Eosinophilic Esophagitis: Developing Drugs for Treatment Guidance for Industry

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

Eosinophilic Esophagitis:
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)
September 2020
Clinical/Medical

Eosinophilic Esophagitis:
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
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
September 2020
Clinical/Medical

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 1
III. 	DEVELOPMENT PROGRAM ....................................................................................... 3
A. 	Trial Population ............................................................................................................................. 3
B. 	Trial Design .................................................................................................................................... 4
C. 	Efficacy Considerations ................................................................................................................. 4
1. Efficacy Assessments ........................................................................................................................ 4
2. Clinical Outcome Assessments ........................................................................................................ 5
3. Statistical Considerations ................................................................................................................ 6
D. 	Safety Considerations .................................................................................................................... 7
IV. 	PEDIATRIC CONSIDERATIONS................................................................................. 8
REFERENCES............................................................................................................................ 10

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Eosinophilic Esophagitis:
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 clinical development of drugs and
therapeutic biologics for the treatment of eosinophilic esophagitis (EoE).2 Specifically, this
guidance addresses FDA’s current thinking regarding clinical trials and development programs
for EoE drugs, including recommendations for the necessary attributes of patients for enrollment,
trial designs, efficacy considerations, safety assessments, and pediatric considerations.3
This guidance does not address the clinical development of drugs for the treatment of non-EoE,
eosinophilic gastrointestinal disorders.
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
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. 	BACKGROUND
EoE is a chronic immune or antigen-mediated esophageal disease clinically characterized by
signs and symptoms related to esophageal dysfunction and histologically characterized by
eosinophil-predominant inflammation (Liacouras et al. 2011). Left untreated, EoE leads to
1 This guidance has been prepared by the Division of Gastroenterology (the Division) in the Center for Drug
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.
3 In addition to consulting guidances, sponsors are encouraged to contact the Division to discuss specific issues that
arise during the development of drugs to treat EoE.

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esophageal stricture, dysphagia, and risk of food impaction (Warners et al. 2018). Furthermore,
treatment cessation can lead to a recurrence of EoE clinical symptoms and histologic activity
(Dellon et al. 2019). EoE has an estimated incidence of 5–10 cases per 100,000 persons per year
and prevalence of approximately 50–100 cases per 100,000 persons (Dellon and Hirano 2017).
Clinical signs4 and symptoms vary with age of the patient. Infants and toddlers present with
feeding difficulties, school-aged children are more likely to present with vomiting or pain, and
adolescents and adults often present with dysphagia and food impaction (Straumann and Katzka
2018).
In patients with EoE, clinical features and histologic activity can vary independently. Patients
can have a reduction or resolution in signs and symptoms despite ongoing histologic activity;
conversely, patients can have histologic remission (defined as a change in peak eosinophils per
high-power field (HPF) from a count greater than or equal to 15 to less than or equal to 6) with
persistent clinical symptoms (Dellon et al. 2013).
For these reasons, the treatment goals of EoE include resolution or reduction of the signs and
symptoms of active disease to provide relief to the patient, and healing or control of the
esophageal inflammation and its complications.
The variability of symptomatology across pediatric and adult populations creates challenges to
the development of fit-for-purpose clinical outcome assessments (COAs),5 such as patient-
reported outcome (PRO)6 or observer-reported outcome (ObsRO)7 instruments, for evaluation of
treatment response in EoE for regulatory use. Recommendations for sponsor development of
COAs are discussed later in this guidance.
4 For the purposes of this guidance, the term sign is used to describe both observable behaviors and findings on
clinical examination unless otherwise specified.
5 A COA can be made through a report by a clinician, a patient, or a nonclinician observer or through a
performance-based assessment. For more information on the four types of COAs (clinician-reported outcome,
observer-reported outcome, patient-reported outcome, and performance outcome), see the glossary of the BEST
(Biomarkers, EndpointS, and Other Tools) Resource available at
https://www.ncbi.nlm.nih.gov/books/NBK338448/?report=reader.
6 A PRO is a type of COA that is a measurement based on a report that comes directly from the patient (i.e., trial
subject) about the status of a patient’s health condition without amendment or interpretation of the patient’s response
by a clinician or anyone else. A PRO can be measured by self-report or by interview provided that the interviewer
records only the patient’s response. Symptoms or other unobservable concepts known only to the patient can only
be measured by PRO measures. PROs can also assess the patient perspective on functioning or activities that may
also be observable by others. See the glossary of the BEST Resource available at
https://www.ncbi.nlm.nih.gov/books/NBK338448/?report=reader.
7 An ObsRO is a type of COA that is a measurement based on a report of observable signs, events, or behaviors
related to a patient’s health condition by someone other than the patient or a health professional. Generally,
ObsROs are reported by a parent, caregiver, or someone who observes the patient in daily life and are particularly
useful for patients who cannot report for themselves (e.g., infants, individuals who are cognitively impaired). An
ObsRO measure does not include medical judgment or interpretation. See the glossary of the BEST Resource
available at https://www.ncbi.nlm.nih.gov/books/NBK338448/?report=reader.

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III. 	DEVELOPMENT PROGRAM
A. 	Trial Population
Sponsors developing drugs for the treatment of EoE should consider the following for clinical
trial populations:
• 	Patients should be sufficiently symptomatic to warrant clinical trial enrollment. Signs
and symptoms to support patient eligibility should be documented in a standardized case
report form for all patients within a trial. The severity of symptomatology needed for
enrollment can be influenced by the anticipated risks of the drug. We recommend that
sponsors include a screening period before randomization of the patients to confirm
histologic eligibility criteria, document persistence of clinical signs and symptoms, and
train patients and/or care providers to collect the COA data appropriately.
• 	Esophagogastroduodenoscopy (EGD) is needed to establish a histologic diagnosis of
EoE; this can be provided by historical record, although such patients should also
undergo EGD to ensure they meet histologic eligibility criteria at time of enrollment.
Currently, histologic diagnostic criteria for EoE include a peak count of greater than
or equal to 15 eosinophils per HPF (400X). Two to four biopsies should be obtained
from the proximal esophagus and two to four biopsies should be obtained from the
distal esophagus. Biopsies can be taken from the midesophagus for additional
evaluation. To decrease potential variability across sites, the area of the HPF should
be recorded (in mm2 or μm2
), and eosinophil density per mm2 should be included in
the report. We encourage the use of a central reader to ensure consistent histological
evaluations.
• 	During the diagnostic EGD, biopsy specimens from the stomach and/or duodenum should
be taken to rule out alternate etiologies in all pediatric patients. Biopsy specimens from
the stomach and/or duodenum should also be obtained in adult patients with gross
endoscopic abnormalities or clinical signs and symptoms that indicate that gastric or
small intestinal conditions are possibilities. Adult and pediatric patients with abnormal
biopsy specimens from the stomach and/or duodenum should be excluded from
enrollment, if appropriate, as this may support an alternative diagnosis.
• 	Sponsors should provide justification for the inclusion or exclusion of patients with
strictures. We recommend including patients with a history of strictures if there are
existing data or a compelling scientific rationale to suggest that these patients may respond
to the proposed treatment. Patients with esophageal strictures that require dilation at the
initial endoscopy should undergo additional screening to document persistence of clinical
signs and symptoms following dilation to confirm eligibility.
• 	Because dietary restriction is a known effective treatment for EoE and signs and
symptoms may be highly dependent on eating behaviors (Hirano et al. 2017), patients
should maintain a stable diet preceding enrollment and throughout the duration of the
trial period.

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• 	Patients should maintain stable doses of proton pump inhibitor therapies; leukotriene
inhibitors; or nasal, inhaled, and/or orally administered locally or topically acting
corticosteroid drugs for comorbid conditions (e.g., asthma, allergic rhinitis) before
enrollment and throughout the duration of the trial period.
B. 	Trial Design
Sponsors developing drugs for the treatment of EoE should consider the following for clinical
trial design:
• 	We recommend a randomized, double-blind, placebo-controlled trial design with a
prespecified screening period before randomization of patients to confirm eligibility
criteria.
• 	The trial duration and timing of efficacy assessments should be guided by the goal of
therapy, the 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.
• 	For drugs intended to be administered chronically, we recommend a treatment period of
at least 24 weeks’ duration to assess efficacy for both clinical and histologic endpoints,
followed by an extension period to provide a total treatment period of at least 52 weeks’
duration to ensure adequate exposure to allow for characterization of the safety profile and
the durability of response. Long-term data from the treatment and extension period
should be available before the submission of an application for registration. Sponsors
should discuss with the Agency the number of patients with a minimum exposure of 1
year that will be available at the time of application submission.
• 	When scientifically appropriate, the inclusion of a randomized withdrawal design
following the initial demonstration of efficacy may help to inform the incidence of relapse
and need for redosing. FDA does not recommend a randomized withdrawal design for
trials of therapeutic protein products (see section III. D., Safety Considerations).
C. 	Efficacy Considerations
1. 	Efficacy Assessments
Sponsors developing drugs for the treatment of EoE should consider the following regarding a
drug’s efficacy:
• 	Trials intended to support marketing approval of a drug for the treatment of EoE should
evaluate a drug’s effect on signs and symptoms and the related underlying inflammation.

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Therefore, sponsors should include coprimary endpoints8 in phase 3 trials that assess the
following:
— 	Signs and symptoms, using a well-defined and reliable COA instrument, assessed on
a continuous or ordinal scale.
— 	Histologic response of peak esophageal eosinophil per HPF count of less than or
equal to 6 across all available esophageal levels at the final treatment period
evaluation. Two to four biopsies should be obtained from the proximal esophagus,
and two to four biopsies should be obtained from the distal esophagus. Biopsies can
be taken from the midesophagus for additional evaluation.
• 	We encourage the systematic collection of additional data on endoscopic findings (e.g.,
edema, rings, exudates, furrows, strictures) and histologic features of EoE (e.g., eosinophil
density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated
intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, lamina
propria fibrosis).
2. 	Clinical Outcome Assessments
Sponsors developing drugs for the treatment of EoE should consider the following when using
COA instruments, including PRO and ObsRO instruments:
• 	FDA encourages sponsors to seek FDA input as early as possible and at important
milestones throughout the drug development process to meet the challenges of COA
development in this patient population.9
• 	Until a well-defined and reliable PRO or ObsRO instrument that measures the clinically
important signs and symptoms of EoE is available and accepted for regulatory use, we
recommend modifying or developing a PRO or ObsRO instrument based on patient or
observer input regarding the relevant and meaningful signs and symptoms of EoE (e.g.,
food getting stuck). Sponsors should use instruments with daily assessments (e.g., past
24-hour recall period, event log) in which respondents complete the instruments at the
same time each day (e.g., evening before bedtime) that focus on these items.10
8 Demonstration of treatment effects on both distinct endpoints is necessary to establish clinical benefit for this
indication. See the draft guidance for industry Multiple Endpoints in Clinical Trials (January 2017). 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/regulatory-information/search-fda-guidance-documents.
9 For general recommendations regarding PRO instruments (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).
10 For additional recommendations, see the guidance for industry, FDA staff, and other stakeholders Patient-
Focused Drug Development: Collecting Comprehensive and Representative Input (June 2020).

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• 	Sponsors also can assess, once identified, important and common effects of EoE signs
and symptoms on patients’ daily lives. If adequately captured, this information could be
included as a distinct endpoint from the core signs and symptoms.
• 	Capturing both patient-reported and observer-reported data can be explored if patients are
able to report some, but not all, signs and symptoms. For example, some school-aged
pediatric patients may be able to report on abdominal pain severity using a simple
pictorial scale but may not be able to reliably and validly report other important signs and
symptoms. An observer should not be asked to rate, as a proxy, unobservable aspects of
the pediatric patient’s condition (e.g., abdominal pain severity). Observers should only
be asked to rate signs and behaviors that are observable or verbalizations made by the
pediatric patient on how he or she is feeling.11
• 	When modifying an existing or developing a new COA instrument, FDA recommends
that sponsors use data obtained in phase 2 trials to help inform finalization of scoring
algorithms and endpoint definitions. Piloting the proposed COA instrument in phase 2
trials can provide the sponsor an opportunity to evaluate the instrument’s psychometric
properties and performance (reliability, validity, and ability to detect change) as well as
provide guidelines for interpretation of clinically meaningful within-patient change and
confirm the endpoint definition. These results can further inform plans for
implementation of the proposed COA instrument in phase 3 trials.
3. 	Statistical Considerations
FDA recommends the following statistical considerations for sponsors developing drugs for the
treatment of EoE:
• 	Sponsors should prespecify a primary estimand of interest for each endpoint and justify
that it is meaningful and can be estimated with minimal and plausible assumptions with
the proposed analysis.12
The proposed estimand should discuss how important intercurrent events will be handled
such as the following:
— 	Initiation of treatment with systemic corticosteroid drugs for comorbid conditions
during the trial period
— 	Use of rescue medications or emergency dilation
— 	Change in diet and adaptive eating behaviors
11 The analysis plan for programs including both patient- and observer-reported data should be discussed with the
Agency early in development as it may not be appropriate to integrate the data into a combined analysis.
12 For additional recommendations, see the International Council for Harmonisation draft guidance for industry
E9(R1) Statistical Principles for Clinical Trials: Addendum on Estimands and Sensitivity Analysis in Clinical Trials
(October 2017). When final, this guidance will represent the FDA’s current thinking on this topic.

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• 	To gain precision in the evaluation of overall treatment effects, we recommend that
statistical analyses adjust for patient characteristics at baseline that may affect efficacy
outcomes (e.g., presence of strictures, dietary restrictions).
• 	We recommend that the sponsor analyze COA endpoints as continuous or ordinal
variables using baseline values as covariates. For COA endpoints, FDA does not
recommend a percent change from baseline endpoint, or a responder analysis endpoint,
unless the targeted response is complete resolution of signs and symptoms.
• 	Small but statistically significant group-level mean differences in the COA endpoint may
not establish whether the effect is clinically meaningful.
— 	To aid in the interpretation of the COA endpoint results, the sponsor should propose
an appropriate range of within-patient score change that patients consider to be
clinically meaningful using anchor-based methods (e.g., patient global impression
scale as an anchor), supplemented with empirical cumulative distribution function
(eCDF) curves using data pooled across trial arms.
— 	Additionally, the sponsor should submit for review eCDF curves by treatment arm
and supportive descriptive analyses of within-patient changes from baseline.
• 	FDA recommends that the sponsor analyzes the histologic coprimary endpoint (i.e., a
binary endpoint defined as a peak esophageal eosinophil per HPF count of less than or
equal to 6 across all available esophageal levels) by evaluating the difference in the
proportions of responders across treatment arms.
D. 	Safety Considerations
Sponsors developing drugs for the treatment of EoE should consider the following regarding
safety in clinical trials:13
• 	For trials of corticosteroid drugs, sponsors should consider the following:
— 	A physical examination to identify signs of glucocorticoid excess should be
performed at every visit.
— 	FDA recommends that hypothalamic pituitary adrenal (HPA) axis suppression
potential be assessed by an adrenocorticotropic hormone (ACTH) stimulation test.
The ACTH stimulation test should be performed at preestablished time points
throughout the phase 2 and 3 trials as well as during any extension trials (including at
13 For recommendations regarding duration of exposure and number of patients to be included in the safety database,
see the guidance for industry Premarketing Risk Assessment (March 2005).

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the end of treatment, either at the end of the trial or at drop out) and 6 weeks after the
completion of the trial.
— 	Patients showing signs of HPA axis suppression or having abnormal ACTH
stimulation test results at the end of treatment should be followed closely until
complete resolution.
• 	For trials of therapeutic protein products, such as monoclonal antibodies, sponsors should
see recommendations in the guidance for industry Immunogenicity Assessment for
Therapeutic Protein Products (August 2014). Sponsors should include neutralizing
capabilities in the evaluations for antidrug antibodies.
IV. 	PEDIATRIC CONSIDERATIONS
Sponsors developing drugs for the treatment of EoE should consider the following when
enrolling pediatric patients in clinical studies:14, 15
• 	We encourage the inclusion of adolescent patients (patients 12–17 years of age inclusive)
in registration clinical trials, provided that preliminary safety and efficacy data in adult
patients support enrollment. These trials should include design elements to ensure that all
enrolled pediatric patients have the opportunity for exposure to active treatment (e.g.,
open-label extension) and should be followed by trials in patients younger than 12 years
of age. Trial design for studies in pediatric patients younger than 12 years of age should
be informed by the safety and efficacy results in the adolescent and adult populations.
• 	EGD is necessary to evaluate the histologic diagnostic criteria for EoE, as well as for
assessment of response of a therapeutic intervention. For trials including pediatric
patients, repeated procedures, such as EGD, should be conducted in accordance with the
standard of care for the individual patient (i.e., not for research purposes only).
• 	The number of adolescent patients included in adult studies may be guided by disease
prevalence; however, a sufficient number of adolescent patients should be included to
allow for a reliable estimate of the event of interest and the uncertainty about this
estimate to support the determination of safety and efficacy.
• 	For trials utilizing corticosteroid drugs, growth measurements for pediatric patients
should be made using stadiometry and recorded to the nearest 10th of a centimeter. The
stadiometric measurement protocol should be specific (e.g., no socks, shoes, or hats;
three reproducible measurements; calibration frequency). Tanner stage should be
obtained, and the growth data should be analyzed by pubertal stage (i.e., pre- and post-
14 For nonclinical program recommendations, see the guidance for industry Nonclinical Safety Evaluation of
Pediatric Drug Products (February 2006).
15 See 21 CFR part 50, subpart D, Additional Safeguards for Children in Clinical Investigations.

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puberty).16 Additionally, the potential of these therapies to cause HPA suppression
should be evaluated independently in the pediatric population (see section III. D., Safety
Considerations).
• 	For drugs with potential to affect bone mineralization, the sponsor should, early in
development, discuss with FDA the plan for evaluating effects on bone mineral density
and composition.
16 See the guidance for industry Orally Inhaled and Intranasal Corticosteroids: Evaluation of the Effects on Growth
in Children (March 2007).

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REFERENCES
Literature
Dellon, E. S., Gonsalves, N., Hirano, I., Furuta, G. T., Liacouras, C. A., Katzka, D. A., and
American College of Gastroenterology, 2013, ACG Clinical Guideline: Evidenced Based
Approach to the Diagnosis and Management of Esophageal Eosinophilia and Eosinophilic
Esophagitis (EoE), Am J Gastroenterol, 108(5), 679–692.
Dellon, E. S., and Hirano, I., 2017, Epidemiology and Natural History of Eosinophilic
Esophagitis, Gastroenterology, 154(2):319–332.
Dellon E.S., Woosley, J.T., Arrington, A., McGee, S.J., Covington, J., Moist, S.E., et al., 2019,
Rapid Recurrence of Eosinophilic Esophagitis Activity After Successful Treatment in the
Observation Phase of a Randomized, Double-Blind, Double-Dummy Trial, Clin Gastroenterol
Hepatol, epub ahead of print September 6, 2019, doi: 10.1016/j.cgh.2019.08.050.
Hirano, I., Spechler, S., Furuta, G., and Dellon, E. S., 2017, White Paper AGA: Drug
Development for Eosinophilic Esophagitis, Clin Gastroenterol Hepatol, 15(8):1173–1183.
Liacouras, C. A., Furuta, G. T., Hirano, I., Atkins, D., Attwood, S. E., Bonis, P. A., et al., 2011,
Eosinophilic Esophagitis: Updated Consensus Recommendations for Children and Adults, J
Allergy Clin Immunol, 128(1):3–20.
Straumann, A., and Katzka, D. A., 2018, Diagnosis and Treatment of Eosinophilic Esophagitis,
Gastroenterology, 154(2):346–359.
Warners, M. J., Oude Nijhuis, R. A. B., de Wijkerslooth, L. R. H., Smout, A., and Bredenoord,
A. J., 2018, The Natural Course of Eosinophilic Esophagitis and Long-Term Consequences of
Undiagnosed Disease in a Large Cohort, Am J Gastroenterol, 113(6):836–844.
Guidances1
Draft guidance for industry and FDA staff Qualification Process for Drug Development Tools
(December 2019)2
Draft guidance for industry Multiple Endpoints in Clinical Trials (January 2017)3
1 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
2 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/regulatory-information/search-fda-guidance-
documents.
3 When final, this guidance will represent the FDA’s current thinking on this topic.

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Guidance for industry, FDA staff, and other stakeholders Patient-Focused Drug Development:
Collecting Comprehensive and Representative Input (June 2020)
Guidance for industry Immunogenicity Assessment for Therapeutic Protein Products (August
2014)
Guidance for industry Nonclinical Safety Evaluation of Pediatric Drug Products (February
2006)
Guidance for industry Orally Inhaled and Intranasal Corticosteroids: Evaluation of the Effects
on Growth in Children (March 2007)
Guidance for industry Patient-Reported Outcome Measures: Use in Medical Product
Development to Support Labeling Claims (December 2009)
Guidance for industry Premarketing Risk Assessment (March 2005)
International Council for Harmonisation draft guidance for industry E9(R1) Statistical Principles
for Clinical Trials: Addendum on Estimands and Sensitivity Analysis in Clinical Trials (October
2017)