Contains Nonbinding Recommendations 
 
Premarket Studies of Implantable 
Minimally Invasive Glaucoma Surgical 
(MIGS) Devices
 
______________________________________________________________________________ 
Guidance for Industry and  
Food and Drug Administration Staff 
Document issued on December 15, 2015. 
This guidance has been updated on December 21, 2015 to include figures that 
were omitted in error.  
The draft of this document was issued on February 11, 2015. 
 
For questions about this document, contact the Division of Ophthalmic and Ear, Nose, and Throat 
Devices (DOED) at 301-796-5620.   
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
Office of Device Evaluation 
Division of Ophthalmic and Ear, Nose, and Throat Devices 
Intraocular and Corneal Implants Branch  
1 
  Contains Nonbinding Recommendations 
 
Preface 
Public Comment 
 
You may submit electronic comments and suggestions at any time for Agency consideration to 
http://www.regulations.gov . Submit written comments to the Division of Dockets Management, 
Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 
20852. Identify all comments with the docket number FDA-2015-D-0288. Comments may not be 
acted upon by the Agency until the document is next revised or updated. 
Additional Copies 
Additional copies are available from the Internet. You may also send an e-mail request to 
CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document 
number 1400049 to identify the guidance you are requesting. 
2 
  Contains Nonbinding Recommendations 
 
Table of Contents
 
I.  Introduction ........................................................................................................................................................... 4 
II.  Scope..................................................................................................................................................................... 5 
III.  Definitions ............................................................................................................................................................ 5 
IV.  Non-Clinical Testing Recommendations .............................................................................................................. 6 
A.  Biocompatibility Testing .................................................................................................................................. 7 
B.  Physical and Mechanical Testing ..................................................................................................................... 9 
C.  Sterility and Package Integrity ....................................................................................................................... 10 
D.  Shelf Life and Shipping Testing ..................................................................................................................... 11 
V.  Clinical Studies ................................................................................................................................................... 13 
A.  Study Design .................................................................................................................................................. 13 
B.  Subject Selection Factors................................................................................................................................ 13 
C.  Effectiveness Endpoints ................................................................................................................................. 15 
D.  Safety Outcomes ............................................................................................................................................. 19 
VI.  References ........................................................................................................................................................... 20 
3 
  Contains Nonbinding Recommendations 
 
Premarket Studies of Implantable 
Minimally Invasive Glaucoma Surgical 
(MIGS) Devices
 
 
Guidance for Industry and  
Food and Drug Administration Staff  
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 staff 
or Office responsible for this guidance as listed on the title page. 
 
I.  Introduction 
This guidance document recommends non-clinical and clinical studies to support a premarket 
approval (PMA) for implantable minimally-invasive glaucoma surgical (MIGS) devices. 
Glaucoma is a progressive condition that damages the optic nerve of the eye, is commonly 
associated with elevated intraocular pressure, and leads to irreversible vision loss. It is the second 
leading cause of visual disability and blindness in the world.  One in 40 adults over 40 years of 
age has glaucoma severe enough to cause loss of visual function.1,2 Current treatments for 
glaucoma are designed to reduce the intraocular pressure (IOP). Many options are available to 
lower the IOP including medications, laser treatments, and surgical interventions. Current 
surgical treatments for glaucoma are aimed at reducing intraocular pressure through the 
reduction of aqueous inflow or the enhancement of aqueous outflow. While trabeculectomy is 
the standard surgical intervention for glaucoma, it is often reserved for moderate to severe 
disease. During the past decade, novel medical devices, called MIGS devices, have emerged. 
These devices are designed to treat less severe glaucoma by enhancing physiological aqueous 
outflow with an approach that causes minimal tissue disruption.  
This guidance represents the Agencys initial thinking and our recommendations may change as 
more information becomes available. The Agency strongly encourages manufacturers to engage 
with CDRH through the Pre-Submission process to obtain more detailed feedback for 
implantable MIGS devices. For more information on Pre-Submissions, please see Requests for 
Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with 
Food and Drug Administration Staff 
4 
  Contains Nonbinding Recommendations 
 
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocu
ments/UCM311176.pdf). 
For the current edition of the FDA-recognized standard referenced in this document, see the 
FDA Recognized Consensus Standards Database website at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm. 
 
FDAs guidance documents, including this guidance, 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 guidance means that something is suggested or 
recommended, but not required.  
II.  Scope 
The recommendations made in this guidance are applicable to implantable MIGS devices, a type 
of Intraocular Pressure Lowering Implant (associated with product code OGO) used to lower 
intraocular pressure using an outflow mechanism with either an ab interno or ab externo 
approach and associated with little or no scleral dissection and minimal or no conjunctival 
manipulation.  Intraocular Pressure Lowering Implants are Class III devices and are defined as 
devices intended to reduce intraocular pressure when implanted in eyes which have not failed 
conventional medical and surgical treatment.  This guidance provides additional details on non-
clinical and clinical study recommendations not described in the currently FDA-recognized 
version of ANSI Z80.27: American National Standard for Ophthalmics  Implantable Glaucoma 
Devices.  
The recommendations in this guidance document do not apply to implants used to reduce IOP in 
the anterior chamber of the eye in patients with neovascular glaucoma or with glaucoma when 
medical or conventional surgical treatments have failed, associated with product code (KYF) and 
regulated as class II devices under 21 CFR 886.3920, Aqueous Shunt. 
III.  Definitions  
 
For purposes of this guidance document, the following definitions apply: 
Glaucoma:  An ophthalmic disease usually characterized by increased intraocular 
pressure (IOP) resulting in damage to the optic nerve and documented by typical visual 
field defects. 
 
Humphrey Visual Field (HVF):  Automated test method to measure retinal 
sensitivity  During this test, lights of varying intensities are presented in different parts of 
the visual field while the subject focuses on one spot. The perception of these lights is 
charted in decibel (dB) units of light sensitivity. 
Hypotony:  An intraocular pressure (IOP) less than 6mm Hg.   
5 
  Contains Nonbinding Recommendations 
 
Intraocular Pressure (IOP): Assessment of pressure in the eye with a tonometer.  
It is measured in millimeters of mercury (mmHg). 
IOP Lowering Implant:  A device intended to reduce IOP when implanted in eyes 
that have not failed conventional medical and surgical treatment. 
Hypotony Maculopathy:  Abnormality of the macula in the setting of hypotony 
characterized by optic nerve head swelling, and chorioretinal folds.  
Glaucoma Hemifield Test:  A particular analysis of the HVF that compares points 
in the upper field to corresponding points in the lower field and then interprets the results 
as (a) outside normal limits indicating the upper and lower fields are different and may 
signify glaucoma, (b) borderline, and (c) within normal limits. 
 
Mean Deviation (MD):  Average difference between the subjects overall sensitivity 
for each point on the visual field when compared with   that of the reference population.   
Minimally-Invasive Glaucoma Surgical (MIGS) Device:  A type of IOP 
lowering device used to lower IOP using an outflow mechanism with either an ab interno 
or ab externo approach, associated with little or no scleral dissection and minimal or no 
conjunctival manipulation.  
Ocular Hypertension:  A condition with elevated IOP but no signs of visual field 
loss or optic nerve damage associated with glaucoma. These subjects may also be called 
glaucoma suspects. 
Pattern Deviation (PD) Plot:  This measure from the automated visual field 
provides information about localized defects by adjusting for generalized visual field 
depression due to non-glaucomatous factors such as media opacity (e.g., cataract or a 
vitreous hemorrhage).   
Washout:  Part of a clinical trial when a subject is asked to stop taking all medications. 
This can occur prior to initiating the investigational treatment as well as before assessing 
clinical endpoints.   
IV.  Non-Clinical Testing Recommendations 
All non-clinical testing should be performed on the finished sterilized product that is intended to 
be marketed.  
6 
  Contains Nonbinding Recommendations 
 
A.  Biocompatibility Testing   
 
If the actual device cannot be used in testing (e.g., due to the small area of the device), 
test samples (e.g., coupons) that are representative of the final device may be employed 
for biocompatibility testing. 
 
1.  Recommended Biocompatibility Tests 
The following tests should be performed as recommended by Bluebook 
Memorandum G95-1 Use of International Standard ISO-10993, Biological 
Evaluation of Medical Devices Part 1: Evaluation and Testing. 
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceD
ocuments/ucm080735.htm).  
a.  Cytotoxicity 
b.  Sensitization 
c.  Ocular irritation 
d.  Systemic toxicity (acute toxicity) 
e.  Sub-chronic toxicity (subacute toxicity) 
f.  Genotoxicity 
g.  Carcinogenicity 
h.  Pyrogens Testing.  If the device contacts blood then material-
mediated pyrogenicity testing is also recommended. 
In addition, ocular implantation testing should be conducted as outlined in Annex 
B of the currently FDA-recognized version of ANSI Z80.27: American National 
Standard for Ophthalmics  Implantable Glaucoma Devices. There might be 
cases (e.g., inflammation) in which the 6-month implantation study recommended 
in ANSI Z80.27 is not sufficient and longer implantation studies may be needed. 
For recommended implant test periods for various animal models, please refer to 
FDA-recognized sections of ISO 10993-6: Biological evaluation of medical 
devices  Part 6: Tests for local effects after implantation. 
 
2.  Recommended Physico-Chemical Tests 
a.  Test of Extractables and Hydrolytic Stability:  Testing should be 
conducted as outlined in Annex C of the currently FDA-recognized 
version of ISO 11979-5: Ophthalmic Implants  Intraocular 
Lenses  Part 5: Biocompatibility. 
b.  Test of Extractables by Exhaustive Extraction (Annex C of ISO 
11979-5) 
c.  Leachables (Annex D of ISO 11979-5) 
d.  Insoluble Inorganics (ISO 11979-5) 
7 
  Contains Nonbinding Recommendations 
 
3.  Bioabsorbable Materials   
 
This testing should be performed if the material is in situ polymerizing and 
bioabsorbable. 
 
Toxicity should be assessed for the finished product as well as at various time 
points over the course of polymerization and/or degradation to ensure that 
starting, intermediate and final degradation products are evaluated. Assessments 
should continue until the polymer is no longer present in the tissue, or until the 
biological tissue response is demonstrated to be stable. For additional guidance, 
please refer to the currently FDA-recognized sections of ISO 10993-6 and the 
currently FDA-recognized version of ANSI Z80.27. 
4.  Biological Response from Device Mechanical Failure 
For devices incorporating a coating or multiple material components, it is possible 
that mechanical failure could alter the biological response to the device. For 
devices with the potential for biological hazard due to mechanical failure, the 
biocompatibility testing should include testing to address this concern.  We 
encourage manufacturers to propose a minimum limit for device failure as 
determined with scientific justification. This should be based on considerations 
such as the device material and design, risk analysis, anatomical location, and 
insertion method. 
5.  Sample Preparation 
For biocompatibility testing using extracts of samples, the extraction should be 
conducted using both polar (water, physiological saline) and non-polar (sesame 
oil, cotton oil) extraction vehicles under conditions as described in the currently 
FDA-recognized version of ISO 10993-12: Biological evaluation of medical 
devices -- Part 12: Sample preparation and reference materials. For permanently 
implanted devices, extraction at 37C for 72 hours may not be sufficient to obtain 
an extract that represents the chemicals that may leach out over the use life of the 
device. However, in some cases, temperatures over 37C may result in degradants 
and toxicities that are not representative of the device. Therefore, a justification 
for the selected extraction conditions should be provided. 
 
Extraction should be performed based on surface area of the device. If the area 
cannot be determined than a mass/volume should be used. The test extract should 
not be processed (e.g., filtered or centrifuged) and should be used immediately 
after preparation. 
 
Extraction in tissue culture media supplemented with serum is acceptable for 
cytotoxicity testing and should be performed according to the currently FDA-
recognized version of ISO 10993-5: Biological evaluation of medical devices -- 
Part 5: Tests for in vitro cytotoxicity. 
8 
  Contains Nonbinding Recommendations 
 
A scientifically-based rationale for omission of any recommended test should be 
included with the submission. We recommend that sponsors who do not intend to 
conduct biocompatibility testing submit a pre-submission to obtain feedback from 
the Division of Ophthalmic and Ear, Nose, and Throat Devices on the their 
rationale. For more information on Pre-Submissions, please see FDAs guidance 
Medical Devices:  The Pre-Submission Program and Meetings with FDA Staff 
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/UCM311176.pdf). 
B.  Physical and Mechanical Testing 
 
Device properties should be determined at in situ conditions with the temperature 
tolerance of  2 C. The precise composition of the solution used should be reported in 
all cases. FDA recommends that testing be conducted as outlined in Physical and 
Mechanical Testing of Section 5 of ANSI Z80.27 with the following additions and 
exceptions. 
1.  Validation of Dimensional Tolerances 
(Section 5.4 of ANSI Z80.27) Dimensions for which tolerances are given should 
be specified in the manufacturers design documentation. The sponsor should 
validate that their production meets their tolerances to appropriate statistical 
levels. 
2.  Surface and Edge Quality 
 
(Sections 5.2 and 5.3 of ANSI Z80.27) The device should be essentially free from 
surface defects and all edges should appear smooth when viewed at 10x 
magnification with a stereo microscope using optimal lighting conditions. Any 
questionable or critical areas should be viewed at higher magnification. 
3.  Structural Integrity 
(Section 5.7 of ANSI Z80.27) The manufacturer should provide evidence that the 
device can withstand surgical manipulations without failure. An appropriate test 
method and specification should be established by the manufacturer to ensure that 
the device does not fail at typical deformations. 
4.  Insertion Testing 
The purpose of this testing is to evaluate the integrity of the delivery system and 
of the delivered device, if the MIGS device is designed to be delivered from an 
injector system. The injector system should be evaluated following the 
instructions supplied by the manufacturer and using recommended lubricants and 
9 
  Contains Nonbinding Recommendations 
 
instrumentation. There should be no change in the physical properties of the 
MIGS device and no damage to the injector system as a result of the delivery. The 
results should be reported and are acceptable if the physical properties of the 
MIGS device remain within manufacturing specifications of the product. 
5.  Coated Devices 
MIGS devices with surface coatings should conduct testing per Section 9.2 of 
ANSI Z80.27. 
 
6.  Metallic Devices 
 
MIGS devices manufactured with metallic materials should be evaluated for 
Magnetic Resonance Imaging (MRI) safety according to FDA Guidance for 
Industry and FDA Staff: Establishing Safety and Compatibility of Passive 
Implants in the Magnetic Resonance (MR) Environment 
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/UCM107708.pdf) and for corrosion resistance according to 
the currently FDA-recognized version of ASTM F2129: Standard Test Method for 
Conducting Cyclic Potentiodynamic Polarization Measurements to Determine the 
Corrosion Susceptibility of Small Implant Devices. 
 
C.  Sterility and Package Integrity 
1.  Sterilization Method 
 
The sterilization method should be validated according to one of the following 
standards: 
a.  For moist heat (steam), use the currently FDA-recognized version 
of ANSI/AAMI/ISO 17665-1: Sterilization of Health Care 
Products  Moist Heat  Part 1: Requirements for the 
Development, Validation, and Routine Control of a Sterilization 
Process for Medical Devices. 
b.  For ethylene oxide, use the currently FDA-recognized version of 
ISO 11135: Sterilization of Health Care Products  Ethylene 
Oxide  Requirements for the Development, Validation, and 
Routine Control of a Sterilization Process for Medical Devices. 
c.  For gamma radiation, use the currently FDA-recognized version of 
ANSI/AAMI/ISO 11137-1: Sterilization of Health Care Products 
 Radiation  Part 1: Requirements for the Development, 
Validation, and Routine Control of a Sterilization Process for 
Medical Devices. 
10 
  Contains Nonbinding Recommendations 
 
2.  Ethylene Oxide Sterilant Residues 
 
If the MIGS device is sterilized via ethylene oxide, then the maximum level of 
ethylene oxide residuals that remain on the device should be quantified and 
assessed according to the currently FDA-recognized version of ISO 10993-7: 
Biological evaluation of medical devices  Part 7: Ethylene oxide sterilization 
residuals. An exhaustive solvent or head space extraction method should be 
chosen and the amount of residue should conform to those for intraocular lenses. 
If the extraction is not exhaustive, release criteria should be lowered in proportion 
to the relative efficiency of the method. 
The residue of ethylene chlorohydrin should not exceed a release of more than 2.0 
g per device per day and not exceed 5.0 g in total per device. 
3.  Bacterial Endotoxins 
 
The recommended endotoxin limit for MIGS devices is 0.2 EU/device as stated 
in the FDAs guidance Endotoxin Testing Recommendations for Single-Use 
Intraocular Ophthalmic Devices 
(http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/gui
dancedocuments/ucm393376.pdf). This limit applies to the segment of the device 
placed in the anterior chamber and the segment(s) contacting the aqueous humor 
even though the main portion of the device may reside outside the eye. For 
devices that have a segment that contacts the aqueous humor and the vitreous or 
posterior segment, please contact the Division. 
 
4.  Package Integrity Testing 
 
Package integrity testing should be performed regardless of the sterilization 
method and may consist of a validated whole package physical integrity test in 
combination with a validated seal integrity test.  Examples of whole package 
physical integrity testing can be found in FDAs guidance Container and Closure 
System Integrity Testing in Lieu of Sterility Testing as a Component of the 
Stability Protocol for Sterile Products 
(http://www.fda.gov/RegulatoryInformation/Guidances/ucm146074.htm) or the 
currently FDA-recognized version of ANSI/AAMI/ISO 11607-1: Packaging for 
Terminally Sterilized Medical Devices  Part 1: Requirements for Materials, 
Sterile Barrier Systems and Packaging Systems. 
D.  Shelf Life and Shipping Testing 
1.  Development of Shelf Life Protocol 
 
The protocol for the shelf life study should be developed prior to initiation of the 
study. If, during the course of the study, a parameter no longer conforms to the 
11 
  Contains Nonbinding Recommendations 
 
manufacturing specifications at two or more time intervals, the maximum shelf-
life of the MIGS device under study has been reached at the last conforming 
measurement point. If a manufacturer wishes to maintain the possibility to re-
sterilize finished device lots, the finished device lot(s) used in the stability study 
should undergo the maximum number of sterilization cycles allowed under the 
manufacturers procedures. References to suggested test methods can be found in 
the currently FDA-recognized version of ISO 11979-6: Ophthalmic Implants  
Intraocular Lenses  Part 6: Shelf-life and Transport Stability. 
 
2.  Real-time Shelf-Life Study 
FDA recommends conducting the following stability and integrity studies: 
a.  Product Stability Studies 
(1)  Dimensions 
(2)  Surface and Edge Quality 
(3)  Structural Integrity 
(4)  Pressure/Flow Characterization 
(5)  Insertion Testing 
(6)  Coating Stability, if applicable 
b.  Package Integrity Studies 
(1)  Whole Package Physical Integrity 
(2)  Seal/Closure Integrity 
 
3.  Accelerated Shelf-Life Studies  
 
These studies are the same as those performed for real-time shelf life studies with 
the exception of the conditions in which they are performed.   It is important that 
devices to be measured be allowed to equilibrate to the same conditions as at the 
initial measurements before being tested. The corresponding real-time shelf-life is 
calculated by multiplying the studied time period by 2(T - T )/10, where T  is the 
a  o a
accelerated temperature and T is the typical storage temperature (usually room 
o 
temperature). The maximum acceptable storage temperature is 45C. While an 
initial shelf-life can be established with accelerated testing, a confirmatory real-
time shelf-life study should be performed. 
 
4.  Transport Stability 
The complete, filled device packages (in their normal transport package) should 
be able to withstand extremes of the temperature and humidity (as expected in 
shipping), vibration and being dropped. Both the packaging and the product 
should be inspected following completion of the pre-test conditioning. The device 
should be considered to have satisfactorily passed the test if the device is free 
from physical damage when visually inspected under magnification. The 
packaging should also continue to provide functional protection to the device. 
12 
  Contains Nonbinding Recommendations 
 
FDA recommends that the following tests be performed, at a minimum: 
a.  Legibility of Labeling (empty packages can be used); 
b.  Surface and Edge Quality (sealed packages should be used); 
c.  Seal/Closure Integrity (empty packages can be used); 
d.  Whole Package Physical Integrity (empty packages can be used). 
V.  Clinical Studies 
A.  Study Design 
1.  Patient Follow-up 
It is strongly recommended that all subjects be followed for a minimum of 12 
months prior to submission of any premarket application, as discussed at the 
FDA/AGS Workshop on Supporting Innovation for Safe and Effective Minimally 
Invasive Glaucoma Surgery, February 26, 2014.  For additional information, refer 
to the workshop materials and transcript available on FDAs website at 
http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm38
2508.htm. For follow-up of less than 24 months, you should provide justification 
based upon the benefit-risk analysis. For further information on the principal 
factors FDA considers when making benefit-risk determinations during the 
premarket review process, please see Factors to Consider When Making Benefit-
Risk Determinations in Medical Device Premarket Approvals and De Novo 
Classifications 
(http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocu
ments/ucm267829.htm).  If the benefit-risk analysis raises concerns beyond 24 
months after implantation, longer follow-up may be appropriate. The 
investigational plan should include the possibility that long-term follow-up (e.g., 
up to five years) may be necessary. It is recommended that informed consent for 
up to five years of follow-up is obtained. 
 
2.  Washout Period 
All eligible subjects should undergo a washout prior to surgery and at the key 
timepoints of interest for the study.  
  
B.  Subject Selection Factors 
Subjects included in clinical trials for MIGS devices should have evidence of early or 
moderate open angle (confirmed by gonioscopy) glaucoma.* For the purpose of this 
                                                           
* Based on discussion at the FDA/ AGS Workshop on Supporting Innovation for Safe and Effective Minimally 
Invasive Glaucoma Surgery, February 26, 2014, we do not believe that pre-perimetric glaucoma (i.e., optical 
coherence tomography (OCT) changes and optic nerve changes without any field abnormalities) should be included 
13 
  Contains Nonbinding Recommendations 
 
guidance, glaucoma is defined as characteristic visual field and optic nerve changes as 
outlined below. 
1.  Inclusion Criteria 
a.  Humphrey Visual Field (HVF) 
The HVF should be reliable, which is defined as fixation  losses, false 
positives, and false negatives all less than 33%.3  The following 
characteristics should also be noted on the HVF:  
(1)  Visual field defects consistent with glaucomatous optic 
nerve damage;4 and 
(2)  Mean deviation  not worse than -12 dB; and at least one of 
the following two findings: 
(a)  A cluster of 3 or more points in an expected 
location of the visual field depressed below the 5% 
level, at least 1 of which is depressed below the 1% 
level on the  pattern deviation (PD) plot 
(b)  Glaucoma hemi-field test outside normal limits. 
While these recommendations are based on HVF, equivalent perimetric 
criteria using a different device could be considered for trial enrollment.   
b.  Glaucomatous Optic Nerve Damage 
Glaucomatous optic nerve damage as evidenced by any of the following 
optic disc or retinal nerve fiber layer structural abnormalities: 
(1)  Diffuse thinning, focal narrowing, or notching of the optic 
disc rim, especially at the inferior or superior poles with or 
without disc hemorrhage; 
(2)  Localized abnormalities of the peripapillary retinal nerve 
fiber layer, especially at the inferior or superior poles; or 
(3)  Optic disc neural rim asymmetry of the two eyes consistent 
with loss of neural tissue 
 
2.  Exclusion Criteria 
 
Subjects that should be excluded from clinical trials for MIGS devices include but 
are not limited to the following: 
                                                                                                                                                                                           
in these interventional studies because there are differing opinions amongst experts about whether this condition 
warrants surgical treatment. Because this guidance focuses on an emerging topic, it represents the Agencys initial 
thinking and our recommendations may change as more information becomes available. The current 
recommendations are designed to provide a conservative approach to protection of human subjects. 
14 
  Contains Nonbinding Recommendations 
 
a.  Subjects that cannot perform HVF or equivalent perimetric testing 
in either eye 
b.  Subjects who cannot undergo a medication washout in the study 
eye or who are at high risk for adverse outcomes, including 
subjects: 
(1)  Requiring oral medications (e.g., acetazolamide)for IOP 
control  
(2)  With severe glaucoma in either eye, defined as mean 
deviation (MD) of -12.00 or worse and at least one of the 
following: 
(a)  On PD plot, greater than or equal to 75% of points 
depressed below the 5% level and greater than or 
equal to 50% of points depressed below 1% level; 
or 
(b)  At least 50% of points (i.e., 2 or more) within 
central 5 degrees with sensitivity of < 0dB on the 
dB plot; or 
(c)  Points within the central 5 degrees of fixation with 
sensitivity < 15dB in both hemifields on the dB 
plot. 
(3)  With fixation-threatening glaucoma in either eye noted at 
the qualifying visit: Subjects with visual field defects 
threatening fixation defined as any (1 or more) point(s) 
within the central 5 depressed below the 5th percentile on 
PD plot unless this/these points are >25 dB on Threshold 
Values (decibel) plot. 
(4)  With best corrected visual acuity of 20/200 or worse in the 
study eye due to glaucoma. 
  
c.  Subjects with ocular hypertension 
d.  Subjects at high risk for adverse outcomes due to placing a device 
in the angle 
For details of other subject inclusion and exclusion characteristics (e.g., minimal 
endothelial cell density), please refer to the non-refractory section of the currently 
FDA recognized version of ANSI Z80.27: American National Standard for 
Ophthalmics  Implantable Glaucoma Devices. 
C.  Effectiveness Endpoints 
1.  Washout 
 
All subjects should undergo a washout period of all IOP-lowering medications 
prior to surgery to establish a baseline IOP.  In addition, if IOP-lowering 
medications are re-instituted postoperatively, all subjects should undergo a 
15 
  Contains Nonbinding Recommendations 
 
washout period prior to the time point(s) for data collection used in the 
effectiveness analyses. 
2.  Primary effectiveness 
 
The recommended primary effectiveness endpoint is the percentage of subjects 
with reduction of at least 20% (i.e., 20%) in mean diurnal IOP from baseline. 5-9  
The proposed hypothesis test for the primary effectiveness endpoint should be 
described in the statistical analysis plan. 
 
3.  Secondary effectiveness 
 
The recommended secondary effectiveness endpoint is the mean diurnal IOP 
change from baseline. 
4.  Recommended Analyses 
 
In addition to the analyses described in ANSI Z80.27: American National 
Standard for Ophthalmics  Implantable Glaucoma Devices, FDA recommends 
the following:  
a.  Scatter Plots of Postoperative IOP as a function of 
Preoperative IOP 
Scatter plots should be provided for the mean diurnal IOP measurements.  
Reference lines should be added to the scatter plots at various 
postoperative IOP levels of interest (e.g., 18 mmHg), and the percentage 
of subjects falling on either side of each of the reference lines should be 
presented (e.g., the percent of subjects achieving postoperative IOP of less 
than 18 mmHg and the percent with postoperative IOP of greater than or 
equal to 18 mmHg).  Appropriate reference lines should be selected based 
upon such considerations as the specific enrollment criteria for the study, 
such as the IOP and severity of disease criteria. 
b.  Percent Reduction in Mean Diurnal IOP   
The number and percent (e.g., n/N & %) of subjects achieving percent 
reduction (or increase) in mean diurnal IOP at each annual visit from 
baseline across the entire distribution should be presented.  This analysis 
should be presented with and without further stratification by baseline 
mean diurnal IOP.     
 
c.  Changes in the Mean, Range, and Maximum of the Diurnal 
IOP Measurements, and Box-plots of Mean, Range, and 
Maximum of Diurnal IOP Measurements 
16 
  Contains Nonbinding Recommendations 
 
In addition to analyses of the changes in the mean diurnal IOP 
measurements from baseline described in ANSI Z80.27, , analyses of the 
changes in the range of the diurnal IOP measurements and maximum of 
the diurnal IOP measurements from baseline should be conducted.  
Descriptive statistics should be performed as described in ANSI Z80.27 
with additional stratification by baseline mean diurnal IOP.  In addition to 
the box plots of mean diurnal IOP measurements outlined in the standard, 
box plots of the range of diurnal IOP measurements and of the maximum 
diurnal IOP measurements should be presented.  An example of a box-plot 
representation of IOP data can be found in the World Glaucoma 
Associations (WGA) Guidelines on Design and Reporting of Glaucoma 
Surgical Trials, Consensus on definitions of success, Section II, General 
Data Presentation Requirements.10  
d.  Fluctuation of IOP Measurements Over Time 
For each subject, we recommend plotting the diurnal IOP measurements 
(y-axis) versus time of measurements (x-axis) for baseline and each of the 
postoperative diurnal IOP visits on the same graph using a different 
symbol for each visit (See examples in Figures 1 and 2).10  
17 
  Contains Nonbinding Recommendations 
 
e.  Change in Number of Medications 
At each postoperative visit, a graphical representation of the number pre-
operative (before washout, when applicable) on the x-axis versus post-
operative IOP-lowering medications (counting combination drops as 
separate medications) on the y-axis should be made. An example of such a 
graphical representation is presented below in Figure 3. The size of each 
bubble represents the number of subjects. 
18 
  Contains Nonbinding Recommendations 
 
f.  Assessment of Balance in Baseline Variables 
In addition to the analyses recommended in ANSI Z80.27 and above, we 
recommend checking for imbalances in baseline variables that may affect 
the outcome (e.g., baseline IOP, age, race, gender, number of medications 
at screening) among the arms of the trial. 
D.  Safety Outcomes 
1.  Adverse Events and Device Malfunctions 
 
The adverse events and device malfunctions for MIGS devices are listed in ANSI 
Z80.27. The definition of each adverse event should specify the grade or severity, 
the degree of involvement of the anatomical structure, the timing, and the duration 
of the event, as applicable, in order to distinguish findings that should be reported 
as adverse events from those observations that should be routinely recorded. 
Case report forms should include a forced-choice method of recording listed 
adverse events as well as a method of recording other adverse events not listed. 
a.  Hypotony should be classified as an early (i.e., at 2 weeks or less 
following surgery) or late (i.e., more than 2 weeks after surgery) 
adverse event if it occurs with at least one of the following 
conditions: 
(1)  Flat anterior chamber requiring anterior chamber 
reformation 
(2)  Corneal folds  
(3)  Choroidal effusions requiring or undergoing surgical 
drainage  
(4)  Suprachoroidal hemorrhage 
(5)  Maculopathy   
(6)  Corneal astigmatism 
b.  Chronic anterior uveitis should be defined as inflammation of 
grade 1+ or worse persisting for more than 3 months post-
operatively or that recurs less than three months after discontinuing 
treatment.11 Two line or greater decrease in best corrected visual 
acuity (BCVA) 
 
2.  Device Removal 
 
Reasons for device removal should be recorded in the case report forms. 
19 
  Contains Nonbinding Recommendations 
 
VI.  References 
1.  Resnikoff S, Pascolini D, Etya'ale D, et al. Global data on visual impairment in the year 
2002. Bulletin of the World Health Organization. 2004;82(11):844-851. 
2.  Quigley HA. Glaucoma. Lancet. 2011;377(9774):1367-1377. 
3.  Birt CM, Shin DH, Samudrala V, Hughes BA, Kim C, Lee D. Analysis of reliability 
indices from Humphrey visual field tests in an urban glaucoma population. 
Ophthalmology. 1997;104(7):1126-1130. 
4.  Hodapp E, Parrish RK, 2nd, Anderson DW. Clinical decisions in glaucoma. St. Louis, 
MO: The CV Mosby Co; 1993. 
5.  Craven ER, Katz LJ, Wells JM, Giamporcaro JE, iStent Study G. Cataract surgery with 
trabecular micro-bypass stent implantation in patients with mild-to-moderate open-angle 
glaucoma and cataract: two-year follow-up. J Cataract Refract Surg. 2012;38(8):1339-
1345. 
6.  Gedde SJ, Schiffman JC, Feuer WJ, et al. The tube versus trabeculectomy study: design 
and baseline characteristics of study patients. Am J Ophthalmol. 2005;140(2):275-287. 
7.  Barton K, Gedde SJ, Budenz DL, Feuer WJ, Schiffman J, Ahmed Baerveldt Comparison 
Study G. The Ahmed Baerveldt Comparison Study methodology, baseline patient 
characteristics, and intraoperative complications. Ophthalmology. 2011;118(3):435-442. 
8.  Christakis PG, Tsai JC, Zurakowski D, Kalenak JW, Cantor LB, Ahmed, II. The Ahmed 
Versus Baerveldt study: design, baseline patient characteristics, and intraoperative 
complications. Ophthalmology. 2011;118(11):2172-2179. 
9.  Samuelson TW, Katz LJ, Wells JM, Duh YJ, Giamporcaro JE. Randomized evaluation of 
the trabecular micro-bypass stent with phacoemulsification in patients with glaucoma and 
cataract. Ophthalmology. 2011;118(3):459-467. 
10.  Heuer DK, Barton K, Grehn F, Shaarawy TM, Sherwood MB. Consensus on definitions 
of success. In: Shaarawy TM, Sherwood MB, Grehn F, eds. World Glaucoma Association 
Guidelines on Design and Reporting of Glaucoma Surgical Trials. Amsterdam: Kugler 
Publications; 2009. 
11.  Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature 
Working G. Standardization of uveitis nomenclature for reporting clinical data. Results of 
the First International Workshop. Am J Ophthalmol. Sep 2005;140(3):509-516. 
 
20