................... 17 
 
  Contains Nonbinding Recommendations 
Smoking Cessation and Related Indications: 
Developing Nicotine Replacement Therapy Drug Products 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION 
 
The purpose of this guidance is to assist sponsors2 in the clinical development of nicotine 
replacement therapy (NRT) drug products, including but not limited to those intended to help 
cigarette smokers stop smoking cigarettes.3  As used in this guidance, NRT drug products are 
nicotine-based drug products intended to help individuals quit smoking cigarettes.  Smoking 
cessation products that do not contain nicotine are not considered NRT drug products.  This 
guidance reflects the FDAs current recommendations regarding overall development programs to 
support NRT drug products for smoking cessation and related chronic indications (e.g., reduction in 
risk of relapse).4  FDA hosted a public hearing and published a notice in the Federal Register 
requesting comments on the Agencys approach to evaluating the safety and effectiveness of NRT 
drug products, including how the drug products should be used and labeled.5  This guidance takes 
 
1 This guidance has been prepared by the Division of Anesthesia, Analgesia, and Addiction Products and the Office 
of Nonprescription Drugs in the Center for Drug Evaluation and Research at the Food and Drug Administration, 
with the assistance of the Center for Devices and Radiological Health (CDRH) and the Office of Combination 
Products (OCP) at the Food and Drug Administration. 
 
2 For the purposes of this guidance, the term sponsor includes any sponsor of an investigational new drug  application 
or applicant for a new drug application or abbreviated new drug application under section 505 of the  Federal Food, 
Drug, and Cosmetic Act. 
 
3 This document does not address the development of nicotine replacement therapies to aid in cessation of non-
combustible tobacco products (e.g., e-cigarettes) or other forms of tobacco use.  At this time we do not have 
sufficient data to outline potential cessation endpoints that would be generally applicable to the range of non-
combustible tobacco products currently on the market.  We encourage sponsors to work with the Agency to develop 
appropriate development programs for cessation of tobacco products other than cigarettes. 
 
4 As used in this guidance, the term chronic indications involves intermittent or continuous use resulting in 6 months 
or more exposure over a lifetime. 
 
5 See the Federal Register notice The Food and Drug Administrations Approach to Evaluating Nicotine 
Replacement Therapies; Public Hearing; Request for Comments, published on November 30, 2017 (82 FR 56759; 
Docket No. FDA-2017-N-6529). 
1  Contains Nonbinding Recommendations 
 
into consideration the feedback received and is intended to serve as a focus for continued discussions 
among the Agency, pharmaceutical sponsors, the academic community, and the public on this topic.6 
 
This guidance focuses on drug development and trial design issues that are specific to the study of 
NRT drug products.7  
 
Nonclinical studies are recommended to develop NRT drug products depending on specific 
aspects of the drug product, such as the route of administration, excipients in the formulation, 
impurities, and leachables.  This guidance does not address recommendations for nonclinical 
development of NRT drug products.  That topic can be addressed through feedback from the 
relevant FDA review division.  Nonclinical development of an NRT drug product with an oral 
inhalation route of administration is addressed in the guidance for industry Nonclinical Testing of 
Orally Inhaled Nicotine-Containing Drug Products (October 2020).8  Regarding novel excipients 
in products developed for a different route of administration, refer to principles in the guidance 
for industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (May 
2005). 
 
This guidance does not contain discussion of the general issues of statistical analysis or clinical 
trial design that are not specific to development of NRT drug products.  Those topics are 
addressed in the International Council for Harmonisation (ICH) guidances for industry E9 
Statistical Principles for Clinical Trials (September 1998), E10 Choice of Control Group and 
Related Issues in Clinical Trials (May 2001), and E9(R1) Statistical Principles for Clinical Trials: 
Addendum:  Estimands and Sensitivity Analysis in Clinical Trials (May 2021).    
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of the 
word should in Agency guidances means that something is suggested or recommended, but not 
required.  
 
 
II.  BACKGROUND 
 
All existing FDA-approved NRT drug products (prescription and nonprescription) are approved 
for cessation of cigarette smoking.  The Agency is committed to increasing access to and use of 
therapies, including NRT drug products, which could help more smokers quit.    
 
 
6 In addition to consulting guidances, sponsors are encouraged to contact the appropriate review division to discuss 
specific issues that arise during the development of NRT drug products. 
 
7 For information on development programs for other drugs, biologics, or devices for smoking cessation and related 
indications, sponsors should contact the Division of Anesthesia, Analgesia, and Addiction Products, CDERs Office 
of Nonprescription Drugs; the Office of Product Evaluation and Quality in CDRH; or the Office of Therapeutic 
Products in the Center for Biologics Evaluation and Research. 
 
8 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
  2  Contains Nonbinding Recommendations 
 
NRT drug products are typically studied and labeled for use as adjuncts to behavioral self-help 
materials and to date have involved single treatment regimens that begin on the patients quit day 
(first day without a cigarette).  However, other treatment regimens (e.g., pretreatment before quit 
day, quitting by gradual reduction (reduce to quit), using two NRT drug products together) could 
also be developed to help cigarette smokers quit.  These alternate regimens are discussed further 
in section III., Development Program. 
 
NRT drug products can be developed for the following chronic indications: 
 
  Smoking cessation 
  Reduction in risk of relapse9 
 
NRT drug products that first have demonstrated effectiveness for smoking cessation or reduction 
in risk of relapse can also include additional information in labeling by demonstrating 
effectiveness in the following secondary endpoints: 
 
  Reduction of urge to smoke and relief of cue-induced craving in former smokers 
  Relief of withdrawal symptoms not associated with a cessation attempt 
 
These indications are discussed further in section III., Development Program. 
 
 
III.  DEVELOPMENT PROGRAM 
 
Both the regulatory pathway for an NRT drug product and the amount of nonclinical or clinical 
information needed to support approval can depend on the characteristics of the investigational 
NRT drug product relative to an approved NRT drug product. 
 
The need for nonclinical studies to develop NRT drug products depends on specific aspects of 
the drug product, such as the excipients, impurities, leachables, and the route of administration.  
The safety of chemicals derived from a delivery system, including leachables should be addressed 
based on levels detected during stability testing and under the proposed conditions of use.10  FDA 
encourages sponsors to consult the appropriate review division to discuss whether toxicity testing 
is recommended for their drug products. 
 
As discussed in section III.A., Recommended Studies and Application Type to Support 
Approval, in certain cases, a sponsor can rely on FDAs finding of safety and effectiveness for a 
drug product approved under section 505(c) of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) to the extent the products share characteristics.  An application for an NRT drug 
product that is the same as an approved product in many respects (including active ingredient, 
 
9 Relapse is defined as return to smoking after cessation. 
 
10 The sponsor should consult the appropriate review division for feedback on a proposed nonclinical development 
plan.  For more information on considerations for an NRT drug product with an oral inhalation route of 
administration, see the guidance for industry Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug 
Products.  
  3  Contains Nonbinding Recommendations 
 
dosage form, strength, route of administration, and, with certain exceptions, labeling) and 
bioequivalent to the approved product can be submitted as an abbreviated new drug application 
(ANDA) under section 505(j) of the FD&C Act.  In addition, an application for an NRT drug 
product in a new drug application (NDA) submitted pursuant to section 505(b)(2) of the FD&C 
Act may rely, in part, on FDAs findings of safety and effectiveness for an approved product, 
provided the application establishes that such reliance is scientifically appropriate (e.g., by 
demonstrating sufficiently similar bioavailability) and includes data to support any aspects of the 
proposed NRT product that represent modifications to the approved product relied upon.  A 
505(b)(2) application may or may not require clinical trials to establish safety or effectiveness, 
depending on the drug products characteristics.11  FDA anticipates that most sponsors will 
submit marketing applications for NRT drug products using one of these regulatory pathways. 
 
Although the systemic effects of nicotine are well characterized, there are many sources of 
variability in the effectiveness of specific regimens and drug products.  Additionally, innovations 
such as a new route of administration may raise different safety questions, such as local tissue 
tolerability.  Therefore, in general, FDA recommends two adequate and well-controlled trials to 
demonstrate that an investigational NRT drug product with characteristics different from an 
approved NRT drug product is effective for smoking cessation or reduction in risk of relapse.  For 
drug products that have different characteristics, an NDA under section 505(b)(2) of the FD&C 
Act or an NDA under section 505(b)(1) of the FD&C Act (containing full reports of 
investigations of safety and effectiveness that were conducted by or for the sponsor or for which 
the sponsor has a right of reference), will generally be necessary. 
 
FDA considers tobacco dependence to be a serious or life-threatening condition.  The Agency 
determines on a case-by-case basis whether an NRT drug product meets the criteria (e.g., 
significant improvement over existing therapies, address an unmet medical need) for inclusion in 
FDAs expedited development and review pathways.12  FDA encourages a sponsor that believes 
its drug product represents a significant improvement over approved NRT drug products to 
consult FDA early in the development program to discuss whether the drug product may be 
eligible for review under one of the expedited pathways. 
 
 
11 Under these abbreviated approval pathways, in general, a sponsor can rely on FDAs finding of safety and 
effectiveness for a drug product approved under section 505(c) of the FD&C Act to the extent the products share 
characteristics.  An application submitted under the pathway described in section 505(b)(2) of the FD&C Act may 
rely on published literature or FDAs finding of safety and effectiveness for an approved drug, when certain 
requirements are met.  See the draft guidance for industry Applications Covered by Section 505(b)(2) (October 1999).  
When final, this guidance will represent the FDAs current thinking on this topic.  For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents. 
 
12 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014). 
  4  Contains Nonbinding Recommendations 
 
If the NRT drug product includes a device constituent part or parts to enable use of the drug 
product, FDA generally would regulate the drug product as a drug-device combination product 
with the Center for Drug Evaluation and Research (CDER) as the lead regulatory center.13  
 
Sponsors should address issues related to the device constituents to establish the safety and 
effectiveness of the drug-device combination product as a whole.14  
 
A.  Recommended Studies and Application Type to Support Approval 
 
Sponsors developing NRT drug products should consider the following regarding recommended 
studies and types of drug applications. 
 
1.  Investigational NRT Drug Products That Rely on an Approved NRT Drug Product 
 
a.  Generic versions of approved NRT drug products 
 
For an investigational NRT smoking cessation drug product that has the same active ingredient, 
dosage form, strength, route of administration, and, with certain exceptions, labeling, as an 
approved reference NRT drug product, comparative bioavailability pharmacokinetic (PK) studies 
can be conducted to confirm that the investigational NRT drug product is bioequivalent to the 
approved reference listed NRT drug product.  For these drug products, provided they are 
bioequivalent, FDA believes that additional clinical efficacy trials are not needed if the 
investigational drug product does not claim any additional benefit or superiority over the 
reference drug product.  The sponsor should submit an ANDA to support approval of such a drug 
product.15  
 
13 The term combination product is defined at 21 CFR 3.2.  A combination product is comprised of any combination 
of a drug, device, and biological product constituent parts.  See 21 CFR 4.3. The center with primary jurisdiction 
(the lead) for premarket review and regulation of a combination product is assigned based on which constituent part 
provides the combination products primary mode of action (PMOA) (i.e., makes the greatest contribution to the 
combination products overall intended therapeutic effect (see 21 U.S.C. 353(g)(1)(C), 21 CFR 3.2)).  For example, 
an NRT combination product composed of a drug product and of a device that serves to deliver the drug product 
would have a drug PMOA, and CDER would have the lead for the combination products regulation.  Examples of 
such NRT combination products would include transdermal patches and e-cigarettes containing or copackaged with 
a drug.  For such combination products, in general, CDER will be the point of contact and will coordinate with 
CDRH as well as OCP as appropriate to ensure utilization of relevant expertise and consistency of regulatory 
treatment.  OCP is also available to assist sponsors, as needed, in identifying appropriate contact points (including 
those in the lead center), resolving substantive issues, or otherwise facilitating interactions with the Agency and 
collaboration among Agency components. 
 
14 For example, delivery device constituent parts should be shown to be suitable for use with the final formulation of 
the drug constituent part including, in some cases as appropriate, through extractable and leachable studies, 
performance testing, and stability studies.  In addition, in vitro performance testing data may be needed to support 
the delivery device constituent part of the proposed combination product and design validation of the combination 
product.  For additional guidance and information regarding regulatory considerations for combination products, see 
the Office of Combination Products web page at https://www.fda.gov/about-fda/office-clinical-policy-and-
programs/office-combination-products. 
 
15 FDA encourages sponsors that intend to submit an ANDA to consult FDAs product-specific guidances for 
demonstrating bioequivalence for generic nicotine-containing drug products for additional information.  Check the 
FDA product-specific guidance web page at https://www.accessdata.fda.gov/scripts/cder/psg/index.cfm.  
  5  Contains Nonbinding Recommendations 
 
 
For drug products for smoking cessation that otherwise would meet the requirements for an 
ANDA relying on an approved NRT drug product but are intended to have advantages over 
approved NRT drug products, as expected for designation for expedited development programs 
(e.g., superior effectiveness, improved safety), sponsors should demonstrate these improvements 
in head-to-head clinical trials.  In general, demonstrating shorter time to maximum plasma 
concentration (more rapid PK), alone, is not sufficient to qualify the drug product for expedited 
development programs.  The sponsor should submit a 505(b)(2) NDA to support approval of such 
a drug product.16  
 
b.  Drug product modifications that alter the delivery of nicotine 
 
Currently, the available NRT drug products approved for smoking cessation use either a 
transdermal or transmucosal route of delivery, including delivery by the nasal mucosa (nasal 
sprays) or the oral mucosa.17   
 
Certain NRT drug products may have the same route of administration (e.g., buccal), but the drug 
products may differ in the method an individual uses to self-administer the nicotine.  For example, 
both a chewing gum and a mouth spray are oral-transmucosal products, but the nicotine delivery 
from some types of chewing gum may be actively controlled by the consumers chewing process, 
allowing a single chewing gum piece to deliver multiple doses, while a mouth spray would need to 
be redosed from the dispenser.  Even two products that seem very similar (e.g., chewing gum 
pieces) may require different behaviors from the consumer to control self-administration.  For 
purposes of reviewing these drug products, FDA will refer to these drug products as having 
different modes of administration.  For example, a proposed different mode of administration for 
an NRT gum product for smoking cessation could involve a new18 method of user extraction, 
such as instructing users to chew the gum product as a conventional gum (swallowing the liquid), 
instead of instructing users to repeat a process of chewing and then placing the piece of gum 
product between their cheek and gums, as is set forth in the labeling for currently approved NRT 
gum products for smoking cessation.  
 
For sponsors seeking approval for a drug product, the amount of data necessary to support 
approval will depend on the extent to which the new drug product is similar to an approved drug 
product. 
 
 
16 Sponsors should note that an approved product will not receive 3-year exclusivity for bioavailability studies.  See 
section 505(c)(3)(E)(iii) of the FD&C Act and 21 CFR 314.108. 
 
17 Oral-transmucosal products are generally listed in FDAs Approved Drug Products With Therapeutic Equivalence 
Evaluations (commonly known as the Orange Book) as oral inhalants, oral troches/lozenges, or buccal chewing gums.  
The Orange Book is available at https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm. 
 
18 As used in this guidance, the term new is used when describing drug product characteristics that FDA has not 
previously approved for an NRT drug product. 
  6  Contains Nonbinding Recommendations 
 
Same route of administration and product type, different mode of administration 
 
If a sponsor proposes to develop a drug product with the same route of administration as an 
approved NRT drug product but that alters the mode of administration compared to that product 
(e.g., gums with buccal route of administration but different modes of administration  chewing 
the gum product as a conventional gum versus chewing the gum product and placing it in the 
cheek, as described above), the Agency anticipates that no efficacy trials would be needed for 
these types of NRT drug products and that sponsors would be able to submit a 505(b)(2) NDA if 
the pharmacokinetics are sufficiently similar to the approved product.  
 
Sponsors may be able to rely on a previous Agency finding of safety and efficacy for a reference 
NRT drug product, if the application establishes that such reliance is scientifically appropriate 
(e.g., confirm via PK studies that the investigational NRT drug product provides sufficiently 
similar venous plasma levels of nicotine) and novel formulation-specific (e.g., local safety) issues 
are addressed.   
 
Same route of administration, different product type 
 
If a sponsor proposes to develop an NRT drug product with the same route of administration but  
a different product type (e.g., an oral spray referencing an approved product that is chewed), the 
Agency anticipates that the application could rely, for the purposes of establishing systemic 
safety of nicotine, on a previous Agency finding of safety as above, but would need to establish 
the product could be used effectively through at least one adequate and well-controlled clinical 
trial. 
 
c.  Different instructions for use 
 
If the investigational NRT drug product is similar to an approved NRT drug  product, but the 
sponsor proposes instructions for use that are different from the reference NRT  drug product 
(e.g., instructions for a new use regimen for achieving smoking cessation), the  Agency 
anticipates that the sponsor would need to submit either a 505(b)(2) NDA or a full  505(b)(1) 
NDA.  FDA would expect the sponsor to conduct a PK study and one or more clinical efficacy 
trials.  For example, in cases where the investigational NRT drug products active  ingredient and 
route of administration are otherwise the same as those of an approved NRT drug product, but the 
drug product proposes a different treatment regimen (e.g., quitting by gradual  reduction, or a 
longer duration of use), a single adequate and well-controlled efficacy trial and appropriate PK 
bridging  studies may suffice.19  For a proposed nonprescription NRT drug product, in addition to 
the other investigations that would be necessary to demonstrate effectiveness in the prescription 
setting, the development program should include an actual-use efficacy trial (see section III.C.2., 
Sequential Approach for Development of Nonprescription Drug Products).  As discussed below, 
for these nonprescription NRT drug products, FDA recommends an incremental approach leading 
up to the actual-use efficacy trial.  
 
 
19 In limited cases where a sponsor demonstrates an NRT drug products bioequivalence to an approved NRT drug 
product with a very similar dosage form using the intended dosing regimen, FDA may not request efficacy studies. 
  7  Contains Nonbinding Recommendations 
 
2.  NRT Drug Products That Are Significantly Different From Approved NRT Drug 
Products 
 
a.  New route of administration 
 
NRTs are currently approved with the following routes of administration: transdermal, oral (via 
mucosa), buccal, and nasal (via mucosa).  For investigational NRT drug products that introduce a 
new route of administration (e.g., enteral or pulmonary20), FDA anticipates that more than one 
adequate and well-controlled clinical trial could be needed to characterize effectiveness.  PK 
studies comparing the product to an approved product generally would not be adequate to 
demonstrate efficacy because the relationship of venous plasma levels and smoking cessation 
effectiveness is likely to be substantially different from approved NRT drug products and 
effectiveness cannot be predicted.21  Sponsors of drug products with a new route of administration 
will generally need to submit a 505(b)(2) NDA or a full 505(b)(1) NDA. 
 
b.  New indication 
 
Currently, all approved NRT drug products are indicated as aids to smoking cessation.  Some 
sponsors of NRT drug products may also seek to demonstrate effectiveness for reduction in risk 
of relapse in former smokers. 
 
Sponsors of approved NRT drug products (i.e., approved for smoking cessation) that seek to add 
a reduction in risk of relapse indication should conduct one clinical efficacy trial in a population 
of recent quitters (i.e., smokers who have quit within the past month).  The data supporting the 
drug products previous approval as a cessation treatment can serve as confirmatory evidence of 
the drug products effectiveness.22  These sponsors should submit an efficacy supplement for 
approval of the new indication.  See section III.C.5.a., Reduction in risk of relapse, for discussion 
of primary endpoints. 
 
A sponsor seeking an indication for reduction in risk of relapse for a new (not previously 
approved for smoking cessation) NRT drug product should conduct two clinical efficacy trials in 
a population of recent quitters.  Sponsors of drug products proposing such a new indication will 
generally need to submit a 505(b)(2) NDA or a full 505(b)(1) NDA. 
 
3.  Secondary Endpoints 
 
Sponsors may also seek to include information about secondary endpoints in the NRT drug 
products labeling for a drug product that has already demonstrated effectiveness in cessation or 
reduction in risk of relapse.  Such secondary endpoints could include a reduction in the urge to 
 
20 For example, electronic nicotine delivery system (e-cigarettes) or other inhaled product. 
 
21 For additional guidance on the nonclinical safety information that FDA expects to be necessary to support the 
development of orally inhaled nicotine-containing drug products, see the guidance for industry Nonclinical Testing 
of Orally Inhaled Nicotine-Containing Drug Products.  
 
22 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological 
Products (May 1998). 
  8  Contains Nonbinding Recommendations 
 
smoke or relief of cue-induced craving in former smokers, using patient-reported outcome (PRO) 
instruments adequately developed for this purpose.23  
 
NRT drug products help smokers to quit smoking by ameliorating the acute symptoms of 
nicotine withdrawal, including nicotine craving associated with quitting smoking, by providing 
pharmaceutical nicotine.  Currently approved NRT drug products that have demonstrated 
effectiveness as an aid to smoking cessation may be labeled for relief of withdrawal symptoms in 
patients who are trying to quit smoking.  Additionally, a sponsor that can demonstrate, as a 
secondary endpoint, that the drug product provides relief of withdrawal symptoms in smokers 
who are not trying to quit smoking, may be able to include labeling instructions to cover 
situations in which such individuals are required to abstain and experience withdrawal (e.g., 
while traveling on an airplane).  Given the current lack of scientific consensus on how to 
establish a clinically relevant effect on withdrawal symptoms alone, FDA does not envision that 
relief of withdrawal symptoms would be granted as a stand-alone indication for an NRT drug 
product that has not been shown to be effective as an aid to smoking cessation. 
 
FDA expects that a sponsor evaluating secondary endpoints for an NRT drug product could 
demonstrate effectiveness in a single clinical trial.  The trials sample size should be large enough 
to provide sufficient power to show a treatment effect on the secondary endpoints.24  A sponsor 
seeking to include information about secondary endpoints in the labeling of an approved NRT 
drug product should submit an efficacy supplement to the NDA with supporting data as  described 
in section III.C.5., Other Efficacy Endpoints. 
 
B.  General Considerations: Early Phase Clinical Development 
 
In the phase 1 program, the sponsor should enroll healthy nicotine-experienced adults (typically, 
current smokers) and characterize the PK profile of the drug product and any sources of 
variability (e.g., user technique) to provide information to determine the recommended dose, 
interdose interval, instructions for use, etc.  This part of the program should usually compare the 
pharmacokinetics of the drug product to that of an approved NRT drug product.  For some drug 
products, the phase 1 program may include bioavailability comparisons to more than one 
approved drug product.  In certain cases, when the PK profile for the investigational NRT drug 
product falls between the profiles for two approved NRT products, the sponsor can apply a 
bracketing strategy.  Using this approach, the application may rely in part on the Agencys 
previous finding of safety for the higher nicotine exposure drug product and, in part, on  the 
Agencys previous finding of effectiveness for the lower nicotine exposure drug product.  FDA 
notes that the sponsors ability to use the bracketing approach depends on the shape of the  PK 
curve and the similarity of the drug products being bracketed. 
 
Early phase clinical development for NRT drug products should characterize drug activity for a 
range of nicotine doses.  Dose-ranging studies are generally performed in phase 2 trials.  The 
 
23 See the guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product Development to 
Support Labeling Claims (December 2009). 
 
24 Sponsors should consult the guidance for industry Multiple Endpoints in Clinical Trials (October 2022) for 
guidance on designing a clinical trial that is sufficiently powered to evaluate secondary endpoints.  
  9  Contains Nonbinding Recommendations 
 
sponsor should characterize the investigational NRT drug products pharmacokinetics and 
toxicity in a broad population of smokers, without excluding those with comorbidities and those 
at higher risk of experiencing adverse events (e.g., smokers with hepatic, renal, pulmonary, or 
other organ impairment, smokers on certain psychiatric medications).  If the information is not 
available by reference to other approved drug products or literature, drug-drug interaction studies 
may be needed to assess the safety of concomitant use with medications commonly used in the 
target population, including other smoking cessation medications.  Specific safety studies related 
to the route of administration (e.g., dermal sensitization, oral mucosal safety, effect of high-pH or 
low-pH beverages), expected duration of therapy, or drug product novelty may also be needed for 
some NRT drug products. 
 
Certain flavors (e.g., menthol) could affect absorption of nicotine or modify the way that the 
consumer uses the product; either of these can affect the pharmacokinetics of the product. If 
several flavors are planned, the PK effect of the flavorings should be evaluated. This is 
particularly important for menthol flavors.  In addition, we do not recommend use of flavor 
names that might be appealing to nonsmokers or encourage use of the product for reasons other 
than to quit smoking (e.g., alcoholic beverage flavor names). 
 
In planning comparative bioavailability studies, sponsors should first understand the single-dose 
pharmacokinetics and pharmacodynamics of the product and determine an appropriate multidose 
regimen that is related to the duration of action of the product.  Using a regimen specifically 
chosen to yield results bioequivalent to an approved product instead of conducting efficacy or 
safety studies may not be appropriate if that regimen does not reflect how consumers will use the 
product. If sponsors include in proposed labeling a dose and dosing regimen that suggests 
bioequivalence to an approved regimen, the regimen for the new product should reflect expected 
actual use and be related to the duration of action of the investigational drug product.  If not, 
users are unlikely to follow the instructions. 
 
C.  General Considerations: Efficacy Trials 
 
For applications requiring an efficacy trial, consider the following: 
 
1.  General Efficacy Trial Design for All NRT Drug Products 
 
The sponsor should compare the investigational NRT drug product to placebo in a randomized, 
double-blind trial design.  The placebo should be indistinguishable from the  investigational NRT 
drug product in all relevant aspects (appearance, taste, texture, etc.).  For  NDAs for drug 
products intended to be advancements or improvements over existing therapy (as discussed in 
section III.A.1.a., Generic versions of approved NRT drug products), sponsors may  be able to 
use an approved NRT drug product as the active comparator in the head-to-head trial 
demonstrating superiority to active control, if there are no outstanding questions about the safety 
of the investigational NRT drug product.  If questions remain about the safety of the 
investigational NRT drug product, the trial design should also include a placebo control. 
 
Subjects should be randomized to treatment with the investigational NRT drug product or 
control(s).  Sponsors should document a rationale for the number of doses and regimens being 
  10  Contains Nonbinding Recommendations 
 
studied, to address the various populations of smokers.  If the intent is that smokers will use the 
drug product for a longer term (e.g., for reduction in risk of relapse), sponsors should test more 
than one dose and document a justification for each dosage level.  Enrollment may be stratified 
based on the number of previous quit attempts, the number of cigarettes used per day, or the 
severity of dependence to ensure representation across categories.  For adult subjects, measures 
such as baseline scores on the Fagerstrom Test of Nicotine Dependence or the time-to-first- 
cigarette method can be used for treatment allocation when stratifying by severity of  dependence.  
Trial visits should occur at approximately weekly intervals for monitoring of  adverse events and 
collection of efficacy data. 
 
At efficacy ascertainment visits, the subject should be queried about any smoking since the last 
trial visit, and biological markers of smoking or tobacco exposure should be collected.  The use of 
other smoking cessation drugs and any non-study nicotine or tobacco products should be 
recorded.  At a minimum, exhaled breath carbon monoxide (CO) should be assessed.  FDA 
encourages incorporation of other markers that can differentiate exposure to tobacco from 
exposure to NRT drug products.  For investigational NRT drug products with novel delivery 
systems, it may be necessary to demonstrate that customary tests such as exhaled CO are 
unaffected by use of the drug product and/or placebo. 
 
2.  Sequential Approach for Development of Nonprescription Drug Products 
 
Sponsors developing a nonprescription drug product should bear in mind that it is often not 
possible to answer all regulatory questions in a single trial.  Therefore, the development program 
for these NRT drug products may include several trials to identify and refine the proper dosing 
regimen and self-help materials before undertaking the real-world or actual-use trial that would 
support approval. 
 
The sponsor should develop a label that it believes may be close to the to-be-marketed Drug 
Facts label and test that label in a label comprehension study.  The label comprehension testing 
process should be iterative and should lead to the development of the best understood label.25  If 
the drug product has instructions for use, these should be tested in a human factors study to 
demonstrate that consumers can understand the instructions on how to use the drug product.26  
 
Label comprehension and human factors studies should be conducted at the early stages of 
development because if the NRT drug product package (e.g., product/regimen, self-help 
materials) does not perform as expected, the source of failure may be difficult to determine. 
Furthermore, subsequent changes to the drug product may require retesting in additional clinical 
trials. 
 
Sponsors should then provide clinical trial subjects with a package containing the NRT drug 
product with the planned Drug Facts label, along with any instructions or self-help materials that 
 
25 See the guidance for industry Label Comprehension Studies for Nonprescription Drug Products (August 2010). 
 
26 Regarding NRT combination products, see the draft guidance for industry and FDA staff Human Factors Studies 
and Related Clinical Study Considerations in Combination Product Design and Development (February 2016).  
When final, this guidance will reflect FDAs current thinking on this topic. 
  11  Contains Nonbinding Recommendations 
 
are intended to be marketed with the drug product.  An efficacy trial that features assistance from 
trial staff to ensure that the subjects follow directions on the label provides evidence that the drug 
product, when properly used, is effective.  However, at least one efficacy trial should involve an 
all-comers population (e.g., any person who self-selects to use the product) where no training and 
education on how to use the drug product is  provided by the clinical trial staff.  This real-world 
or actual-use trial is intended to provide  evidence that consumers can use the drug product 
effectively and safely based on the label  without assistance. 
 
In general, it is desirable that the nonprescription development program proceeds in the following 
incremental and sequential fashion: formative label comprehension study; formative human 
factors study (if relevant); clinical trial with training/education from trial staff; pivotal label 
comprehension and human factors studies with the refined labeling utilizing clinical trial results; 
actual-use trial with no training or education from trial staff.  One or more self-selection studies 
may also be necessary at some point in development to evaluate if the drug product use would be 
limited to the intended population (such as those looking to quit smoking, rather than 
nonsmokers) and/or to populations for whom a drug product would not be contraindicated.27  
Note that depending on the particulars of the drug product, the sponsor may be able to 
incorporate a self-selection component into a real-world or actual-use trial. 
 
3.  Study Population 
 
In general, phase 3 clinical trials for an NRT drug product indicated for smoking cessation should 
study active smokers 18 years of age and older who wish to quit smoking, including subjects 
with comorbidities similar to those of the target population for the NRT drug product.  In some 
circumstances, sponsors can consider setting study inclusion criteria that subjects use a certain 
minimum number of cigarettes per day at baseline.  This may be the case, for example, if an 
investigational NRT drug product provides a nicotine dose that exceeds the nicotine delivered by 
light smoking.  Efficacy trials for certain indications may need a population of recent quitters, 
regardless of the method used. For discussion of studies in pediatric populations, see section 
III.D.1., Pediatric Populations. 
 
Please refer to the draft guidance for industry Diversity Plans to Improve Enrollment of 
Participants From Underrepresented Racial and Ethnic Populations in Clinical Trials (April 
2022)28 for recommendations on developing a Race and Ethnicity Diversity Plan to enroll 
representative numbers of participants from underrepresented racial and ethnic populations in the 
United States in clinical trials. 
 
4.  Cessation Efficacy Endpoints 
 
The endpoint for a smoking cessation trial is the proportion of subjects who are abstinent from 
cigarette use over the entire efficacy ascertainment period.29  A trial is considered to demonstrate 
 
27 See the guidance for industry Self-Selection Studies for Nonprescription Drug Products (April 2013). 
 
28 When final, this guidance will represent the FDAs current thinking on this topic.   
 
29 Note that the sponsor can allow for a grace period before the beginning of the efficacy ascertainment period. 
Subjects who smoke only during the grace period could be adjudicated as quitters. 
  12  Contains Nonbinding Recommendations 
 
effectiveness if significantly more subjects achieve abstinence when treated with the 
investigational NRT drug product as compared to subjects treated with the placebo.  However, 
FDA will take the size of the effect into consideration during its benefit-risk assessment. 
 
In general, abstinence is defined as no cigarette use over the entire course of the efficacy 
ascertainment period by subject self-report and biological verification at intervals of 
approximately 1 to 2 weeks.  A longer interval between self-reporting and verification visits may 
be acceptable in some instances (e.g., trials that are more than 3 months long).  For trials with 
longer efficacy ascertainment periods of 6 or 12 months, sponsors can consider defining 
abstinence to incorporate a maximum allowable number of cigarettes.30  The efficacy 
ascertainment period generally runs from the first day of treatment to the last day of treatment. 
The duration of the efficacy ascertainment period should be sufficient to justify the intended 
duration of treatment.  Thus, an investigational NRT drug product that a sponsor intends to label 
as a 6-month course of treatment should be supported by 6 months of documented abstinence.  If 
the effect of the treatment is not expected to result immediately upon initiation of the drug 
product because of the mechanism of action, pharmacokinetics, or other factors, then efficacy 
ascertainment can take place over a period that begins after a protocol-specified grace period. 
The sponsor should justify the duration of any such grace period. 
 
FDA recommends a minimum 4-week period of efficacy ascertainment.  The proportion of 
subjects abstaining for less than 4 weeks is not considered informative because such short 
periods of abstinence are not known to confer health benefits.  Similarly, a floating period of 
efficacy ascertainment (e.g., any 4 consecutive weeks) is not considered informative because 
subjects who relapse while still on treatment cannot be viewed as successful quitters. 
 
Subjects reporting use of non-study nicotine or smoking cessation products should be 
adjudicated as nonresponders (e.g., nonquitters) for the purposes of evaluating the therapeutic 
effect of the study drug under the relevant protocol. 
 
5.  Other Efficacy Endpoints 
 
a.  Reduction in risk of relapse 
 
Sponsors seeking a reduction in risk of relapse indication should provide evidence from clinical 
trials showing that recent quitters (i.e., smokers who have quit within the past month), regardless 
of the method used, even without the use of NRT or other medications (cold turkey), can benefit 
from a course of treatment with the NRT drug product to reduce the risk of relapse.  The clinical 
trials intended to support this maintenance indication should have the definition of relapse 
prespecified in the protocol, an ascertainment window, at a minimum, of 6 months to 1 year, and 
use the proportion of trial subjects not relapsing as the primary endpoint.31  
 
 
30 See, for example, the Russell Standard as described in Robert West et al., 2005, Outcome Criteria in Smoking 
Cessation Trials: Proposal for a Common Standard, Addiction, 100(3):299303. 
 
31 Ibid. For example, sponsors may consider a study design where treatment success is defined as smoking no more 
than five cigarettes during the efficacy ascertainment period. 
  13  Contains Nonbinding Recommendations 
 
For example, these clinical trials could have a double-blind, placebo-controlled design in which 
recent quitters are randomized to treatment or placebo, then followed for the efficacy 
ascertainment period for evaluation of relapse.  Alternatively, a randomized withdrawal design 
could be employed, in which responders to an open label period of treatment with the drug 
product are randomized to continue on the drug product or to blindly switch to a matching 
placebo, then followed for the efficacy ascertainment period for evaluation of relapse. 
 
b.  Reduction in urge to smoke and relief of cue-induced craving in former 
smokers 
 
Former smokers, even those with a long period of successful abstinence from smoking, can have 
episodes in which they experience uncomfortable feelings of a desire to smoke.  These episodes 
may be provoked by circumstances or cues that have been previously associated with smoking. 
Even in successful abstainers at low risk for relapse, the experience of these provoked urges or 
cravings are unpleasant and can be a target for treatment. 
 
Drug products that have already demonstrated effectiveness in smoking cessation or reduction in 
risk of relapse may be able to include information in labeling about effectiveness in relieving the 
urge to smoke and cue-induced cravings in populations of former smokers based on suitable 
trials.  Sponsors should identify or develop fit-for-purpose PRO instruments and recruit former 
smokers who report experiencing urges or cravings and who are interested in finding ways to 
relieve this symptom.32  
 
c.  Relief of withdrawal symptoms not associated with a cessation attempt 
 
Drug products that have already demonstrated effectiveness in smoking cessation or reduction in 
risk of relapse may be able to include information in labeling about effectiveness in relieving 
withdrawal symptoms not associated with a cessation attempt.  Sponsors seeking to establish 
their NRT drug products effectiveness in relieving withdrawal symptoms not associated with a 
cessation attempt can demonstrate this effect in behavioral pharmacology laboratory studies 
using suitably designed PRO instruments.33  
 
6.  New Regimens for Cessation and Reduction in Risk of Relapse 
 
NRT drug products may be used in a variety of ways to achieve smoking cessation or to reduce 
the risk of relapse.  FDA considers these to be treatment regimens, not separate indications.  Any 
treatment regimen that the sponsor believes may be effective for smoking cessation or reduction 
in risk of relapse can be evaluated in randomized, double-blind trials of the design described 
above.  This includes regimens in which subjects gradually reduce their smoking over time while 
using the drug product (i.e., reduce to quit) and regimens in which the drug product is introduced 
 
32 For additional guidance on selecting endpoints, see the guidance for industry Multiple Endpoints in Clinical 
Trials.  For additional guidance on developing validated PRO instruments, see the guidance for industry Patient-
Reported Outcome Measures:  Use in Medical Product Development to Support Labeling Claims. 
 
33 For guidance on development of measures for assessing PROs, see the guidance for industry Patient-Reported 
Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 
  14  Contains Nonbinding Recommendations 
 
before the subjects planned quit day (i.e., pretreatment), or other regimens the sponsor may wish 
to study.  In each case, the recommended design and endpoints are as described above. 
 
The sponsor should give careful attention to providing clear instructions to trial subjects on how 
to follow new regimens.  Phase 2 initial trials and label comprehension studies (for 
nonprescription drug products) of the appropriateness of the instructions are likely to be needed. 
 
Clinical trials to demonstrate the effectiveness of a particular combination of NRT drug products 
should employ randomized, double-blind, double-dummy, factorial design.  The contribution of 
each component to the effectiveness should be demonstrated.34  The design and endpoints for 
such trials are as described above.  Sponsors should evaluate the optimal dose combinations in 
phase 2 trials before undertaking definitive trials. 
 
As described above in section III.C.2, Sequential Approach for Development of Nonprescription 
Drug Products, drug products with alternative regimens being developed for nonprescription use 
should demonstrate effectiveness of the alternative regimen in an actual-use efficacy trial. 
 
Sponsors interested in studying new NRT regimens (for prescription or nonprescription use) or 
combination of NRT drug products for smoking cessation should contact the CDER Division of 
Anesthesia, Analgesia, and Addiction Products or the Office of Nonprescription Drugs and the 
Office of Device Evaluation in the Center for Devices and Radiological Health, as appropriate, to 
discuss the development plan for the drug product. 
 
D.  Other Considerations 
 
1.  Pediatric Populations 
 
To comply with the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c),35 an NDA for a 
new active ingredient, new indication, new dosage form, new dosing regimen, or new route of 
administration must contain data that are adequate to assess the safety and effectiveness of the 
drug for the claimed indication(s) to support dosing and administration in all pediatric 
subpopulations unless the requirement is waived or deferred.  The sponsor must submit an initial 
pediatric study plan  outlining the studies it plans to conduct in the pediatric population  and 
addressing any plans for waiver, partial waiver, or deferral requests of PREA-required trials  no 
later than 60 days after the end-of-phase 2 meeting, unless FDA and the sponsor agree upon 
another submission date.36  Sponsors should consult the guidance for industry Pediatric Study 
Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial 
Pediatric Study Plans (July 2020).  
 
FDA encourages development of alternative products and treatment modalities for smoking 
cessation and vaping cessation in youth, both of which are outside the scope of this guidance. 
 
34 See 21 CFR 300.50. 
 
35 See PREA (Public Law 108-155; section 505B of the FD&C Act; 21 U.S.C. 355c). 
 
36 See section 505B(e) of the FD&C Act. 
  15  Contains Nonbinding Recommendations 
 
 
The initial pediatric study plan for NRT drug products for smoking cessation or related 
indications should include an  up-to-date estimate of the size of the pediatric smoking population, 
the use of NRT drug products and smoking cessation services by adolescents, and the feasibility 
of conducting clinical studies with the NRT drug product in the pediatric population.37  Based on 
the current prevalence of smoking in younger children, the Agency has waived the PREA 
requirements for clinical studies of NRT drug products in patients younger than 12 years of age 
because clinical studies would be highly impracticable in that age group.  However, the Agencys 
thinking may change, and any request for waiver of clinical studies in any specific pediatric age 
group should include appropriate justification(s).  If the Agency determines that studies are highly 
impracticable in pediatric patients 12 years of age and older, or data are submitted that support a 
different waiver criterion under PREA, the Agency may also grant a waiver of PREA studies in 
this population. 
 
Efficacy data from adult subjects cannot be extrapolated to pediatric patients because of 
differences, such as patterns of tobacco use and nicotine dependence, between adult and pediatric 
smokers.  Thus, if a pediatric assessment in a pediatric population is required, effectiveness should 
be established in the relevant pediatric age cohort.  Dose selection in pediatric patients should be 
based on adolescent PK data, and any PRO instruments should be fit-for-purpose in the adolescent 
population. 
 
PREA-required studies are based on the indication(s) approved or sought in adults.  Interested 
sponsors may also submit a proposed pediatric study request for the Agency to issue a written 
request for pediatric data for pediatric studies under the Best Pharmaceuticals for Children Act as 
described in section 505A(d)(1)(A) of the FD&C Act; 21 U.S.C. 355a(d)(1)(A). 
 
2.  Behavioral Counseling 
 
Behavioral counseling, if provided, should be standardized.  In addition, for pediatric patients, 
behavioral counseling should be developmentally appropriate and intended for this pediatric 
population.  For a prescription medication, the counseling provided should be feasible for 
delivery in a typical primary care setting.  Behavioral counseling can be provided at trial visits, 
but the sponsor should define behavioral counseling in the protocol, and it should be standardized 
across sites.  If more complex or extensive behavioral programs are included, the sponsor can 
consider marketing the drug product as an adjunct to the specific behavioral treatment studied.  If 
behavioral counseling is provided in conjunction with a drug product intended for nonprescription 
marketing, the behavioral counseling should be in a self-help format that can  be marketed with 
the drug product. 
 
 
37 For additional guidance on PREA requirements, see the draft guidance for industry How to Comply with the 
Pediatric Research Equity Act (September 2005).  When final, this guidance will represent the FDAs current 
thinking on this topic. 
  16  Contains Nonbinding Recommendations 
 
3.  Statistical Considerations 
 
a.  Analysis populations 
 
Subjects who were exposed to any treatment, including those who received only self-help 
materials, and discontinued the trial without post baseline efficacy evaluations should be 
included in the intent-to-treat population as nonresponders (continuing smokers) for the primary 
endpoint.  The protocol should clearly describe the primary estimand of interest.38 
 
The safety population should include all randomized subjects who received at least one dose of 
the investigational NRT drug product and were evaluated for any on-treatment safety 
information.  Subjects who did not return for any on-treatment evaluations should be excluded 
from the denominator for the purposes of calculating rates of adverse events. 
 
b.  Missing efficacy data 
 
The protocol should explain how missing data will be addressed relative to the primary estimand 
and describe the plan for imputation of smoking status information for subjects with intermittent 
missing data.  Generally, in a trial with closely spaced efficacy ascertainment visits, the sponsor 
can consider a subject abstinent for a single missing visit if the subject had documented 
confirmed abstinence before and after the missing visit and self-reports abstinence at the time of 
the missing visit.  The sponsor should consider the subject nonabstinent if the subject misses two 
or more visits during the efficacy ascertainment period, if data for the subject are missing at the 
end of the period or if the subject withdraws from the trial before the end of the efficacy 
ascertainment period, regardless of smoking status at the time of withdrawal. 
 
4.  Clinical Benefit of Smoking Cessation 
 
Quitting smoking can lower a persons chances of having lung disease and heart disease and of 
getting certain types of cancer that are related to smoking.  For NRT drug products that have 
demonstrated effectiveness for cessation or reduction in risk of relapse, sponsors do not need to 
provide additional data to include information in the labeling about these therapeutic benefits of 
smoking cessation or maintaining abstinence from cigarettes. 
 
38 For guidance on estimands, see the ICH guidance for industry E9(R1) Statistical Principles for Clinical Trials: 
Addendum:  Estimands and Sensitivity Analysis in Clinical Trials. 
  17