Guidance for Industry and for FDA
Reviewers/Staff
Aqueous Shunts - 510(k)
Submissions
Document issued on: November 16, 1998
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
Intraocular and Corneal Implants Branch
Division of Ophthalmic Devices
Office of Device Evaluation Preface
Public Comment:
Comments and suggestions may be submitted at any time for Agency consideration
to Ms. Claudine Krawczyk, HFZ-460, 9200 Corporate Blvd., Rockville, MD
20850. Comments may not be acted upon by the Agency until the document is
next revised or updated.  For questions regarding the use or interpretation of this
guidance contact Ms. Claudine Krawczyk at (301) 594-2053 or by electronic mail
at cdh@cdrh.fda.gov.
Additional Copies:
World Wide Web/CDRH home page: http://www.fda.gov/cdrh/ode/aqshunt.pdf or CDRH
Facts on Demand at 1-800-899-0381 or 301-827-0111, specify number 2236 when
prompted for the document shelf number. I. Introduction
A. Scope
This guidance document serves as a special control for the regulation of aqueous
shunts through the submission of premarket notifications [510(k)s]. This guidance
does not pertain to devices intended for use in patients with open-angle glaucoma
or other conditions not included in the Indication(s) for Use described below.
B. Device Description
Name: Aqueous Shunt (Eye Valve Implant)
Class: 886.3920 (III, proposed reclassification to II)
Panel: Ophthalmic (OP)
Procode: KYF
An aqueous shunt is defined as an implantable device intended to reduce
intraocular pressure in the anterior chamber of the eye.
C. Intended Use and Indication(s) for Use
The aqueous shunt is intended to reduce intraocular pressure in neovascular
glaucoma or glaucoma where medical and conventional surgical treatments have
failed.
II. Pre-clinical Data
The following recommendations apply to the aqueous shunt in its final form, after
sterilization, as it is intended for implantation.  Where appropriate (e.g., with certain
biocompatibility tests), the material used in the tests may be a sample of the material
fabricated and processed in a manner equivalent to that used for the aqueous shunts.  The
manufacturer should establish and document equivalency in material and in test sensitivity,
where appropriate, for the test sample and the sterile finished aqueous shunt.
A. Physical stability: The functional and dimensional properties of the aqueous shunt
should be demonstrated to be stable with all test parameters within tolerance after
immersion in distilled water for 14 days at a temperature of 37(cid:176) C +/- 2(cid:176) C.
B. Pressure/flow characteristics: The resistance and pressure/flow characteristics of
the device under physiological conditions should be substantially equivalent to that
of a predicate device.  The opening and closing pressures of valved devices in an
aqueous environment should be within tolerances of the designed target. The shunt
should be free of leaks during testing.  Appendix A describes recommended test
methods for determining the theoretical flow characteristics of these devices. C. Structural integrity: The junctions of any components of the aqueous shunt should
be able to withstand a force of 0.5 N without breaking or resulting in the loss of
the leak-free junction.
D. Biocompatibility recommendations: The aqueous shunt should be evaluated for
biological safety.  The general recommendations specified in FDAs Office of
Device Evaluation (ODE) Guidance Memorandum #G95-1 should apply, together
with the following particular recommendations.  The following in vivo and in vitro
tests should be used to assess the biocompatibility of the aqueous shunt material
and to quantify and evaluate the toxicity of biologically active chemical entities that
may diffuse out of the finished device material.
 Intramuscular implantation (including macroscopic and microscopic
evaluation);
 Animal ocular implantation of device in designed configuration (minimum 6
animals with data to six months).  Appendix B contains a test procedure that
may be used to perform the animal ocular implantation study;
 Cytotoxicity test
- Saline and cotton seed oil extracts
- Cell growth inhibition test (9 point)
- Aqueous extract (MEM elution)
 Sensitization test
- Guinea pig maximization
 Intracutaneous test
 Mutagenicity
E. Chemical testing:  For silicones, the composition of the basic formulation should
have any volatile elements (molecular weight less than 1,000) reduced to not
greater than 1.0 wt% by gravimetric method to minimize the potentially leachable
compounds.
For PMMA and other polymers, the level of residual monomers should be no
greater than 1.0 wt%, determined for the finished aqueous shunt using an
exhaustive extraction method with an appropriate solvent to swell the device
material.
F. Aqueous aging test:  Aqueous shunt materials should be evaluated for monomer
content, molecular weight, and identification and quantification of degradation
products following aqueous aging.  ANSI Z80.7 - 1994 Annex A describes a
method that may be used to perform this test.  The shunt should be stable in all test
parameters within tolerances for equivalent to a one-year period.
G. Dimensional and surface quality:  All of the components of the aqueous shunt
should be essentially free from pits, scratches, cracking and crazing at a minimum
of 6x magnification.  The edges of the shunt should appear smooth and free of burrs and flash when inspected at 6x magnification.  The overall dimensions of the
aqueous shunt and the dimensions of the drainage area in terms of thickness, length
and width should be within   5% of the design nominal.  The inlet and discharge
tubes should have an outer diameter and inner diameter within 15% of design
nominal.
III. Clinical Data
Clinical data are needed in each 510(k) to confirm the clinical performance of the aqueous
shunt.  Aqueous shunts are considered significant risk devices, and clinical investigations
performed in the United States must take place under an investigational device exemptions
(IDE).  Aqueous shunts that have a long history of clinical usage may be able to satisfy
this recommendation with published clinical studies that demonstrate the safety and
effectiveness of the device.
New aqueous shunts (i.e., new materials, new designs) should be evaluated with a clinical
investigation developed with the protocol elements provided in Appendix C or an
equivalent protocol which has similar statistical power to detect clinically significant
differences between the test and the control populations.
IV. Examples of Predicate Devices
Krupin Eye Valve K885125 and K905703
Molteno Implant K890598 and K902489
Glaucoma Pressure Regulator K903462
Baerveldt Glaucoma Implant K905129 and K955455
Ahmed Glaucoma Valve Implant K925636
V. Sterilization Information
The method used to sterilize the device should be validated using a method appropriate for
the sterilization method. The test methods specified below are suggested methods.
Alternative methods are permitted if appropriately validated.
The recommendations for sterilization outlined in FDAs ODE Guidance Memorandum
#K90-1 should be evaluated for sterile devices.  The aqueous shunt should be provided
sterile.  Whenever possible, the product should be terminally sterilized in its final
container. However, if the device is provided non-sterile, the ODE Guidance Labeling of
Reusable Medical Devices for Reprocessing in Health Care Facilities: FDA Reviewer
Guidance should be consulted and the issues identified and addressed. A. Steam Sterilization
Validation of steam sterilization should be carried out in accordance with the
requirements of ANSI/AAMI/ISO 11134-1993 (Sterilization of health care
products -- Requirements for validation and routine control -- Industrial moist heat
sterilization).
B. Ethylene Oxide (EO) Sterilization
Validation of EO sterilization should be carried out in accordance with the
requirements of ANSI/AAMI/ISO 11135-1994 (Medical devices -- Validation and
routine control of ethylene oxide sterilization).
EO residual testing should be carried out in accordance with ISO 10993-7 (1995)
(Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization
residuals) with the following modifications:
  The procedure should consist of a solvent exhaustive extraction or a headspace
exhaustive extraction.
Note - Sponsors should choose a solvent that adequately swells or dissolves
the aqueous shunt material to facilitate extraction of the EO molecules. A
headspace method may be used if it has been validated to demonstrate that the
extraction is as exhaustive as a solvent method. Alternatively, a sponsor may
demonstrate the relative efficiency of an extraction method and adjust the
internal release specifications accordingly.
  The ethylene chlorohydrin (ECH) residue in aqueous shunts should not exceed
2.0 m g ECH per device per day, not to exceed 5.0 m g per device.
Note - Ethylene glycol residues should be sufficiently controlled by the limits set
for EO and ECH residues.
Alternatively, the methods described in AAMI ST29-1988 (Recommended
practice for determining residual ethylene oxide in medical devices) may be used
with the following specified limits:
Residue Limit
Ethylene oxide 25 ppm
Ethylene chlorohydrin 25 ppm
Ethylene glycol 500 ppm C. Radiation Sterilization
Validation of radiation sterilization should be carried out in accordance with the
requirements of ANSI/AAMI/ISO 11137 (Sterilization of health care products --
Requirements for validation and routine control -- Radiation sterilization).
VI. Packaging and Labeling
A. Packaging:  The packaging is intended to provide adequate protection to the
aqueous shunt from damage during shipping and maintain the sterility of the device
for the duration of its shelf-life.  Therefore, the following information should be
submitted:
a. A description of the packaging, including the packaging materials and the
configuration of the final packaged product should be provided.
b. The sponsor should demonstrate that the package maintains the sterility of
the device for the duration of the proposed shelf life. A validated seal
integrity test in combination with a validated microbial barrier test of the
packaging material(s) or a validated whole package physical integrity test
should be performed on the finished product before and after aging.
Examples of such testing may be found in ISO 11607 (Packaging for
terminally sterilized medical devices).
FDA prefers real-time aging be performed for establishing shelf life;
however, accelerated aging up to 5 years may be acceptable for device
materials with a history of use in ocular implants (e.g.,
polymethylmethacrylate (PMMA)) and for package materials with a history
of use in similar sterilization conditions (e.g., Tyvek pouches sterilized with
100% EO).
B. Labeling:  The labeling for the aqueous shunt should contain the following:
 Name of manufacturer
 Trade name of the product
 A description (materials) and diagram (including top and side views) of the
device which contains its dimensions (including the maximum thickness, length
and width of both the overall device, the drainage area, and the explant surface
area)
 Lot/batch number
 Indications for use
 Instructions for use
 Clinical results (including adverse events)
 Warning that the device is sterilized until opened
 Precautions to be taken for handling and safe use  Statement that the device is for single use only
Definitions provided in ODE Guidance Memorandum #G91-1 should be
referenced when necessary.  The labeling requirements described in 21 CFR Part
801 also apply. Appendix A
(informative)
Recommended standard practices for in-vitro flow characterization of aqueous shunts
A.1 Gravity Flow Test
A.1.1 Purpose
The purpose of this test is to evaluate the pressure/flow characteristics of an aqueous shunt when
exposed to a decreasing pressure gradient in an aqueous environment.  The experimental data
obtained from this test may be used to calculate a theoretical resistance to flow for the aqueous
shunt.
A.1.2 Study Design
A minimum of five finished aqueous shunts (randomly chosen) should be used (from separate lots,
if available).
A.1.3 Test Material
The aqueous shunts should be fabricated according to intended production methods, and be the
same as those used in clinical studies.
A.1.4 Materials and Equipment
-T-connector
-3-way valve
-Pressure transducer
-Manometer (may be assembled by attaching a cylinder vertically to a ring-stand)
-Tubing
-Syringe
-Deaerated, distilled water
-Water bath (35(cid:176) C) in reservoir
-27-gauge cannula (or other as necessary)
-Clamp
A.1.5 Set-up
Insert cannula into drainage tube of aqueous shunt.  Prime test samples prior to testing by wetting
all internal surfaces (for valved devices, the valve should be primed by opening the valve) by
injecting water into shunt through a syringe.  Check for leaks.  The aqueous shunt is placed in
water bath for at least one hour prior to testing to assure stable pressure/ flow characteristic.
Connect cannula of aqueous shunt to syringe and tubing via a 3-way valve.  The manometer is connected via a t-connector to the pressure transducer and the tubing to the aqueous shunt.  Fill
system from syringe with water, ensuring that no air bubbles are present in the system.  System
should be filled so that the initial pressure that the shunt is exposed to at least 40 mmHg.  This
allows for a recording of a large enough range of pressure data for calculations.  Isolate
manometer from system with the clamp.  Adjust level of water bath until surface is level with the
pressure transducer and the pressure reading is zero mmHg. The reservoir for the water bath
should be large enough such that any changes in the surface level result in negligible effects on the
pressure.  Isolate syringe from system at 3-way valve.  Remove clamp.  Record pressure and time
as fluid drains through shunt.  Stop recording data when pressure readings are steady (within +/-
0.3 mmHg) for several minutes.
A.1.6 Evaluation of Data
Conservation of mass dictates that the flow, Q, through the device can be calculated by recording
the change in volume over time:
Q(t) = A dh/dt,
where A is the constant cross-sectional area of the gravity feed tube and h is the height of the
saline in the tube that is changing over time.  Pressure, P, can be calculated from fluid height by
P = r gh,
where r  is the density of the fluid and g is gravity.  The equation for flow then becomes
Q(t) = (A/r g) dP/dt.
Therefore, the measurement of pressure over time, P(t), may be used to calculate the flow over
time, Q(t).  Define resistance to fluid flow, R, (analogous to electrical resistance) as
R = P/Q,
where P is the pressure drop between two points in a pipe and Q is the fluid flow that results.  The
resistance of an aqueous shunt will depend on various characteristics of the shunt, including
drainage tube material (and its flexibility), flow restrictor design, and characteristics of the
attachment of the drainage tube to the explant.  Solving for P and inserting into the equation for
flow results in a differential equation for pressure for which the solution can be expressed as an
exponential of the following form:
P = a e-bt + c.
The pressure versus time data obtained can be fit to an exponential curve.  Once the equation of
this curve is obtained, the flow, Q, can be calculated from dP/dt, and plotted against the pressure.
The slope of the line resulting from this plot is the resistance.  The resistance calculated from this
plot will be the resistance of the testing apparatus and cannula as well as that of the shunt.
Therefore, since resistance is additive in series, testing should be performed with the cannula
attached to the testing apparatus to obtain the resistance of the testing apparatus and cannula.
The resistance of the shunt is obtained by the following:
R  = R  - R .
implant total system + cannula A.2 Constant Flow Test
A.2.1 Purpose
The purpose of this test is to evaluate the pressure/flow characteristics of an aqueous shunt when
exposed to a constant flow rate (mimicking physiological flow rates) in an aqueous environment.
The experimental data obtained from this test may be used to calculate a theoretical resistance to
flow for the aqueous shunt.  Additionally, the opening pressure of a valved shunt can be obtained
from this test method.
A.2.2 Study Design
A minimum of five finished aqueous shunts (randomly chosen) should be used (from separate lots,
if available).
A.2.3 Test Material
The aqueous shunts should be fabricated according to intended production methods, and be the
same as those used in clinical studies.
A.2.4 Materials and Equipment
-T-connector
-Pressure transducer
-Variable-speed pump
-Tubing
-Syringe
-Deaerated, distilled water
-Water bath (35(cid:176) C) in reservoir
-27-gauge cannula (or other as necessary)
A.2.5 Set-up
Insert cannula into drainage tube of aqueous shunt.  Prime test samples prior to testing by wetting
all internal surfaces (for valved devices, the valve should be primed by opening the valve) by
injecting water into shunt through a syringe.  Check for leaks.  The aqueous shunt is placed in
water bath for at least one hour prior to testing to assure stable pressure/ flow characteristic.
Connect cannula of aqueous shunt to syringe pump and pressure transducer via a t-connector and
required tubing.  Using fluid filled syringe from syringe pump, inject fluid into the testing system
and assure that there are no air bubbles present. Adjust level of water bath until surface is level
with the pressure transducer and the pressure reading is zero mmHg.  The reservoir for the water
bath should be large enough such that any changes in the surface level result in negligible effects
on the pressure.  Adjust the pump speed to provide a flow rate of 2 l/minute.  Record pressure
after stabilization.  For valved devices, record pressure peak at which valve opens and subsequent stabilization pressure.  Repeat flow experiment with at least five flow rates ranging between 0.5
l/minute to 5 l/minute.
A.2.6 Evaluation of Data
Plot the average of the results obtained from the two devices (indicate individual data points for
discrepancies) with flow on the horizontal axis and pressure on the vertical axis.  Fit a regression
line to the plotted data and report the r-value (the measure of how well the data meets the
regression line).  Report the resistance as the slope of the line.  As discussed above, the resistance
of the testing system without the shunt should be deducted from the results to obtain the
resistance of the shunt.
For a valved shunt, an opening pressure should be evidenced by a pressure peak.  Report the
average and standard deviation of the opening pressure for the five flow rates.  If a closing
pressure is noted during testing, this value should be reported also.
A.3 Valve Open/ Close Pressures Test
A.3.1 Purpose
The purpose of this test is to evaluate the pressures at which the valve of a valved aqueous shunt
will open and close in an aqueous environment.
A.3.2 Study Design
A minimum of five finished aqueous shunts (randomly chosen) should be used (from separate lots,
if available).
A.3.3 Test Material
The aqueous shunts should be fabricated according to intended production methods, and be the
same as those used in clinical studies.
A.3.4 Materials and Equipment
-T-connector
-Pressure transducer
-Tubing
-Hand pump
-Deaerated, distilled water
-27-gauge cannula (or other as necessary)
-Syringe A.3.5 Set-up
Insert cannula into drainage tube of aqueous shunt.  Prime test samples prior to testing by wetting
all internal surfaces (for valved devices, the valve should be primed by opening the valve) by
injecting water into shunt through a syringe.  Check for leaks.  Connect cannula to tubing and
pressure transducer via t-connector.  Fill tubing with water.  Calibrate pressure transducer to
indicate zero at the point where fluid fails to flow from the tip of the cannula.  Insert cannula into
drainage tube of shunt.  Gently increase the pressure in the device using the hand pump until fluid
flows through the valve of the shunt.  Increase pressure to a value around 100 mmHg to check for
continuous flow through the valve.  Slowly reduce pressure while intermittently blotting fluid
from the explant until all flow is observed to stop for a period of 30 seconds.  Record the closing
pressure.  Gradually increase pressure until fluid flows through the valve for a period of 30
seconds.  Record the opening pressure.  Repeat five times with same device and average.
A.3.6 Evaluation of Data
The average opening and closing pressures for each of the two samples should be reported. Appendix B
(informative)
Recommended standard practices for biocompatibility testing of aqueous shunts
B.1 Ocular implant study (six months) with pathology
A subcommittee of the American National Standards Institute (ANSI) Z80 Committee is currently in
the process of developing a standard that includes this test method.
B.1.1 Purpose
The purpose of this test is to evaluate the biocompatibility of an aqueous shunt material in an ocular
environment by surgical implantation in the eye of an appropriate animal model for six months. This
test serves to assess the suitability of the shunt material and design for human clinical use.
B.1.2 Rationale for the selection of the animal model
Historically, several animal species have been used for this test including rabbits, cats, and primates
(usually the cynomolgus or rhesus monkey). The rationale for the choice of animal is based on the
experimental question(s) being considered, and therefore the scientific judgment of the investigator is
important. The choice of animal model should be appropriate to answer all of the theoretical concerns
relating to the biocompatibility of the material including, but not limited to the following:
- inflammatory response of the eye (both implanting and fellow eye) to the material;
- adhesion of cells to the surface of the implant;
- biodegradation of the implant material(s).
B.1.3 Study design
A minimum number of animals should be used, such that a minimum of six tests are available at the end
of the six-month period. One eye in each of the animals will be implanted with the test shunt.  The
treated eyes will be monitored by slit lamp biomicroscopy and indirect ophthalmoscopy for up to 6
months. The minimum of six tests should be followed for six months to be considered a valid test.
B.1.4 Test material
The  aqueous  shunt  material  should  be  fabricated  into  an  aqueous  shunt  according  to  intended
production methods. To allow for dimensional differences between human and animal eyes, the explant
might require custom design to fit the anatomical placement site.
B.1.5 Materials and equipment
- Operating microscope;
- Slit lamp;
- Indirect ophthalmoscope; - Lid speculum;
- Beaver blades;
- Balanced Salt Solution, Sterile (BSS);
- Ketamine;
- Antibiotic steroid ointment.
B.1.6 Animals
The animals will be acquired from approved vendors in accordance with the requirements of the
Animal Welfare Act. Animals of either sex can be used as long as the sex is identified in the records.
They are to be housed in a facility fully accredited by the American Association for Accreditation of
Laboratory Animal Care. Each animal will be tattooed and individually housed for identification
purposes. All animals will be subjected to slit lamp biomicroscopy and indirect ophthalmoscopy prior
to use and animals with any ocular abnormalities will be rejected. The animals are to be fasted the day
before surgery and weighed prior to use. The animals will be given appropriate food and water ad
libitum during the course of the study.
B.1.7 Surgery
The surgical techniques and intraoperative and postoperative regimen should be those appropriate for
the particular animal used as determined by the surgeon based on his/her experience. The following
describes briefly a generalized method.
The animal is anesthetized with an intramuscular injection of a combination drug containing ketamine.
The animal is then placed on the operating table and draped.  Procedures are done under an operating
microscope using aseptic techniques.
After insertion of a lid speculum, a fornix-based conjunctival flap is dissected between the insertion of
two adjacent rectus muscles.  The shunt explant is sutured to the sclera an appropriate distance
posterior to the limbus.  The shunt tube is inserted into the anterior chamber through an appropriate-
sized needle tract (typically 23-gauge).  A patch graft may be placed over the anterior portion of the
tube.  The conjunctival wound is closed and an antibiotic/steroid ointment is applied to the eye. The
animal is returned to its cage.
Intraoperative observations should include the following:
- tube/material and endothelium touch;
- collapse of the anterior chamber;
- significant anterior chamber bleeding;
- iris damage;
- placement of the shunt explant and tube, where applicable;
- excessive fibrin formation;
- unusual surgical problems that are not common to the group as a whole B.1.8 Postoperative evaluations
The operated eyes will be grossly examined at days 1 and 3. Slit lamp biomicroscopy and indirect
ophthalmoscopy will be performed at 7 days, 4 weeks, and at months 3 and 6. Observations should
include, but not be limited to, flare, cells, adhesions, neovascularization, corneal edema, location of the
tube and explant, where applicable. These examinations can be carried out more often if needed.
B.1.9 Evaluation of explanted eyes
The animals will be sacrificed at the end of their respective follow-up periods and the eyes enucleated.
The eyes of any animals that die during the course of the study other than from surgical trauma or
complications should also be evaluated.  A minimum of three of the enucleated eyes should be
immersed immediately in neutral buffered formalin for fixation and storage. The retrieved eyes will be
sectioned  equatorially  and  an  internal  examination  performed.  Any  visible  abnormalities  and  the
location/placement of the implant is noted, and photographs taken. Histopathological evaluations will
be performed on the anterior and posterior segments of the eye by an ophthalmic or a veterinary
pathologist.
B.1.10 Evaluation of explanted shunts
The shunts should be examined for cellular and fibrinous deposits as well as other abnormalities,
particularly at the tube/explant junctions and inside the tubes, where applicable. Photographs should be
taken at appropriate magnifications to document findings.  A minimum of two shunts that have been
implanted for six months should be submitted for pressure/flow testing after the cellular debris is
carefully removed.  Following pressure/flow testing, the structural integrity of the shunts should be
tested.
B.1.11 Interpretation of results
The  clinical  results  and  histological  data  obtained  for  the  test  group  should  be  evaluated  for
biocompatibility and physical properties.  The aqueous shunt material will be judged biocompatible if
placement  of  this  material  in  the  animal  eye  does  not  elicit  a  significant  response  clinically  or
histologically, and if there is no detectable change in the flow properties. Appendix C
(informative)
Recommended standard practice for the clinical evaluation of aqueous shunts
C.1 Aqueous shunt clinical protocol elements
The following are important elements of a clinical protocol which will assist the sponsor in
collecting sufficient, relevant and appropriate data to determine the safety and effectiveness of
aqueous shunts which are within the scope of this guidance.  These elements were derived from
the clinical experience with these devices, beginning in 1977 (Krupin-Denver and Molteno).
C.1.1 Control population
The clinical performance of the aqueous shunt under investigation should either be compared to
an appropriate historical population with an appropriate methodology or to the results of a
concurrently run control population.  The sponsor should be aware that clinical performance
levels for a large historical control population have never been established.
C.1.2 Number of subjects
The clinical investigation should include a minimum of 50 subjects with one-year follow-up.  The
performance of the aqueous shunt will be compared to the performance of either the historical
control or a concurrently studied control.  The sponsor should strive to use an historical
population with at least 50 subjects or as large as possible so that the rates of adverse events and
changes in intraocular pressure (IOP) are as close as possible to the true rates for the indicated
population.  For optimal clinical comparison of the aqueous shunt to an appropriate, concurrently
studied control population, the sponsor should enroll a minimum of 50 subjects per study arm to
evaluate changes in IOP and adverse events. Expert help with study design and statistical analysis
is essential. The sponsor should be aware that any additional claims beyond the safety and
effectiveness of the aqueous shunt may require the calculation of an appropriate sample size in all
cases.  Study design should allow for subjects lost to follow-up during the clinical investigation.
The sponsor should refrain from enrolling significantly larger numbers of subjects than originally
planned to minimize the number of subjects which are exposed to the risks associated with the
implantation of an aqueous shunt model which has not yet been determined to be safe and
effective.
To assist in achieving a balance in the number of subjects from each investigator in multi-center
trials, the sponsors clinical protocol should state that each surgeon/investigator enroll a minimum
of 5 subjects, and no more than 25% of the total subjects in the investigation.  Each center should
not enroll more than 33% of the total subjects in the investigation. C.1.3 Duration of the clinical investigation
The follow-up duration of the clinical investigation should be at least one-year.
C.1.4 Reporting periods
As a minimum, the clinical data for the subjects should include the postoperative reporting forms
up to Form 4 for a one-year clinical investigation:
Form 0: Preoperative/Operative reporting
Form 1: Postoperative reporting 1-3 days postoperatively
Form 2: Postoperative reporting 7-35 days postoperatively
Form 3: Postoperative reporting 150-210 days postoperatively
Form 4: Postoperative reporting 330-420 days postoperatively
Unscheduled visits and the procedures to capture adverse events that may occur between
reporting forms should be addressed in the investigation plan. IOP should be reported at each
reporting form; additionally, IOPs between forms should be recorded (if reported).
C.2 Clinical data collection and analysis
Additional clinical guidance which will assist the sponsor in designing their aqueous shunt clinical
investigation protocol and in analyzing the data from that investigation is listed below.
C.2.1 Standardization of the clinical evaluation
The sponsor should ensure to the extent possible that the criteria used by all investigators for
evaluation of adverse events, and the parameters associated with IOP, visual acuity, and visual
field examinations (if performed) conform to the standards recommended by the National Eye
Institute (Eye Care Technology Forum Recommendations).
C.2.2 Adverse Events
Any undesirable clinical occurrence in a subject whether it is considered to be device related or
not should be reported.  Adverse events may be intraoperative or postoperative.  The following
adverse events are recommended to be included as forced-choice items on your clinical report
forms.
Intraoperative adverse events:
 Device malfunction identified prior to implantation;
 Inadvertent perforation of sclera;
 Hyphema;
 Inadvertent loss of vitreous; and
 Choroidal hemorrhage or effusion. Postoperative adverse events:
 Flat anterior chamber (central lens, corneal touch);
 Visual acuity loss (loss of two Snellen lines or more, or loss of light perception; no light
perception is always reportable; beyond 20/400, the increments corresponding to one line are
as follows:  5/200, 2/200, 1/200, hand movement, and light perception);
 Tube malposition;
 Device malfunction (including presumed tube compression/kink);
 Tube insertion within choroid (for pars plana);
 Tube and/or flow restrictor obstruction by iris, vitreous, lens, fibrous overgrowth, fibrin,
blood, etc.;
 Unintended implant exposure (including tube);
 Wound dehiscence (persistent aqueous leak or fistula formation);
 Inflammation (persistent at 6 months and non-preexisting anterior or posterior uveitis in same
or fellow eye, sterile hypopyon, or pupillary membrane formation);
 Infection (localized to area of device or endophthalmitis);
 Bleeding (vitreous hemorrhage or persistent and non-preexisting hyphema);
 Corneal complications (corneal edema, opacification, or graft decompensation);
 Cataract (formation or progression);
 Retinal complications (dialysis, flap tears, retinal detachment, or proliferative
vitreoretinopathy);
 Choroidal complications (massive choroidal hemorrhage);
 Strabismus (any new restriction of ocular movement or secondary diplopia);
 Unplanned surgical reintervention;
 Loss of eye;
 Chronic pain;
 Ptosis; and
 Atrophy/phthisis.
C.2.3 Guidance on data analysis
The sponsor should consider the following clinical data analyses:
- IOP vs. medications at each visit (Goldmann applanation or equivalent);
- IOP and VA by preoperative ocular pathology;
- VA by amount of change (i.e., within one line, increase of two lines or more, and decrease
of two lines or more with explanation);
- rates of cumulative and persistent adverse events;
- rates of other (undefined in this document) adverse events;
- IOP by investigator; and
- rates of adverse events by investigator.
This clinical data evaluation should demonstrate whether or not an aqueous shunt's failure to meet
the clinical performance levels associated with historical or concurrent control populations is
device related. Although rates of all adverse events should be reported, rates for the following should be
compared to those from the control population: aqueous shunt malfunction identified prior to or
during implantation (such as inability to irrigate through with a syringe, leaks, etc.); massive
choroidal hemorrhage; unplanned surgical reintervention; visual loss at six months; unintended
implant (including tube) exposure; infection; flat anterior chamber; persistent severe inflammation
(sterile hypopyon or pupillary membrane formation); and aqueous shunt malfunction
postoperatively.