Dry Eye: 
Developing Drugs 
for Treatment 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 90 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Wiley Chambers at 301-796-0690. 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2020 
Clinical/Medical
15092dft.docx 
12/14/2020   
Dry Eye: 
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) 
 
December 2020 
Clinical/Medical
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  CONSIDERATIONS FOR CLINICAL TRIALS .......................................................... 1 
A.  Trial Design .................................................................................................................................... 1 
B.  Comparator .................................................................................................................................... 2 
C.  Trial Population ............................................................................................................................. 2 
D.  Efficacy Considerations ................................................................................................................. 3 
E.  Safety Considerations .................................................................................................................... 4 
F.  Clinical Evaluations ....................................................................................................................... 4 
G.  Pediatrics ........................................................................................................................................ 5 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Dry Eye:  Developing Drugs 
2  for Treatment 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  This guidance is intended to provide recommendations to sponsors regarding eligibility criteria, 
18  trial design considerations, and efficacy endpoints to enhance clinical trial data quality and to 
19  foster greater efficiency in development programs for drugs for the treatment of dry eye.2 
20   
21  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
22  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
23  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
24  the word should in Agency guidances means that something is suggested or recommended, but 
25  not required.  
26   
27   
28  II.  CONSIDERATIONS FOR CLINICAL TRIALS 
29   
30  A.  Trial Design  
31   
32  Sponsors developing drugs for the treatment of dry eye should consider the following regarding 
33  trial design: 
34   
35    Both traditional environmental exposure trials and challenge-model trials (utilizing a 
36  controlled chamber with regulated temperature, air flow, humidity, etc.) can be acceptable.  
37   
                                                 
1 This guidance has been prepared by the Division of Ophthalmology in the Center for Drug Evaluation and 
Research at the Food and Drug Administration.  For biological products regulated by the Center for Biologics 
Evaluation and Research, sponsors should contact the Office of Tissues and Advanced Therapies. 
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
38    FDA recommends parallel, randomized by patient, double-masked trials in which the 
39  investigational drug group demonstrates superiority over the control group (control agent 
40  can be the vehicle).   
41   
42    Trials in which the investigational drug is used as an add-on to a standardized treatment 
43  regimen are also acceptable.   
44   
45    FDA recommends that efficacy be demonstrated in single-day, controlled environment 
46  trials or in multiday, natural exposure trials of 2-weeks duration or longer.  FDA 
47  recommends that safety trials be conducted at least 6 weeks in duration if efficacy trials 
48  are of shorter duration. 
49   
50  B.  Comparator 
51   
52  Sponsors developing drugs for the treatment of dry eye should consider the following regarding 
53  comparative clinical trials: 
54   
55    Water is known to be an effective component of topically applied treatments for dry eyes.  
56  Therefore, in general, comparative clinical trials should use the investigational drugs 
57  vehicle as a control agent.  
58   
59    Trials should demonstrate statistical and clinical superiority over a vehicle control or 
60  another treatment regimen. 
61   
62    Clinical trials for the treatment of dry eyes, even with known effective therapies, can fail 
63  to demonstrate efficacy.  In the absence of good assay validation (sensitivity) methods 
64  (inclusion of both a positive and negative concurrent control), FDA does not recommend 
65  equivalence or noninferiority trials. 
66   
67  C.  Trial Population 
68   
69  Sponsors developing drugs for the treatment of dry eye should consider the following regarding 
70  trial population: 
71   
72    The sponsor should enroll patients with ocular complaints consistent with dry eye 
73  symptoms.  Inclusion criteria should include both objective signs and subjective 
74  symptoms.   
75   
76    Patients from relevant demographic subsets should be studied, including both men and 
77  women and multiple age, racial/ethnic, and eye color groups. 
78   
79    Dry eye secondary to scarring (such as that seen with irradiation, alkali burns, Stevens-
80  Johnson syndrome, cicatricial pemphigoid) or the destruction of conjunctival goblet cells 
81  (as with vitamin A deficiency) represent a specific, severely affected patient population.  
82  In general, these are considered separate indications, and patients with these conditions 
83  should be studied separately from routine dry eye conditions.  
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
84   
85    Severe blepharitis or obvious inflammation of the lid margin can interfere with the 
86  interpretation of trial results.  In general, patients with these conditions should be studied 
87  separately from routine dry eye conditions. 
88   
89  D.  Efficacy Considerations 
90   
91  Sponsors developing drugs for the treatment of dry eye should consider the following regarding 
92  efficacy: 
93   
94    In general, safety and efficacy should be demonstrated in at least two adequate and 
95  well-controlled, multicenter independent trials. 
96   
97    FDA recommends that the sponsor demonstrate one of the following: 
98   
99    A statistically significant difference between the investigational treatment and vehicle 
100  for at least one objective prespecified sign of dry eye (mean group score of test versus 
101  vehicle) and at least one subjective prespecified symptom of dry eye (mean group 
102  score), or  
103   
104    A statistically significant difference between the percentage of patients achieving a 
105  complete resolution of corneal staining, or  
106   
107    A statistically significant difference between the percentage of patients achieving a 
108  10-millimeter increase or more in Schirmers tear test scores. 
109   
110    If a sign and a symptom are used to demonstrate efficacy, FDA recommends a number of 
111  different endpoints for an objective sign or subjective symptom (see bullet points below).   
112   
113    Signs of dry eye include, but are not limited to, corneal staining, conjunctival staining, 
114  decreased tear breakup time, and decreased Schirmers tear test score (with or without 
115  anesthesia).  
116   
117    Symptoms of dry eye include, but are not limited to, blurred vision, light sensitivity, sandy 
118  or gritty feeling, ocular irritation, ocular pain or discomfort, and ocular itching.  Subjects 
119  can self identify their own term for ocular discomfort, which can be used in place of any 
120  other term.   
121   
122    A subjective symptom improvement can also be demonstrated by showing a statistically 
123  significant difference between the percentage of patients achieving a complete resolution 
124  of the symptom.  FDA does not recommend the use of anything less than complete 
125  resolution (complete clearing of a sign or symptom) for a responder analysis.  
126   
127    Efficacy for a sign and efficacy for a symptom do not have to be demonstrated in the same 
128  clinical trial, but each should be demonstrated in more than one clinical trial.  
129   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
130    The sponsor should discuss with FDA any scoring methods or scales used to measure 
131  efficacy variables and should submit a copy of the scoring methods or scales with the 
132  protocol.  
133   
134    FDA recommends that at least one of the clinical trials include treatment of patients with 
135  the proposed final market formulation. 
136   
137  E.  Safety Considerations 
138   
139  Sponsors developing drugs for the treatment of dry eye should consider the following regarding 
140  safety: 
141   
142    The clinical program should include enough patients to identify adverse drug events that 
143  occur at a rate of 1 percent or greater.  To accomplish this, FDA recommends that 
144  approximately 400 or more patients using the investigational drug complete treatment with 
145  a concentration of the investigational drug at least as high as proposed for marketing and 
146  with a frequency at least as frequent as proposed for marketing.   
147   
148    Before submission of a marketing application, the sponsor should ensure that least 300 
149  patients have completed at least 6 weeks of follow-up after the initiation of treatment and 
150  at least 100 patients have completed 12 months of follow-up after the initiation of 
151  treatment. 
152   
153    For reformulations of drug substances that are already approved in the same dosage form, 
154  same route of administration, and the same or lower concentration, FDA recommends the 
155  sponsor ensure that a marketing application has safety information from at least 100 
156  patients treated for at least 6 months. 
157   
158  F.  Clinical Evaluations 
159   
160  Sponsors developing drugs for the treatment of dry eye should consider the following regarding 
161  clinical evaluations: 
162   
163    At a minimum, FDA recommends that the following evaluations be performed in each eye 
164  and reported separately for each eye (regardless of which eye or eyes are treated): 
165   
166    Best corrected, distance visual acuity (4 meters in distance or more) at every visit. 
167   
168    A patient comfort examination before and after drug administration at every visit. 
169   
170    A slit lamp examination of the anterior segment that includes the cornea, conjunctiva, 
171  anterior chamber, iris, lids, and lashes.  At a minimum, examinations should be 
172  performed at baseline, midway through the trial, the end of treatment, and 2 weeks 
173  after treatment discontinuation. 
174   
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
175    Endothelial cell count, systemic clinical and laboratory evaluations, and dilated fundus 
176  examinations at baseline and at the end of trial or at month 3 (whichever is later) in at 
177  least one trial. 
178   
179  G.  Pediatrics 
180   
181  Dry eye rarely occurs in the pediatric population.  Sponsors should consider pediatric assessment 
182  waiver requests when submitting their required pediatric study plans under the Pediatric Research 
183  Equity Act.3 
184   
                                                 
3 See section 505B(e)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act); 21 U.S.C. 355c(e)(1); and 
section 505B(a)(1)(A) of the FD&C Act; 21 U.S.C. 355c(a)(1)(A).   
5