Chronic Rhinosinusitis 
With Nasal Polyps: 
Developing Drugs for 
Treatment 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
June 2023 
Clinical/Medical 
 
   
Chronic Rhinosinusitis 
With Nasal Polyps: 
Developing Drugs 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 
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Silver Spring, MD 20993-0002  
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Email: druginfo@fda.hhs.gov  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs   
 
and/or 
 
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Food and Drug Administration 
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Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances     
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
June 2023 
Clinical/Medical 
 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  DEVELOPMENT PROGRAM ....................................................................................... 2 
A.  Trial Population ............................................................................................................................. 2 
1. Inclusion Criteria ............................................................................................................................. 3 
2. Exclusion Criteria ............................................................................................................................ 3 
B.  Trial Design .................................................................................................................................... 4 
C.  Efficacy Considerations ................................................................................................................. 5 
1. Efficacy Assessments ........................................................................................................................ 5 
2. Statistical Considerations ................................................................................................................ 7 
D.  Safety Considerations .................................................................................................................... 9 
E.  Corticosteroid-Specific Issues ..................................................................................................... 10 
F.  Drug-Device Considerations ....................................................................................................... 10 
REFERENCES ............................................................................................................................ 12 
  Contains Nonbinding Recommendations 
Chronic Rhinosinusitis With Nasal Polyps:  
Developing Drugs 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 drugs or biological 
products2 for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP).  The guidance 
addresses FDAs current thinking regarding trial population and design, effectiveness, statistical 
analysis, and safety for drugs being developed for the treatment of CRSwNP.3   
 
This guidance does not address the clinical development of drugs for the treatment of chronic 
rhinosinusitis without nasal polyps or allergic fungal rhinosinusitis. 
 
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 
 
Chronic rhinosinusitis is characterized by inflammation of the nasal mucosa and paranasal 
sinuses and is further divided into chronic rhinosinusitis with and without nasal polyps.  Nasal 
 
1 This guidance has been prepared by the Division of Pulmonology, Allergy, and Critical Care in the Center for 
Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and 
Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified.  For cell and gene therapy products, additional considerations may apply. 
 
3In addition to consulting guidances, sponsors are encouraged to contact the review division to discuss specific 
issues that arise during the development of drugs to treat CRSwNP. 
1  Contains Nonbinding Recommendations 
polyps are inflammatory hyperplastic growths that protrude into the nasal passages.  Symptoms 
of CRSwNP include nasal congestion, nasal discharge, facial pain or pressure, and loss of smell.  
The estimated prevalence of CRSwNP in adults is approximately 2.5 percent (Fokkens et al. 
2020).  In children, the estimated prevalence is difficult to determine.  Cases of CRSwNP have, 
however, been reported in adolescents.  The prevalence of CRSwNP increases with age and 
peaks in the sixth decade of life (Stevens et al. 2016).  Nasal polyps have associated morbidity 
that can have a substantial effect on day-to-day functioning.  Several studies have shown that 
patients have impaired quality-of-life scores (e.g., decreased general health, emotional function, 
ability to perform daily activities, sleep quality, and productivity) (Aboud et al. 2014).  Mild 
disease can be treated with intranasal corticosteroids and saline irrigation.  Severe disease often 
requires short-term systemic corticosteroids, a monoclonal antibody, and/or surgery.  Treatment 
goals include reduction of symptoms and systemic corticosteroid use as well as avoidance of 
surgery and improved quality of life.   
 
Taking into consideration the anatomic contiguity between the nose and paranasal sinuses, FDA 
supports the use of the term chronic rhinosinusitis, rather than chronic sinusitis, as a more 
accurate description of the underlying pathophysiology.  Nasal polyps are considered a subtype 
of chronic rhinosinusitis.  Because of differences in natural history and treatment between 
chronic rhinosinusitis with and without nasal polyps (Bachert et al. 2020), this guidance 
specifically addresses CRSwNP.   
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  Trial Population 
 
Sponsors should consider the following general recommendations for clinical trial populations 
for CRSwNP investigational drug trials intended to provide evidence of safety and effectiveness 
to support a marketing application. 
 
  The clinical trial population, as defined by the inclusion and exclusion criteria, should 
reflect the intended use of the drug.  In general, a drug intended as an add-on to standard 
of care therapies would be used in a population with greater disease severity. 
 
  Sponsors are encouraged to begin discussions about their pediatric clinical development 
plan as early as is feasible.  FDA encourages enrollment of pediatric subjects (at least 12 
years of age) in clinical trials of adults, depending on the availability of safety data and 
prospect of benefit.4  Sponsors are required to submit pediatric study plans no later than 
 
4 See 21 CFR part 50, subpart D, Additional Safeguards for Children in Clinical Investigations.  See also the draft 
guidance for industry Ethical Considerations for Clinical Investigations of Medical Products Involving Children 
(September 2022). 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. 
 
2  Contains Nonbinding Recommendations 
60 days after an end-of-phase 2 meeting or such other time as may be agreed upon by 
FDA and the sponsor.5 
 
  Sponsors should enroll a diverse trial population, including demographic characteristics 
reflective of the patient population that might require treatment.  Clinical trial sites that 
include higher proportions of racial and ethnic minorities should be considered.6 
 
  Sponsors should consider whether pregnant patients can appropriately be enrolled in 
clinical trials.7   
 
Below are general recommendations for inclusion and exclusion criteria. 
 
1.  Inclusion Criteria 
 
For inclusion in a clinical trial, sponsors should consider subjects with the following: 
 
  Bilateral nasal polyps.8  
 
  A prespecified minimum threshold for endoscopic nasal polyp score on each side using a 
valid scoring system. 
 
  Ongoing symptoms of nasal congestion, with a specified duration.  Sponsors can also 
consider loss of smell and nasal discharge. 
 
2.  Exclusion Criteria 
 
Sponsors should consider excluding subjects from trials if they have the following: 
 
  Sinus or intranasal surgery or nasal septal perforation within a specified time period 
before screening   
 
  Acute sinusitis or upper respiratory infection within a defined time period before 
screening 
 
5 See the Pediatric Research Equity Act (Public Law 108-155; section 505B(e)(2)(A) of the Federal Food, Drug, and 
Cosmetic Act; 21 U.S.C. 355B) as amended by the Food and Drug Administration Safety and Innovation Act 
(Public Law 112-144).  See also 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).  We update 
guidances periodically. 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. 
 
6 See the guidance for industry Enhancing the Diversity of Clinical Trial Populations  Eligibility Criteria, 
Enrollment Practices, and Trial Designs (November 2020).   
 
7 See the draft guidance for industry Pregnant Women: Scientific and Ethical Considerations for Inclusion in 
Clinical Trials (April 2018).  When final, this guidance will represent the FDAs current thinking on this topic. 
 
8 If a sponsor chooses to include subjects with unilateral polyps, this should be discussed with the review division in 
advance.  
3  Contains Nonbinding Recommendations 
 
  A nasal cavity tumor (malignant or benign) 
 
  Evidence of fungal rhinosinusitis 
 
  Presence of another diagnosis associated with nasal polyps (i.e., eosinophilic 
granulomatosis with polyangiitis, granulomatosis with polyangiitis, Youngs syndrome, 
primary ciliary dyskinesia, cystic fibrosis) 
 
  Rhinitis medicamentosa 
 
  Nasal septal deviation occluding at least one nostril 
 
  Antrochoanal polyps 
 
B.  Trial Design 
 
Sponsors should consider the following general recommendations on clinical trial design for 
CRSwNP investigational drug trials intended to provide evidence of safety and effectiveness to 
support a marketing application. 
 
  We recommend randomized, double-blind, placebo-controlled, parallel-group trials, 
preferably with a 2- to 4-week period before randomization to assess symptom severity or 
eligibility.  
 
  The sponsor should describe in the protocol the process of ensuring blinding to the 
investigational drug.  If double-blinding is not possible, the sponsor should provide a 
rationale, along with a discussion of the strategies for reducing or eliminating bias.  For 
topical nasal formulations, a description of the differences between active and placebo 
treatments in the protocol (e.g., differences in the device, odor, taste, characteristic of the 
formulation) can help determine the adequacy of the blinding in the trial.  For insertable 
nasal stents or depots, blindfolding the subject and separating assessors and personnel 
who insert the stents or depots may assist in reduction of bias.  
 
  The trial duration and timing of efficacy assessments should be guided by the goals of 
therapy, mechanism of action of the drug and its expected onset of action, and the time 
frame in which a clinical benefit is expected to be observed.  Because CRSwNP is a 
chronic disease, we recommend trials of at least 24 weeks, but ideally 52 weeks, in 
duration.  Sponsors can consider trials of shorter duration for topical corticosteroids; 
however, this should be discussed with the review division in advance.  Sponsors should 
consider longer trials to determine potential safety concerns and the effect on efficacy 
outcomes such as reduction in systemic corticosteroid use, surgery, and recurrence of 
nasal polyps.  
 
  Sponsors should permit subjects to use standard of care rescue therapies such as 
intranasal corticosteroid sprays, antibiotics, systemic corticosteroids, and surgery.  
4  Contains Nonbinding Recommendations 
 
C.  Efficacy Considerations 
 
Sponsors should consider the following general efficacy recommendations for CRSwNP trials 
intended to provide substantial evidence of effectiveness to support a marketing application.9  
 
1.  Efficacy Assessments 
 
The preferred co-primary endpoints in CRSwNP investigational drug trials are endoscopic nasal 
polyp score and symptoms of CRSwNP using a fit-for-purpose clinical outcome assessment 
(COA) measure.  Demonstrating a statistically significant treatment effect on both endpoints is 
necessary to support evidence of effectiveness.  FDA recommends a patient-reported outcome 
(PRO) measure of nasal congestion because it is the most common symptom experienced by 
patients with CRSwNP (Abdalla et al. 2012).   
 
Details for the assessment of these preferred co-primary endpoints are included below. 
 
  Nasal polyp score (NPS).  A common endoscopic nasal polyp rating system that has 
been used in clinical trials is the following 0-to-4 scale: 
 
  0 = no polyps 
 
  1 = small polyps in middle meatus not reaching below the lower border of middle 
turbinate 
 
  2 = polyps reaching below lower border of middle turbinate 
 
  3 = large polyps reaching lower border of inferior turbinate or medial to middle 
turbinate 
 
  4 = large polyps completely obstructing the inferior nasal cavity 
 
The total score is the sum of both sides (for a total score range of 0 to 8). 
 
We recommend at least two trained physician assessors calculate the NPS from video 
recordings of nasal endoscopies where the assessors are blinded to subject treatment 
assignment.  Generally, a prespecified adjudication process should be performed for 
significant disagreements between two readers.  
 
  Nasal congestion score (NCS).  For the PRO assessment of nasal congestion, we 
recommend using response scales that include verbal descriptors because the absence of 
descriptors may create difficulty in interpretation in this context of use.  Each response 
option should be clearly defined and represent clinically meaningful gradations and 
 
9 See the draft guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and 
Biological Products (December 2019).  When final, this guidance will represent the FDAs current thinking on this 
topic.   
5  Contains Nonbinding Recommendations 
distinct response categories.  Accordingly, using response scales such as visual analog 
scales and 0-to-10 numeric rating scales may result in interpretation difficulties in this 
context.   
 
Although different PRO assessments for nasal congestion may be appropriate, a common 
verbal rating scale (VRS) with four levels that has been used in clinical trials is the 
following (often scored from 0 to 3 where 0 = absent and 3 = severe):  
 
  absent symptoms  
  mild symptoms  
  moderate symptoms  
  severe symptoms  
 
PRO assessments should be well understood by subjects and include clear instructions for 
completion and definitions of the different categories in the scale.  For a daily diary, we 
recommend the use of reminders to encourage subject compliance with daily reporting.  
Using an electronic diary can improve data quality because entries are time-stamped, 
problems with compliance can be identified early, and reminder functions can be 
included.  The recall period should be appropriate for the concept to measure, for 
example, reflective of the worst severity over the past 24 hours.10 
 
FDA recommends the following secondary endpoints: 
 
  Smell.  We recommend assessing patient-reported loss of smell rated from absent to 
severe on a VRS and scored from 0 to 3, and the respondents understanding of the 
response options should be supported by qualitative interviews with the patient.  We do 
not recommend use of smell identification tests (e.g., the University of Pennsylvania 
Smell Identification Test) to assess loss of smell or anosmia because smell identification 
can be affected by ethnicity/cultural background, gender, sex, age, and olfactory 
experience (Hsieh et al. 2017).  
 
  Patient-reported symptom scores.  We recommend analyzing individual symptoms 
relevant and important to patients with CRSwNP that are not already included in other 
efficacy assessments (e.g., anterior or posterior nasal discharge, defined using patient-
friendly language, facial pain or pressure) rated from absent to severe on a VRS and 
scored from 0 to 3.  We do not recommend using Sino-Nasal Outcome Tests (SNOT-22, 
or other versions of SNOT) to derive key study endpoints to support regulatory decision-
making because of interpretability concerns inherent to the design of this PRO instrument 
 
10 For general recommendations regarding PRO assessments (as well as information relevant for other COAs) and 
the documents to be provided to FDA for review, see the guidance for industry Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims (December 2009).  See also the FDA 
Patient-Focused Drug Development Guidance Series for Enhancing the Incorporation of the Patients Voice in 
Medical Product Development and Regulatory Decision Making, available at 
https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-
series-enhancing-incorporation-patients-voice-medical.   
 
6  Contains Nonbinding Recommendations 
(e.g., inclusion of items that either lack relevance or are not well understood by patients 
with CRSwNP), as well as redundancy of some of the SNOT-22 items with the individual 
symptom items used to derive other study endpoints (e.g., the primary efficacy endpoint). 
 
  Surgery and oral steroid use.  Clinically meaningful secondary endpoints include 
reduction in systemic corticosteroid use and surgery.  We recommend defining what 
constitutes surgical treatment (e.g., in-office polypectomy, fenestrated endoscopic sinus 
surgery).  For rescue medications such as systemic corticosteroids, it is important for 
sponsors to assess the total systemic corticosteroid dose, courses of systemic 
corticosteroids, and days of systemic corticosteroids per course and to define the 
minimum separation in days between courses to not be considered continuous therapy. 
 
  Imaging.  Sponsors can consider sinus imaging as a secondary efficacy endpoint with 
evaluation in subjects with a prespecified minimal threshold score based on baseline 
imaging.  We recommend discussing the choice of imaging score with the review 
division.  
 
2.  Statistical Considerations 
 
Sponsors should consider the following recommendations for statistical analysis: 
 
Estimand 
 
  Sponsors should prespecify a primary estimand of interest (population, treatment, 
variable of interest, population-level summary, and intercurrent events) for each key 
endpoint and justify that it is meaningful and can be estimated with minimal and 
plausible assumptions with the proposed analysis.11  
 
  For each key endpoint, the proposed estimands should describe the handling of important 
intercurrent events, including the following: 
 
  Treatment discontinuation 
 
  Use of rescue surgical treatment for CRSwNP 
 
  Use of rescue systemic corticosteroids for CRSwNP or for comorbid conditions 
 
  Change from study treatment to another drug (e.g., a different intranasal 
corticosteroid spray (INCS) or biologic therapy) for CRSwNP 
 
  Potential strategies for defining and handling intercurrent events include the following: 
 
 
11 See the ICH guidance for industry E9(R1) Statistical Principles for Clinical Trials:  Addendum:  Estimands and 
Sensitivity Analysis in Clinical Trials (May 2021).  
7  Contains Nonbinding Recommendations 
  A treatment policy strategy in which outcomes are collected after the intercurrent 
event occurs and used in analyses 
 
  A composite strategy in which subjects who experience the intercurrent event are 
considered to have an unfavorable outcome (e.g., to have not achieved remission)  
 
  The following are important considerations about different strategies for handling 
intercurrent events: 
 
  We recommend a treatment policy strategy for handling treatment discontinuation. 
 
  We recommend a composite strategy for handling surgery (i.e., sponsors should 
incorporate surgery into the endpoint, and sponsors should consider subjects who 
undergo surgery to have an unfavorable outcome).  One reasonable approach is to 
assign the worst possible score for the co-primary endpoints, NCS and NPS. 
 
  For systemic corticosteroids, sponsors should consider the following: 
 
  For trials evaluating intranasal corticosteroids, a composite or treatment policy 
strategy for handling rescue systemic corticosteroid use may be considered 
depending on trial design or relative impact of the intercurrent event on 
interpretation of study results.  
 
  For trials evaluating therapeutic biological products, we recommend a treatment 
policy strategy for handling rescue systemic corticosteroid use. 
 
  We recommend a treatment policy strategy for handling use of systemic 
corticosteroids for comorbid conditions. 
 
  We recommend a composite strategy for handling a change from study treatment to 
another drug (e.g., a different INCS or biologic therapy) for CRSwNP. 
 
  To minimize missing data in the evaluation of important estimands, the protocol should 
distinguish reasons for treatment discontinuation from reasons for trial withdrawal and 
include plans to follow subjects for collection of relevant data after treatment 
discontinuation and use of rescue therapies.  
 
  Sponsors may consider evaluating prespecified alternative estimands by using different 
strategies for handling intercurrent events (e.g., using a treatment policy rather than a 
composite strategy) or by using different ways to implement a specific strategy (e.g., 
using an alternative value other than worst possible score, with clinical justification, to 
implement a composite strategy).  
8  Contains Nonbinding Recommendations 
 
Other statistical considerations 
 
  As patient-reported symptoms can be variable from day to day, we recommend using an 
average of daily scores over several days or weeks to establish a score at baseline and at a 
landmark time point for each subject.   
 
  For both of the co-primary endpoints, sponsors can consider the change from baseline in 
the score to a landmark time point or the score at a landmark time point.  
 
  To improve the precision of treatment effect inference, we recommend adjusting for 
prespecified prognostic baseline covariates (e.g., baseline value of the outcome measure, 
asthma or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease status, 
prior surgical history). 
 
  The following are important considerations about the prespecified analyses for efficacy 
endpoints: 
 
  Sponsors should conduct the analyses in all randomized subjects.  
 
  For intercurrent events handled with a treatment policy strategy, sponsors should 
continue to collect and analyze outcomes after the intercurrent event. 
 
  We recommend a regression-based approach to compare means between treatment 
groups. 
 
  Sponsors should prespecify plans for sensitivity analyses (e.g., to explore 
assumptions about missing data).  Sensitivity analyses should systematically and 
comprehensively explore the effect of potential deviations in assumptions of the 
analysis on conclusions.  
 
D.  Safety Considerations 
 
Sponsors should consider the following recommendations for safety for CRSwNP investigational 
drug trials intended to support a marketing application: 
 
  CRSwNP is a chronic disease; therefore, sponsors should collect long-term controlled 
safety data.  The extent of the safety database should be consistent with 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 (March 
1995).  We recommend that a sufficient number of subjects receive the highest dose 
proposed for marketing.12  Measurements of efficacy endpoints are recommended in 
long-term safety trials as secondary assessments.  
 
12 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. 
9  Contains Nonbinding Recommendations 
 
 
  For trials of drugs, such as monoclonal antibodies, that have the potential to induce an 
immune response, sponsors should see recommendations in the guidances for industry 
Immunogenicity Assessment for Therapeutic Protein Products (August 2014) and 
Immunogenicity Testing of Therapeutic Protein Products  Developing and Validating 
Assays for Anti-Drug Antibody Detection (January 2019).  
 
  Sponsors should prospectively plan for safety analyses to compare treatment groups with 
respect to risk (e.g., with a risk difference, relative risk, rate ratio, or hazard ratio) along 
with a confidence interval for the chosen metric to help quantify the uncertainty in the 
treatment comparison.  Any analyses of integrated data from multiple studies should 
stratify by trial. 
 
  For topical drugs, 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. 
 
E.  Corticosteroid-Specific Issues 
 
Important safety issues for programs evaluating intranasal corticosteroids that sponsors should 
address in clinical programs include the following: 
 
  Individual drugs may have variations in dose, dosing regimen, and systemic exposure; 
thus, their indications may need different testing procedures.  FDA encourages sponsors 
to contact the review division before carrying out corticosteroid-induced hypothalamic-
pituitary-adrenal axis suppression assessments. 
 
  Sponsors can evaluate enrolled subjects for glaucoma using intraocular pressures 
monitored pre- and posttreatment in trials assessing chronic intranasal steroid use.  
Though corticosteroids are well known to accelerate the development of cataract 
formation, the effect occurs with chronic use and thus limits the utility of monitoring 
during a short-term trial.  Labeling should carry a warning of the potential to accelerate 
cataract development similar to other corticosteroid drugs. 
 
F.  Drug-Device Considerations 
 
Sponsors should consider the following recommendations for drug-device combination products: 
 
  For drugs that include a device (e.g., nasal spray, nasal sinus implant, prefilled syringe, 
autoinjector), 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 
10  Contains Nonbinding Recommendations 
characteristics and affect the clinical performance and user interface of the combination 
product.  Therefore, we recommend that sponsors conduct all key trials in the 
development program, including dose-ranging trials and confirmatory efficacy and safety 
trials, with the to-be-marketed combination product.  Furthermore, the sponsor should 
provide data on the performance and reliability of the new delivery system over the 
period of intended use.  Consider human factors studies as necessary.13 
 
  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 combination 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 combination product with the review division. 
 
  Bridging studies of nasal drugs for local action, particularly drugs that are in a suspension 
state or a drug-coated device, 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 (April 
2003).14 
 
13 See the draft guidance for industry Human Factors Studies and Related Clinical Study Considerations in 
Combination Product Design and Development (February 2016).  When final, this guidance will represent the 
FDAs current thinking on this topic. 
  
14 When final, this guidance will represent the FDAs current thinking on this topic.   
11  Contains Nonbinding Recommendations 
1  REFERENCES 
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3  Literature 
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27   
28  Guidances 
29   
30  Draft guidance for industry Bioavailability and Bioequivalence Studies for Nasal Aerosols and 
31  Nasal Sprays for Local Action (April 2003)1 
32   
33  Draft guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human 
34  Drug and Biological Products (December 2019)2  
35   
36  Draft guidance for industry, sponsors, and IRBs Ethical Considerations for Clinical 
37  Investigations of Medical Products Involving Children (September 2022)3 
38   
 
1 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. 
 
2 When final, this guidance will represent the FDAs current thinking on this topic. 
 
3 When final, this guidance will represent the FDAs current thinking on this topic. 
12  Contains Nonbinding Recommendations 
39  Draft guidance for industry Human Factors Studies and Related Clinical Study Considerations in 
40  Combination Product Design and Development (February 2016)4 
41   
42  Draft guidance for industry Pediatric Study Plans: Content of and Process for Submitting Initial 
43  Pediatric Study Plans and Amended Initial Pediatric Study Plans (July 2020)5 
44   
45  Draft guidance for industry Pregnant Women: Scientific and Ethical Considerations for 
46  Inclusion in Clinical Trials (April 2018)6 
47   
48  FDA Patient-Focused Drug Development Guidance Series for Enhancing the Incorporation of 
49  the Patients Voice in Medical Product Development and Regulatory Decision Making available 
50  at https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-
51  development-guidance-series-enhancing-incorporation-patients-voice-medical. 
52   
53  Guidance for industry Enhancing the Diversity of Clinical Trial Populations  Eligibility 
54  Criteria, Enrollment Practices, and Trial Designs (November 2020)7 
55   
56  Guidance for industry Immunogenicity Assessment for Therapeutic Protein Products (August 
57  2014) 
58   
59  Guidance for industry Immunogenicity Testing of Therapeutic Protein Products  Developing 
60  and Validating Assays for Anti-Drug Antibody Detection (January 2019) 
61   
62  Guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product 
63  Development to Support Labeling Claims (December 2009) 
64   
65  ICH guidance for industry E1A The Extent of Population Exposure to Assess Clinical Safety:  
66  For Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions (March 1995) 
67   
68  ICH guidance for industry E9(R1) Statistical Principles for Clinical Trials:  Addendum:  
69  Estimands and Sensitivity Analysis in Clinical Trials (May 2021) 
 
4 When final, this guidance will represent the FDAs current thinking on this topic. 
 
5 When final, this guidance will represent the FDAs current thinking on this topic. 
 
6 When final, this guidance will represent the FDAs current thinking on this topic. 
 
7 We update guidances periodically.  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. 
 
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