Neovascular Age-Related 
Macular Degeneration: 
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DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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, or 
(CBER) Office of Communication, Outreach and Development at 800-835-4709 or 240-402-
8010. 
 
 
 
 
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) 
 
 
February 2023 
Clinical/Medical
46592050dft.docx 
2/6/2023   
Neovascular Age-Related 
Macular Degeneration: 
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 
 
and/or 
 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; 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) 
 
February 2023 
Clinical/Medical
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  CONSIDERATIONS FOR CLINICAL TRIALS .......................................................... 2 
A.  Trial Design .................................................................................................................................... 2 
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  Neovascular Age-Related Macular Degeneration:  
2  Developing Drugs 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 neovascular 
20  age-related macular degeneration.2, 3 
21   
22  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
23  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
24  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
25  the word should in Agency guidances means that something is suggested or recommended, but 
26  not required. 
27   
28   
 
1 This guidance has been prepared by the Division of Ophthalmology in the Center for Drug Evaluation and 
Research and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.  For 
biological products regulated by CBER, sponsors should contact the Office of Tissues and Advanced Therapies 
(OTAT).  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
 
3 Neovascular age-related macular degeneration is also known as wet age-related macular degeneration. 
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
29  II.  CONSIDERATIONS FOR CLINICAL TRIALS4 
30   
31  A.  Trial Design 
32   
33  Sponsors developing drugs for the treatment of neovascular age-related macular degeneration 
34  should consider the following regarding trial design: 
35   
36    FDA recommends parallel-group, randomized by patient, double-masked trials in which 
37  the investigational drug group demonstrates superiority over the control group.   
38   
39    Alternatively, FDA recommends parallel-group, randomized by patient, double-masked 
40  trials in which the investigational drug group demonstrates noninferiority either to 
41  ranibizumab injection administered intravitreally every 4 weeks or to aflibercept 
42  administered intravitreally either every 4 weeks or every 8 weeks (after 3 monthly 
43  injections).   
44   
45  B.  Comparator 
46   
47  Sponsors developing drugs for the treatment of neovascular age-related macular degeneration 
48  should consider the following regarding comparative clinical trials: 
49   
50    Each investigational drug arm is expected to have at least one other comparative arm in 
51  which the dosing frequency, criterion for dosing adjustments, and criterion for 
52  interventions are the same. 
53   
54  C.  Trial Population 
55   
56  Sponsors developing drugs for the treatment of neovascular age-related macular degeneration 
57  should consider the following regarding trial population: 
58   
59    Trials should include patients older than 50 years of age from relevant demographic 
60  subsets, including both men and women and multiple racial/ethnic and eye color groups. 
61   
62    Patients should have choroidal neovascularization documented by fundus photography, 
63  fluorescein angiography, or optical coherence tomography. 
64   
65    For a trial designed as a superiority trial, the sponsor should enroll patients with 
66  neovascularization caused by age-related macular degeneration who have had visual loss 
67  or would be expected to develop visual loss.   
68   
 
4 For clinical trials involving cellular or gene therapy products, sponsors should discuss their development programs 
with OTAT.  For clinical trials involving gene therapy products, sponsors should also consult the guidance for 
industry Human Gene Therapy for Retinal Disorders (January 2020).  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  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
69    For a trial designed as a noninferiority trial, the sponsor should enroll patients with 
70  neovascularization caused by age-related macular degeneration who have visual loss.  
71   
72    Neovascular macular degeneration secondary to causes other than aging (such as 
73  presumed ocular histoplasmosis or high myopia) are considered separate indications, and 
74  sponsors should study patients with these conditions separately. 
75   
76  D.  Efficacy Considerations 
77   
78  Sponsors developing drugs for the treatment of neovascular age-related macular degeneration 
79  should consider the following regarding efficacy: 
80   
81    In general, safety and efficacy should be demonstrated in at least two adequate and 
82  well-controlled, multicenter trials utilizing different investigative sites. 
83   
84    One eye per patient should be prespecified as the study eye for the purposes of the efficacy 
85  analysis even if both eyes are treated.  Both eyes should be followed for safety. 
86   
87    FDA recommends that the sponsor demonstrate one of the following: 
88   
89   A statistically significant smaller percentage of patients with a doubling of the visual 
90  angle5 in best corrected distance visual acuity6 at 9 months7 or later after the start of 
91  drug administration in the investigational drug treatment group compared to the 
92  control8 group;  
93   
94   A statistically significant larger percentage of patients with a halving of the visual 
95  angle9 in best corrected distance visual acuity6 at 9 months7 or later after the start of 
96  drug administration in the investigational drug treatment group compared to the 
97  control group;  
98   
99   A statistically significant difference between groups in mean best corrected distance 
100  visual acuity6 of 15 or more letters at 9 months7 or later after the start of drug 
101  administration. 
102   
 
5 The phrase doubling of the visual angle is equivalent to 15 letters or more decrease on an ETDRS visual acuity 
chart measured at a distance of 4 meters or longer.   
 
6 Best corrected distance visual acuity can be measured at 3 meters instead of 4 meters if measured using an 
automated threshold testing system. 
 
7 For cellular and gene therapy products, FDA recommends that efficacy be demonstrated at 12 months or later. 
 
8 Control can be the vehicle of the investigational drug or another drug. 
 
9 The phrase halving of the visual angle is equivalent to 15 letters or more improvement on an ETDRS visual acuity 
chart measured at a distance of 4 meters or longer.   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
103   A two-sided, 95 percent confidence interval in which either the lower bound of the 
104  confidence interval for the difference between the investigational drug group and a 
105  ranibizumab injection group is greater than or equal to -4.5 letters or the lower bound 
106  of the two-sided, 95 percent confidence interval for the difference between the 
107  investigational drug group and an aflibercept group is greater than -4.5 letters in mean 
108  best corrected distance visual acuity6 at 9 months7 or later after the start of drug 
109  administration. 
110   
111  A decrease in the number of administrations of available effective therapies alone is not sufficient 
112  for the demonstration of efficacy. 
113   
114  E.  Safety Considerations 
115   
116  Sponsors developing drugs for the treatment of neovascular age-related macular degeneration 
117  should consider the following regarding safety: 
118   
119    FDA recommends that approximately 400 or more patients using the investigational drug 
120  complete treatment with a concentration of the investigational drug at least as high as 
121  proposed for marketing and with a dosing frequency at least as frequent as proposed for 
122  marketing. 
123   
124    Before submission of a marketing application, the sponsor should ensure that at least 300 
125  patients have completed at least 9 months of follow-up after the initiation of treatment. 
126   
127    FDA recommends that at least one concurrently controlled safety trial be conducted for at 
128  least 2 years duration.10 
129   
130  F.  Clinical Evaluations 
131   
132  Sponsors developing drugs for the treatment of neovascular age-related macular degeneration 
133  should consider the following regarding clinical evaluations: 
134   
135    At a minimum, FDA recommends sponsors perform the following evaluations in each eye 
136  and report separately for each eye (regardless of which eye or eyes are treated): 
137   
138   Best corrected distance visual acuity11 at every visit. 
139   
140   Dilated seven-field fundus photographs or equivalent wide-field views at no less than 
141  6-month intervals during the first 2 years. 
142   
 
10 For clinical trials involving gene therapy products, sponsors should consult the guidance for industry Long Term 
Follow-Up After Administration of Human Gene Therapy Products (January 2020) and should discuss their 
development programs with OTAT.   
 
11 Best corrected distance visual acuity can be measured at 3 meters instead of 4 meters if measured using an 
automated threshold testing system. 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
143   A dilated slit lamp examination of the anterior segment including the cornea, 
144  conjunctiva, anterior chamber, iris, lids, and lashes.  At a minimum, examinations 
145  should be performed at baseline and at no less than 3-month intervals during the first 
146  year and no less than every 6 months during the second year. 
147   
148   Applanation tonometry at no less than 3-month intervals.  If the investigational drug is 
149  administered topically, dosing of the drug should be at least 30 minutes after use of 
150  any anesthetic drug. 
151   
152   Endothelial cell count at baseline and at the end of at least one 9-month or longer trial. 
153   
154    If systemic exposure is minimal, systemic clinical and laboratory evaluations are 
155  recommended at baseline and at the end of at least one 9-month or longer trial.  If systemic 
156  exposure is not minimal, systemic clinical and laboratory evaluations are recommended at 
157  regular intervals in all clinical trials. 
158   
159  G.  Pediatrics 
160   
161  Neovascular age-related macular degeneration rarely occurs in the pediatric population.  Sponsors 
162  should consider pediatric assessment waiver requests when submitting their required pediatric 
163  study plans under the Pediatric Research Equity Act.12 
 
12 See section 505B(e)(1) of the Federal Food, Drug, and Cosmetic (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