Nonallergic Rhinitis:  
Developing Drug 
Products for Treatment 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
September 2018 
Clinical/Medical 
 
   
Nonallergic Rhinitis:  
Developing Drug 
Products for Treatment 
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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
September 2018 
Clinical/Medical 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  GENERAL CONSIDERATIONS FOR DEVELOPMENT ......................................... 3 
A.  Patient Selection ............................................................................................................................. 3 
B.  Dose ................................................................................................................................................. 4 
C.  Trial Design .................................................................................................................................... 4 
D.  Formulation Issues ......................................................................................................................... 4 
E.  Evaluation ....................................................................................................................................... 5 
1. Assessment of Patient Compliance .................................................................................................. 5 
2. Assessment of Efficacy ..................................................................................................................... 5 
3. Assessment of Rescue Medication Use ............................................................................................ 6 
4. Adverse Event Recording ................................................................................................................. 6 
IV.  CONSIDERATIONS FOR PEDIATRIC DEVELOPMENT ....................................... 6 
  Contains Nonbinding Recommendations 
Nonallergic Rhinitis:   
Developing Drug Products for Treatment 
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 applicants of new drug applications and biologics 
license applications in developing drug products for the treatment of nonallergic rhinitis (NAR) 
in children and adults.2  The guidance discusses issues regarding the definition of a clinical 
phenotype, trial design, efficacy, and safety for new drug products under development.  In 
particular, the guidance addresses development programs for the treatment of vasomotor rhinitis 
(VMR), which is a subtype of NAR. 
 
This guidance does not contain discussion of the general issues of statistical analysis or clinical 
trial design.  Those topics are addressed in the ICH guidances for industry E9 Statistical 
Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 
Trials3 and the ICH draft guidance for industry E9(R1) Statistical Principles for Clinical Trials:  
Addendum:  Estimands and Sensitivity Analyses in Clinical Trials.4 
 
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 
                                                 
1 This guidance has been prepared by the Division of Pulmonary, Allergy, and Rheumatology Products in the Center 
for Drug Evaluation and Research at the Food and Drug Administration.  
 
2 For the purposes of this guidance, the term drug product is inclusive of the small or large molecule active moiety 
or moieties in the formulation, along with the delivery device, if applicable. 
 
3 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
 
4 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/RegulatoryInformation/Guidances/default.htm.  
  1  Contains Nonbinding Recommendations 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
II.  BACKGROUND 
 
The nomenclature and understanding of the pathophysiology of NAR continue to evolve.  The 
recommendations in this guidance are based on the Agencys current understanding of the 
definition of NAR and an assessment of important issues raised by the presumed heterogeneity 
of NAR.  In general, rhinitis is regarded as a condition characterized by one or more of the 
following nasal symptoms:  congestion, rhinorrhea, sneezing, and itching.  Mucosal 
inflammation may be present but is not necessarily a requirement for all forms of rhinitis.   
 
Rhinitis can be broadly divided into allergic and nonallergic forms.  Allergic rhinitis can be 
clinically defined as rhinitis characterized by typical history and physical exam findings, 
associated with positive evidence of immunoglobin E (IgE) sensitization to relevant 
environmental allergens.  Although specific allergic sensitivities may vary among individuals, 
the pathophysiology is attributed to the same set of chemical mediators.  More information on 
clinical development programs for allergic rhinitis can be found in the guidance for industry 
Allergic Rhinitis:  Developing Drug Products for Treatment. 
 
In contrast, NAR is less well defined.  For the purposes of this guidance, NAR refers to the 
remaining rhinitis patients who do not have positive evidence of IgE sensitization.  Both acute 
and chronic conditions are represented, driven by a wide variety of underlying mechanisms.  
Two major subtypes of NAR that have been described in the current literature are infectious 
rhinitis and vasomotor rhinitis (VMR).  Infectious rhinitis may range from self-limited rhinitis 
secondary to common viral upper respiratory infections to more severe disease caused by other 
pathogens, such as fungal infections in an immunocompromised patient.  In contrast, VMR is 
largely a diagnosis of exclusion.  Other causes of rhinitis, including infections, medications, or 
other inflammatory conditions, must be excluded.  VMR patients often cite increased sensitivity 
to certain stereotypical triggers (e.g., changes in temperature or humidity, airborne irritants, 
strong odors, and exercise), but the pathophysiology for these responses has yet to be fully 
understood. 
 
Less common forms of NAR that have been described include gustatory rhinitis, hormonal 
rhinitis, drug-induced rhinitis, atrophic rhinitis, nonallergic rhinitis with eosinophilia syndrome, 
and rhinitis associated with certain inflammatory immunologic disorders.  It is worth noting that 
the nomenclature for NAR subtypes is far from standard, and there may be overlap among the 
terms.  For the most part, there are no diagnostic tests for the multiple forms of NAR, and the 
diagnosis is usually made by a combination of history, physician and laboratory exam, and the 
absence of positive evidence for allergic sensitization. 
 
 
  2  Contains Nonbinding Recommendations 
III.  GENERAL CONSIDERATIONS FOR DEVELOPMENT 
 
The heterogeneity of NAR poses challenges for drug product development.  Designing a 
development program to address NAR as a single entity may pose issues of feasibility.  
Therefore, the Agency recommends that applicants focus on a specific NAR subtype.  Because 
VMR is thought to be one of the more common forms of noninfectious NAR, this guidance 
addresses clinical trial considerations for a VMR development program as an example.   
 
Depending on the NAR subtype of interest, alternative trial designs and other considerations may 
be relevant.  Given the relative lack of consensus at this time on the classification of NAR 
subtypes, preliminary studies to define and characterize other clinically relevant, reproducible 
phenotypes may be needed before the initiation of a formal clinical program for drug product 
development.  Observational and population-based studies may play a role in characterizing the 
natural history and epidemiology of the particular NAR subtype of interest, and mechanistic 
studies or challenge models may be important for elucidating pathophysiology.  These types of 
investigations, some of which may be beyond the typical scope of a development program for a 
specific drug product, might nevertheless be important for guiding patient selection and 
providing an appropriate context in which to evaluate the risk-benefit of a particular drug 
product.  
 
The Agency encourages applicants to consult the review division early in the development 
program for drug products intended for other subtypes of NAR. 
 
A.  Patient Selection 
 
Patient selection should reflect the NAR subtype of interest, and applicants should base the 
inclusion and exclusion criteria on clinically meaningful, accessible parameters (i.e., health care 
providers should be able to identify and diagnose patients with the NAR subtype of interest in a 
real-world setting).   
 
For VMR trials, the Agency recommends that patients have a history of VMR for a minimum of 
2 years before trial entry.  The Agency recommends documentation of a lack of sensitization to 
environmental allergens relevant to the geographical area of the trial either by negative skin 
testing (by prick or intradermal methods) or by adequately validated in vitro tests for specific 
IgE.  We suggest that these tests be performed during the 12 months before enrollment. 
 
A positive history of increased sensitivity to certain stereotypical VMR triggers (e.g., changes in 
temperature or humidity, airborne irritants, strong odors, and exercise) may be useful for 
screening patients.  However, there is both inter- and intra-patient variability with regard to 
specific VMR triggers, and many healthy individuals without rhinitis will experience acute 
rhinitis symptoms when exposed to similar, intense triggers.  Therefore, although a positive 
history can be helpful in corroborating a VMR diagnosis, the diagnosis cannot rely solely upon 
such history.   
 
  3  Contains Nonbinding Recommendations 
If an applicant intends to seek a VMR indication in the context of a specific trigger, the applicant 
should document sensitivity to that specific trigger for each patient and ensure adequate exposure 
to that trigger during the course of the trial. 
 
B.  Dose 
 
The goal of dose exploration is to identify the optimal dose and dosing frequency, balancing 
benefit with risk.  Dose selection should be based on clinically meaningful endpoints because 
pharmacodynamic markers may not be predictive.  Ideally, dose exploration should be conducted 
in a clinical trial in a real-world setting because other exposure models, such as nasal 
provocation challenges, may not be predictive of real-world clinical responses.  However, the 
utility of such models may vary depending on the subtype of NAR that is being studied.  The 
Agency encourages applicants to consult the review division to discuss the utility of alternative 
exposure models for a specific drug product development program. 
 
C.  Trial Design 
 
The following are general recommendations for efficacy and safety trials in noninfectious NAR.  
Other considerations specific to the NAR subtype of interest may be applicable and should be 
discussed with the review division early in the development program.  
 
  In general, applicants should conduct efficacy and safety trials under real-life conditions.  
However, as noted above in the discussion of dose exploration, alternative exposure 
models may be of use in certain situations, provided that there is evidence to support the 
models relevance to clinical responses in the real world. 
 
  We recommend double-blinded, placebo-controlled, parallel group trials for efficacy and 
safety, preferably with a placebo run-in period.  The run-in period serves to assess for a 
minimum level of compliance and symptom severity under real-life conditions. 
 
  For VMR, the suggested duration of the treatment period for efficacy assessment is at 
least 4 weeks.  The appropriate trial duration for other NAR subtypes may vary. 
 
  Patients with NAR may have concomitant allergic rhinitis.  Therefore, it is helpful for 
efficacy trials to be conducted during a time when relevant seasonal allergens are less 
abundant and therefore less likely to influence results of the trial. 
 
D.  Formulation Issues 
 
For intranasal products, FDA encourages applicants to provide information in the clinical trial 
protocol on the specific formulations used for both the to-be marketed product and the placebo.  
Information on the device used for administration should also be provided, if applicable.  We 
recommend key dose-ranging and efficacy and safety trials use the to-be-marketed formulation 
and device.  If not, the applicant should address how the safety and effectiveness of the studied 
formulation and/or device will be bridged to the to-be-marketed formulation and/or device.  If 
  4  Contains Nonbinding Recommendations 
bridging of one formulation to another is proposed, information about the formulation 
composition and trial lots should be included in the trial reports for the respective products. 
 
One particular consideration for VMR programs is formulation changes that alter the sensorial 
attributes of the drug product because patients with VMR often report sensitivity to scents and 
irritants.  As a result, formulation changes may alter the efficacy and safety of a drug product.  
The applicant should evaluate, on a case-by-case basis, the extent to which previous clinical data 
obtained with a different formulation can be used in support of a new formulation.   
 
E.  Evaluation 
 
1.  Assessment of Patient Compliance 
 
The trial protocol or trial report should provide information about how compliance with drug 
product use will be determined and documented throughout the trial and how noncompliance 
will be dealt with. 
 
2.  Assessment of Efficacy 
 
Patient-reported instantaneous and reflective total nasal symptom scores have been commonly 
used in clinical trials for various forms of rhinitis.  Instantaneous refers to symptoms within a 
limited time frame before the assessment (e.g., 1 hour or less) and reflective refers to the interval 
from the time of last assessment (e.g., 12 hours for morning and evening scoring).  These 
summed scores generally include the following four nasal symptoms:  rhinorrhea, nasal 
congestion, nasal itching, and sneezing rated on a 0 to 3 scale of severity.  Addition or deletion 
of symptoms to or from the total score can be appropriate, based on the mechanism of action of 
the product and the specific form of rhinitis of interest.  Such changes should be discussed with 
the review division.  FDA recommends patient-reported total nasal symptom scores as the 
primary measure of efficacy. 
 
A common nasal symptom rating system that has been used in clinical trials is the following 0 to 
3 scale: 
 
  0 = absent symptoms (no sign/symptom evident) 
 
  1 = mild symptoms (sign/symptom present but minimal awareness; easily tolerated) 
 
  2 = moderate symptoms (definite awareness of sign/symptom that is bothersome but 
tolerable) 
 
  3 = severe symptoms (sign/symptom that is hard to tolerate; causes interference with 
activities of daily living and/or sleeping) 
 
Regardless of the scoring system chosen, a detailed description of the symptom rating scale 
should be provided to patients.  This should include instructions on proper completion of the 
  5  Contains Nonbinding Recommendations 
symptom diary and definitions of the different categories in the scale.5  The protocol should 
define the primary estimand (i.e., the primary measure of treatment effect to be estimated in the 
clinical trial) and justify that the estimand can be estimated with minimal and plausible 
assumptions. 
 
3.  Assessment of Rescue Medication Use 
 
If rescue medications are allowed during the trial, the trial protocol should document how rescue 
medication use will be analyzed in the different treatment groups.  We recommend inclusion of a 
section in the clinical trial report that presents rescue medication use in the different treatment 
groups. 
 
4.  Adverse Event Recording 
 
We recommend that adverse events be recorded in a daily patient diary record, in addition to 
being elicited by trial staff at clinic visits. 
 
 
IV.  CONSIDERATIONS FOR PEDIATRIC DEVELOPMENT 
 
The pediatric age ranges proposed for a drug product, particularly for young patients, should be 
justified by the applicant based on the presence of disease and the need for treatment in that age 
group.  The occurrence of different types of noninfectious NAR, including VMR, in younger 
pediatric patients is uncertain.  For topical drug products, the appropriateness of the delivery 
system for the proposed age range is an additional consideration.  We encourage applicants to 
discuss the specifics of pediatric programs as early as is feasible with the division on a case-by-
case basis because applicants are required to submit pediatric study plans under the Pediatric 
Research Equity Act no later than 60 days after an end-of-phase 2 meeting.  We recommend 
applicants refer to the Pediatric Research Equity Act as amended by the Food and Drug 
Administration Safety and Innovation Act of 2012.6 
                                                 
5 See the guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product Development to 
Support Labeling Claims.  
 
6 See section 505B(e) of the Federal Food, Drug, and Cosmetic Act, as amended by section 506 of the Food and 
Drug Administration Safety and Innovation Act, and the draft guidance for industry Pediatric Study Plans:  Content 
of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans.  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/RegulatoryInformation/Guidances/default.htm.  
  6