Allergic 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 
 
   
Allergic 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.  OVERALL CONSIDERATIONS  ADULT PROGRAM ......................................... 2 
A.  Number of Trials ............................................................................................................................ 2 
B.  Dose ................................................................................................................................................. 3 
C.  Safety Monitoring .......................................................................................................................... 3 
D.  Corticosteroid-Specific Issues ....................................................................................................... 4 
E.  Issues Specific to Topical Products............................................................................................... 4 
IV.  OVERALL CONSIDERATIONS  PEDIATRIC PROGRAM ................................. 5 
A.  Pediatric Dose Selection ................................................................................................................ 5 
B.  Safety Data ...................................................................................................................................... 5 
C.  Corticosteroid-Specific Issues ....................................................................................................... 5 
V.  PROTOCOL ISSUES AND ELEMENTS ...................................................................... 6 
A.  Trial Design .................................................................................................................................... 6 
B.  Inclusion Criteria ........................................................................................................................... 7 
C.  Exclusion Criteria .......................................................................................................................... 7 
D.  Blinding ........................................................................................................................................... 8 
E.  Formulations and Dosage Regimens ............................................................................................ 9 
F.  Evaluation ....................................................................................................................................... 9 
1. Assessment of Patient Compliance .................................................................................................. 9 
2. Assessment of Rescue Medication Use ............................................................................................ 9 
3. Rating System ................................................................................................................................... 9 
4. Recording Scores ........................................................................................................................... 10 
5. Adverse Event Recording ............................................................................................................... 10 
VI.  DATA ANALYSIS ISSUES ........................................................................................... 10 
A.  Symptom Scores ........................................................................................................................... 10 
B.  Onset of Action ............................................................................................................................. 11 
VII.  FIXED-DOSE COMBINATION PRODUCTS ............................................................ 12 
  Contains Nonbinding Recommendations 
Allergic 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 sponsors in the development of drug products for the 
treatment of allergic rhinitis in children and adults.2  The guidance addresses issues of trial 
design, effectiveness, and safety for new products being developed for the treatment of seasonal 
allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). 
 
The recommendations in this guidance are based on an assessment of important issues raised in 
the review of both adult and pediatric allergic rhinitis clinical trials and the Agencys current 
understanding of the mechanism of the two related disorders of SAR and PAR.  The 
pathophysiology of SAR and PAR are similar in terms of the chemical mediators produced and 
end-organ manifestations, with differences between the two entities primarily based on the 
causes and duration of disease.  The trial design issues pertaining to SAR and PAR trials are also 
similar.  Thus, these two categories are treated collectively in this guidance as allergic rhinitis, 
with differences in recommendations for the design of SAR and PAR trials indicated.  Sponsors 
are encouraged to discuss details of trial design and specific issues relating to individual products 
with division review staff before conducting clinical trials.  
 
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 
                                                 
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.  
1 
  Contains Nonbinding Recommendations 
Trials, respectively,3 as well as the draft ICH guidance for industry E9(R1) Statistical Principles 
for Clinical Trials: Addendum:  Estimands and Sensitivity Analysis 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 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
II.  BACKGROUND  
 
Information about the pathophysiology and treatment of allergic rhinitis and its subtypes, SAR 
and PAR, has grown markedly in the past decade.  Patients with allergic rhinitis may have both 
nasal and non-nasal symptoms.  The main nasal symptoms of allergic rhinitis are nasal itching 
(i.e., nasal pruritus), sneezing, rhinorrhea, and nasal congestion.  Nasal pruritus and sneezing are 
induced by sensory nerve stimulation, whereas congestion results from vasodilation with 
resultant engorgement of cavernous sinusoids.  Rhinorrhea can be induced by increased vascular 
permeability as well as direct glandular secretion.  Important non-nasal symptoms commonly 
associated with allergic rhinitis include eye itching, tearing, eye redness, and itching of ears 
and/or palate. 
 
A growing number of chemical mediators are believed to contribute to allergic rhinitis.  Despite 
different causes and temporal patterns of disease, the same groups of chemical mediators appear 
to be regulators of the responses in SAR and PAR.  It is for this reason that distinctions between 
SAR and PAR in terms of clinical trial design are made only in clinically relevant areas. 
 
 
III.  OVERALL CONSIDERATIONS  ADULT PROGRAM 
 
A.  Number of Trials 
 
For approval of a new molecular entity in adults, the Agency recommends at least two adequate 
and well-controlled phase 3 clinical trials to support either the SAR or PAR indication.  
Alternatively, a sponsor can submit one SAR and one PAR trial in support of both indications, if 
both are adequate and well-controlled phase 3 trials and both demonstrate the safety and 
effectiveness of the drug for the indications.  If a drug is approved for one of these two related 
indications, a single trial may support approval for the other indication.  For example, a single 
PAR trial may support approval for a PAR indication if the drug is already approved for SAR. 
 
                                                 
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.  
  2  Contains Nonbinding Recommendations 
B.  Dose 
 
The dose-response relationship for an investigational product should be evaluated in these trials 
or in dedicated dose-ranging trial(s).  The goal of dose exploration is to identify the optimal dose 
and dosing frequency, balancing benefit with risk.  Ideally, dose exploration should be conducted 
in a real-world setting, because other exposure models, such as park or inhalation chamber trials, 
may not be predictive of real-world clinical responses.  Likewise, dose selection should be based 
on clinically meaningful endpoints, because pharmacodynamic (PD) markers may not be 
predictive. 
 
C.  Safety Monitoring 
 
Clinical efficacy trials must also address safety concerns, such as monitoring for adverse events, 
performing routine laboratory tests (i.e., blood chemistry, liver function tests, complete blood 
count with differential), urinalyses, and electrocardiograms, as appropriate (21 CFR 
312.23(a)(6)).  For SAR and PAR phase 3 trials, routine laboratory tests are recommended in 
trial patients at least at the initial screening and at the last visit. 
 
For products with systemic bioavailability, the Agency recommends that the safety program 
include a thorough cardiac safety evaluation.  In general, a risk of clinically significant QT 
prolongation would render the risk-benefit unfavorable for an allergic rhinitis product intended 
for symptomatic benefit.  Clinical electrocardiographic evaluation should be performed early in 
clinical development.  Clinical trials to assess the potential of a product to delay cardiac 
repolarization are described in detail in the ICH guidance for industry E14 Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.  
Sponsors are encouraged to contact the review division regarding appropriate cardiac safety 
monitoring for their respective development programs. 
 
For some classes of products, sponsors may wish to provide some assessment of the degree of 
sedation compared to the placebo in the safety database.  Adequate assessments of sedation are 
primarily based on individual patient adverse event reports of sedation and/or drowsiness (or 
similar terminology, as defined by the sponsors adverse event dictionary).  The need for 
additional evaluation, such as driving simulation trials, depends on the characteristics and 
intended use of the individual product. 
 
Long-term safety data should include at least 300 patients evaluated for 6 months and 100 
patients evaluated for 1 year, with the overall patient database including at least 1,500 patients.  
We recommend that a sufficient number of patients receive the highest dose proposed for 
marketing.  (See the ICH guidance for industry E1A The Extent of Population Exposure to Assess 
Clinical Safety:  For Drugs Intended For Long-Term Treatment of Non-Life-Threatening 
Conditions.)  Measurements of efficacy endpoints are recommended in long-term safety trials as 
secondary assessments.  
 
  3  Contains Nonbinding Recommendations 
D.  Corticosteroid-Specific Issues 
 
Important safety issues for intranasal corticosteroids that ordinarily should be addressed in the 
adult clinical program include: 
 
  Assessment of adrenal function using either 24-hour urinary-free cortisol levels or 24-
hour plasma cortisol area under the curve levels measured pretreatment and after at least 
6 weeks of treatment with the investigational product.  A placebo and an active control 
are recommended in these trials. 
 
  Evaluation for possible cataract formation in long-term trials by slit lamp examination, 
pre- and post-treatment.  
 
  Evaluation for glaucoma in long-term trials, using intra-ocular pressures monitored pre- 
and post-treatment.  
 
E.  Issues Specific to Topical Products  
 
Given the risk for local toxicity, safety monitoring should include baseline and serial nasal 
examinations.  Prespecified grading criteria to assess for the presence of nasal irritation (e.g., 
mucosal edema, erythema, epistaxis), ulceration, and septal perforation can be useful for 
documenting any changes over the course of the treatment period. 
 
The whole product, including the dedicated delivery system, is considered a drug-device 
combination product as defined in 21 CFR 3.2(e).  Changes in the formulation, excipients, 
formulation flow path within the device, or device components (e.g., dimensions, materials of 
construction, coatings) can alter the delivery characteristics and affect the clinical performance 
and user interface of the product.  Therefore, we recommend that all key trials in the 
development program, including dose-ranging trials and confirmatory efficacy and safety trials, 
be conducted with the to-be-marketed product.  Furthermore, data should be provided on the 
performance and reliability of the new delivery system over the period of intended use. 
 
In vitro and clinical bridging data may be needed to support any changes in the formulation and 
delivery system.  Depending on the nature and extent of the changes, the altered product may be 
viewed as a new product, necessitating a separate development program with efficacy and safety 
trials.  We recommend that sponsors discuss any planned changes to a topical product with the 
review division.  
 
Bridging studies of nasal products for local action, particularly products that are in a suspension 
state, can be a substantial undertaking.  Principles that may apply to such a bridging program are 
outlined in the draft guidance for industry Bioavailability and Bioequivalence Studies for Nasal 
Aerosols and Nasal Sprays for Local Action.5   
 
 
                                                 
5 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.  
  4  Contains Nonbinding Recommendations 
IV.  OVERALL CONSIDERATIONS  PEDIATRIC PROGRAM 
 
The pediatric age ranges proposed for a product, particularly for young patients, should be 
justified by the sponsor based on the prevalence of disease and the need for treatment in that age 
group.  Products indicated for the treatment of SAR generally should be evaluated in children 
down to the age of 2 years, while products indicated for the treatment of PAR should be 
evaluated in children down to the age of 6 months.  For topical products, the appropriateness of 
the delivery system for the proposed age range is an additional consideration.  Sponsors are 
encouraged to discuss the specifics of pediatric programs with the division on a case-by-case 
basis and to begin discussions about their pediatric formulation and clinical development plans 
as early as feasible because sponsors 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 sponsors refer to the Pediatric Research Equity Act as amended by the Food and 
Drug Administration Safety and Innovation Act.6 
 
A.  Pediatric Dose Selection 
 
For products already approved and/or adequately studied in adults but not yet studied in children, 
an appropriate pediatric dose should be determined.  In addition, adequate short- and long-term 
safety information for the proposed pediatric age group should be provided.  For oral 
formulations where a reasonable pharmacokinetic (PK)/PD link for efficacy has been 
established, PK data from children can be used to determine comparable exposure to adult 
patients, and therefore the appropriate pediatric dose.   
 
For intranasal formulations, efficacy trials in pediatric patients are recommended, because 
plasma drug levels are not consistently detectable or reliable as measures of local bioavailability 
and topical efficacy. 
 
B.  Safety Data 
 
Typically, 3 months of additional specific pediatric safety data for intranasal products and 
1 month of additional specific pediatric safety data for oral products are recommended.  We 
suggest that these data be collected in controlled trials.  However, the duration and number of 
pediatric patients exposed to the investigational product for safety monitoring should be 
determined on an individual basis for each product, based on anticipated side effects, pediatric 
PK data, and safety concerns. 
 
C.  Corticosteroid-Specific Issues 
 
For intranasal corticosteroids, we recommend a 6-week hypothalamic-pituitary-adrenal (HPA) 
axis trial, with a placebo and an active control.  Such a trial is intended to evaluate influences of 
                                                 
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.  
  5  Contains Nonbinding Recommendations 
the product on the HPA axis that are not limited to HPA axis suppression alone.  Because of 
ethical concerns about the use of oral prednisone as an active control in adrenal response trials in 
children, alternative approaches may be more appropriate.  Such approaches can include use of 
an approved intranasal corticosteroid that is sufficient to cause an HPA axis effect. 
 
Based on information indicating that intranasal corticosteroids have the potential to decrease 
growth velocity in children, a growth trial is recommended for prepubertal children.  If the trials 
are to be conducted postapproval, it may be useful for a sponsor to include a knemometry trial in 
the new drug application to provide PD growth data for consideration during the initial review.  
Recommendations regarding the design and conduct of a growth trial are outlined in the 
guidance for industry Orally Inhaled and Intranasal Corticosteroids:  Evaluation of the Effects 
on Growth in Children.  Sponsors are encouraged to discuss the details of their pediatric growth 
trial designs with the review division. 
 
 
V.  PROTOCOL ISSUES AND ELEMENTS 
 
A.  Trial Design 
 
The following are general recommendations on trial design for phase 3 allergic rhinitis (SAR and 
PAR) trials.  
 
  Double-blind, placebo-controlled, and parallel group trials are recommended, preferably 
with a placebo run-in period.  The placebo run-in period can be used to assess for a 
minimum level of compliance and symptom severity before the double-blind treatment 
period. 
 
  The suggested duration of the double-blind treatment period is at least 2 weeks for SAR 
trials and 4 weeks for PAR trials. 
 
  For SAR trials, the Agency recommends that the protocol include plans for measuring 
pollen counts at the different trial centers.  The final report can then document the 
exposure of patients to the relevant allergens during the trial period.  It may also be 
helpful to collect data on the number of rainy days during the trial and the extent of 
patient exposure to outdoor air. 
 
  For SAR trials, we encourage randomization of patients within each center into the 
double-blind portion over a short time period, because this generally reduces variability 
in allergen exposure.  The time period for randomization should be the shortest period 
that is feasible, given the size of the trial and variability in weather. 
 
  Many patients with PAR may have concomitant SAR.  Therefore, it is helpful if PAR 
efficacy trials are conducted during a time when relevant seasonal allergens are less 
abundant and therefore less likely to influence trial results.  
 
  6  Contains Nonbinding Recommendations 
B.  Inclusion Criteria 
 
The following are general recommendations on the inclusion criteria for phase 3 allergic rhinitis 
trials. 
 
  For SAR trials in older children, adolescents, and adults, it is recommended that patients 
have a history of SAR for a minimum of 2 years before trial entry.  The Agency 
recommends documentation of sensitivity by positive skin testing (by prick or 
intradermal methods) or by adequately validated in vitro tests for specific 
Immunoglobulin E (IgE) (e.g., radioallergosorbent test (RAST), paper 
radioimmunosorbent test (PRIST)) to the relevant seasonal allergen for the geographic 
area of the trial within 12 months before enrollment.  In general a positive skin test is 
defined as a wheal greater than or equal to 3 millimeters (mm) larger than the diluent 
control with erythema for prick testing or greater than or equal to 7 mm larger than the 
diluent control with erythema for intradermal testing.  Positive in vitro tests are 
determined by the standards of the individual reference laboratory.  Positive skin tests or 
in vitro tests for specific IgE should correlate to the allergy history before the results are 
accepted as meeting inclusion criteria. 
 
  For PAR trials, allergy to perennial allergens (e.g., dust mites, cockroaches, cats, dogs, 
molds) can be demonstrated in trial patients by prick or intradermal skin testing (using 
the criteria for positivity above) or by adequately validated in vitro tests for specific IgE 
(e.g., RAST, PRIST).  We suggest that these tests be performed during the 12 months 
before enrollment.  The patient should have a relevant allergy history to the tested 
allergen. 
 
  The Agency recommends that patients not start immunotherapy or have a change in dose 
for approximately 1 month preceding enrollment in the trial.  Ideally, patients should 
maintain the same dose throughout the trial. 
 
  Patients should be experiencing symptoms meeting or exceeding an appropriate 
minimum level at the time of trial enrollment.  This can be ensured by assessing the 
severity of the symptoms for the primary endpoint and requiring at least moderate 
severity for all or the majority of individual symptoms, as defined by the trials symptom 
scoring scale. 
 
C.  Exclusion Criteria 
 
The following are general recommendations on the exclusion criteria for phase 3 allergic rhinitis 
trials: 
 
  Asthma, with the exception of mild intermittent asthma,7 to lessen confounding by 
asthma medications, some of which may modify allergic rhinitis. 
                                                 
7 See the National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Expert 
Panel Report 3:  Guidelines for the Diagnosis and Management of Asthma at https://www.nhlbi.nih.gov/health-
pro/guidelines/current/asthma-guidelines/index.htm.  
  7  Contains Nonbinding Recommendations 
 
  Chronic or intermittent use of inhaled, oral, intramuscular, intravenous, and/or potent 
topical corticosteroids. 
 
  Use of leukotriene modifiers. 
 
  Use of long-acting antihistamines. 
 
  Prohibited medications or inadequate washout periods (for certain drug classes).  The 
following washout periods are generally sufficient: 
 
  Intranasal or systemic corticosteroids (1 month) 
  Leukotriene modifiers (1 month) 
  Intranasal cromolyn (2 weeks) 
  Intranasal or systemic decongestants (3 days) 
  Cetirizine, fexofenadine, loratadine, desloratadine, hydroxyzine (5 to 10 days) 
  Intranasal antihistamines (3 days) 
  Other systemic antihistamines (3 days) 
 
  Documented evidence of acute or significant chronic sinusitis, as determined by the 
individual investigator. 
 
  Chronic use of concomitant medications (e.g., tricyclic antidepressants) that would affect 
assessment of the effectiveness of the investigational product. 
 
  A history of hypersensitivity to the product or its excipients. 
 
  Presence of rhinitis secondary to other causes. 
 
  Presence of ocular herpes simplex or cataracts (for intranasal corticosteroid trials), or a 
history of glaucoma (for intranasal corticosteroid or anticholinergic trials). 
 
  Planned travel outside the trial area for a substantial portion of the trial period. 
 
D.  Blinding 
 
Because allergic rhinitis trials are based on subjective endpoints, blinding is a critical 
consideration.  The process of ensuring blinding to the investigational product should be 
described in the protocol.  If double-blinding is not possible, a rationale should be provided, 
along with a discussion of the means for reducing or eliminating bias.  For topical nasal 
formulations, a description of the differences in appearance between active and placebo 
treatments in the protocol (e.g., differences in the device or in the odor or characteristic of the 
formulation) can help determine the adequacy of the trial blind. 
 
  8  Contains Nonbinding Recommendations 
E.  Formulations and Dosage Regimens 
 
Sponsors are encouraged to provide information in the protocol on the specific formulations used 
for both the to-be marketed product and the placebo, along with a description of the dosing 
regimen.  We recommend that dose-ranging and confirmatory trials use the to-be-marketed 
product.  If not, the sponsor should address how the safety and effectiveness of the studied 
formulation will be bridged to the to-be-marketed formulation.  If bridging of one formulation to 
another is proposed, information about the formulation composition and trial lots should be 
included in the final reports for the respective products. 
 
F.  Evaluation 
 
The following are general recommendations on trial assessments in phase 3 allergic rhinitis 
trials.  
 
1.  Assessment of Patient Compliance 
 
The protocol or final report should provide information about how compliance with the 
investigational product use will be determined and documented throughout the trial and how 
noncompliance will be dealt with. 
 
2.  Assessment of Rescue Medication Use 
 
If rescue medications are allowed during the trial, the 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. 
 
3.  Rating System 
 
The preferred measures of efficacy in allergic rhinitis trials are patient self-rated instantaneous 
and reflective total nasal symptom scores.  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.  Such changes should be discussed with the review division.  
Patient-rated scores are preferred as the primary measure of effectiveness. 
 
A common allergic rhinitis 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) 
  9  Contains Nonbinding Recommendations 
 
  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 
symptom diary and definitions of the different categories in the scale.8 
 
4.  Recording Scores 
 
The Agency recommends that patients be instructed to record their symptom scores in diaries at 
least as often as the daily dosing interval.  Collection of both reflective symptom scores (i.e., an 
evaluation of symptom severity after a predefined time period such as 12 hours) and 
instantaneous symptom scores (i.e., an evaluation of symptom severity immediately before the 
next dose) is recommended.  Reflective symptom scores assess the overall degree of 
effectiveness over a prespecified time interval, whereas instantaneous scores assess effectiveness 
at the end-of-dosing interval and can be used to assess onset of action. 
 
5.  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. 
 
 
VI.  DATA ANALYSIS ISSUES 
 
A.  Symptom Scores 
 
Symptom scores should be collected at baseline and daily over the course of the trial.  Collection 
of baseline symptom scores over several days immediately preceding patient randomization will 
permit the evaluation of baseline comparability of the various treatment arms, as well as the 
determination of treatment effects over time. 
 
An appropriate primary efficacy endpoint is the change from baseline in the reflective total nasal 
symptom score (TNSS) averaged over the entire double-blind treatment period (2 weeks for 
SAR and 4 weeks for PAR).  Depending on the drug class being evaluated, the TNSS is defined 
as a total score composed of at least three of the following four nasal symptoms:  rhinorrhea, 
nasal congestion, nasal itching, and sneezing.  Inclusion of nasal congestion in the TNSS may be 
appropriate for an intranasal corticosteroid or a decongestant, but may not be appropriate for an 
antihistamine, anticholinergic, or cromolyn-like agent. 
 
An appropriate key secondary endpoint is the change from baseline in the instantaneous TNSS 
across the double-blind treatment period to assess the appropriateness of the dosing interval.  The 
                                                 
8 See the guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product Development to 
Support Labeling Claims.  
  10  Contains Nonbinding Recommendations 
development program should demonstrate a significant difference between the product and 
placebo at the end of the dosing interval averaged across the double-blind treatment period. 
 
When designing allergic rhinitis protocols, sponsors are encouraged to numerically define a 
clinically meaningful change in the primary efficacy endpoint, and provide the rationale for this 
selection.  The statistical section of the protocol should include a power calculation using this 
value and should prospectively discuss how missing data will be handled in the analysis plan.  In 
particular, 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.  Furthermore, we recommend continued collection of 
efficacy and safety data after treatment discontinuation and rescue medication use to facilitate 
evaluation of treatment policy estimands. 
 
In addition to evaluating the effectiveness of the product over the entire double-blind period, 
additional data presentations can be helpful in evaluating effectiveness.  These include: 
 
  Presenting the morning and evening symptom scores separately for both the reflective 
and instantaneous symptom assessments. 
 
  Presenting the efficacy data for the first few days of the trial separately for both the 
reflective and instantaneous symptom assessments.  This data presentation also can 
separate the morning and evening scores.  This allows some assessment of the onset of 
action.  
 
  Presenting the efficacy data for each week individually for both the reflective and 
instantaneous symptom assessments.  This allows determination of both the onset of 
action and the durability of the response over the course of the clinical trial. 
 
  Presenting the efficacy data for the individual component symptom scores that comprise 
the total symptom complex. 
 
Other patient-rated and physician-rated measures can be included as secondary efficacy 
endpoints.  For example, assessment of ocular symptoms associated with allergic rhinitis may be 
applicable for certain products.  Patient-rated, reflective, and instantaneous total ocular symptom 
scores, similar to the symptom scoring system used for nasal symptoms, can be used to support 
inclusion of relevant information in labeling.  Information from disease-specific quality-of-life 
measures also can be considered for inclusion in labeling.  We anticipate replicate data from at 
least two trials to support inclusion of such measures in labeling. 
 
B.  Onset of Action 
 
The definition of the onset of action of an allergic rhinitis product is the point at which patients 
might reasonably expect to see a meaningful decrease in their allergic rhinitis symptoms.  For the 
purposes of allergic rhinitis, it is the first time point after initiation of treatment when the product 
demonstrates a greater change from baseline in the primary efficacy endpoint compared to the 
  11  Contains Nonbinding Recommendations 
placebo treatment that proves durable from this point until the end of the proposed dosing 
interval. 
 
Because onset of action information may be included in labeling, at least two trials are 
recommended to support a particular onset of action claim.  It is useful to assess onset of action 
during development, regardless of any proposed claims.  The two trials do not have to be 
identical in design, nor do they have to evaluate both SAR and PAR.  Because onset of action is 
largely a PD issue, a number of different trial designs can be used.  Following are three types that 
have been used: 
 
1.  Standard phase 3 allergic rhinitis efficacy trials in which symptom scoring data are 
collected frequently for the first few days 
 
2.  A single-dose, parallel group, placebo-controlled trial of patients in a park setting in 
which patients are exposed to relevant outdoor seasonal allergens and, following dosing, 
have nasal symptoms evaluated on an hourly basis 
 
3.  An inhalation chamber trial (also known as environmental exposure unit (EEU)) in which 
previously asymptomatic patients are exposed to a relevant allergen (generally a seasonal 
allergen, such as ragweed) in a controlled indoor setting and, following dosing, have their 
nasal symptoms evaluated on an hourly basis 
 
Onset of action data can come from any of these three designs.  However, if EEU and/or park 
trials are used to support an onset of action claim shorter than the onset of action seen in the 
phase 3 trials, the Agency recommends that the results be replicated to be considered 
independently informative.  This is due to the shorter duration of these trials and the restricted 
setting and manner in which they are conducted.  In any case, information about onset of action 
derived from the phase 3 trials used to support approval also can be included in the proposed 
package insert along with any data from park or chamber trials, to reflect the real world setting of 
the treatment trials. 
 
 
VII.  FIXED-DOSE COMBINATION PRODUCTS 
 
In addition to the general principles outlined in 21 CFR 300.50 regarding the development of 
fixed-dose combination products, other considerations for allergic rhinitis combination products 
include the following: 
 
  The contribution of each monotherapy component should be supported by replicate, 
appropriately designed and conducted trials where the combination product is compared 
to each component.  The treatment difference between each component and the 
combination product should be clinically meaningful and statistically significant. 
 
  The efficacy and safety of the dose and dosing regimen for each individual component 
should be established (i.e., the monotherapy components should be tested at an effective 
dose and dosing regimen).   
  12  Contains Nonbinding Recommendations 
 
  For locally acting topical products, pharmaceutical differences between the combination 
product and each component may obscure the comparison of the combination product to 
each of its components used in a clinical trial.  As a result, commercially available 
comparators may not be appropriate for the purposes of factorial comparison.  Sponsors 
will likely need to develop monotherapy comparator products specifically for the 
purposes of the combination product development program. 
 
  Patients who have already failed one component of the combination product should be 
excluded, unless there is scientific justification to an exception.   
 
Given the complexity of development programs for fixed-dose, locally acting combination 
products, sponsors are encouraged to discuss the details of the monotherapy components and trial 
designs with the review division early in the development programs. 
 
  13