Nonallergic Rhinitis: Developing Drug Products for Treatment

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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

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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, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s 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 FDA’s 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.

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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 Agency’s 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.

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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.

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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

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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

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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 FDA’s 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.