**SUMMARY MINUTES**

**OF THE**

**OPHTHALMIC DEVICES PANEL MEETING**

**November 30, 2001**

**OPEN SESSION**

**Holiday Inn Gaithersburg**

**Walker/Whetstone Rooms**

**2 Montgomery Avenue**

**Gaithersburg, MD**

**OPHTHALMIC DEVICES PANEL MEETING**

**November 30, 2001**

**[PANEL PARTICIPANTS]{.underline}**

Joel Sugar, M.D. Consultant, Interim Chair, deputized to vote

Arthur Bradley, Ph.D. Voting Member\*

Michael R. Grimmett, M.D. Voting Member\*

Alice Y. Matoba, M.D. Voting Member

Jayne S. Weiss, M.D. Voting Member\*

Janice M. Jurkus, O.D. Consultant, deputized to vote

Jose S. Pulido, M.D. Consultant, deputized to vote

Timothy T. McMahon, O.D. Consultant, deputized to vote

Andrew J. Huang, M.D. Consultant, deputized to vote

Allen C. Ho, M.D. Consultant, deputized to vote

William D. Mathers, M.D. Consultant, deputized to vote

Ronald E. McCarley Industry Representative

\*Primary Reviewer for PMA P010018

**[FOOD AND DRUG ADMINISTRATION PARTICIPANTS]{.underline}**

Sara M. Thornton Panel Executive Secretary

Bernard E. Statland, M.D., Ph.D. Director, Office of Device Evaluation

A. Ralph Rosenthal, M.D. Director, Division of Ophthalmic Devices

And Ear, Nose and Throat Devices

Everette T. Beers, Ph.D. Chief, Diagnostic and Surgical Devices Branch

James F. Saviola, O.D. Chief, Vitreoretinal and Extraocular Devices
Branch

Acting Chief, Ear, Nose and Throat Devices Branch

Sheryl L. Berman, M.D. Medical Officer, Division of Ophthalmic

and Ear, Nose, and Throat Devices

Team Leader, PMA P010018

Joel P. Glover, M.S. Biomedical Engineer, Intraocular and Corneal
Implants Branch

Team Leader, PMA P010018

**­[SPONSOR REPRESENTATIVES]{.underline}**

Dr. Judy Gordon

Regulatory Consultant to Refractec

Dr. Jon Hayashida

Refractec Vice President for Clinical Affairs

Marguerite McDonald, M.D.

Medical Monitor, Principal Investigator

Peter Hersh, M.D.

Principal Investigator

**OPEN SESSION---November 30, 2001**

# Call to Order and Introductory Remarks

**Joel Sugar, M.D., Interim Panel Chair**, called the meeting to order
at 9:45 a.m. **Sara M. Thornton, Panel Executive Secretary,** welcomed
those present to the 102^nd^ meeting of the Ophthalmic Devices Panel.
She stated that the next panel session was scheduled for January 17-18,
2002. Ms. Thornton introduced three new panel consultants: Allen C. Ho,
M.D., Andrew J. Huang, M.D, and William D. Mathers, and new Industry
Representative Ronald E. McCarley. Ms. Thornton asked the other panel
members to introduce themselves and noted with regret that new Consumer
Representative Glenda V. Such, M.Ed., was unable to be present for
health reasons.

Ms. Thornton read the conflict of interest statement, noting that
Michael R. Grimmett, M.D., had been granted a waiver for his interest in
a firm potentially affected by the day's deliberations. Matters
concerning Arthur Bradley, Ph.D., Timothy T. McMahon, O.D., and Allen C.
Ho, M.D., had been considered but deemed unrelated and their full
participation allowed. She also read appointments to temporary voting
status for Janice M. Jurkus, O.D., Allen C. Ho, M.D., Andrew J. Huang,
M.D., William D. Mathers, M.D., Jose S. Pulido, M.D., and Joel Sugar,
M.D. and an appointment as interim chair for Dr. Sugar.

# OPEN PUBLIC HEARING

There were no requests from the audience to address the panel. Ms.
Thornton read a letter from **I. Howard Fine, M.D.,** President of the
American Society of Cataract and Refractive Surgery and Clinical
Associate Professor of Ophthalmology of the Casey Eye Institute, and an
unpaid member of the Refractec Medical Advisory Board with no equity in
the company. He asked that the panel approve the conductive keratoplasty
procedure under consideration on the grounds that it showed clinical
trial outcomes as safe and effective as those presented by other
refractive technologies and produced little or no postoperative dry eye
effect.

# OPEN COMMITTEE DISCUSSION

# FDA Presentation

#  Bernard Statland, Director of the Office of Device Evaluation, thanked the panel for its hard work and presented letters and plaques of appreciation to outgoing members Joel Sugar, Janice Jurkus, and Jose Pulido. A similar plaque and letter were being sent to former Industry Representative Marcia Yaross, who had finished her term. 

#  Jose Pulido acknowledged the high quality of those in the FDA who walk a fine line between the needs of private enterprise and the need for public safety. He thanked the FDA for its work in defending the public safety and stated that it had been an honor and privilege to work with members of the Agency.

# Division and Branch Updates

**A. Ralph Rosenthal, M.D., Director of the Division of Ophthalmic
Devices,** told the panel that **Eric Mann,** formerly of the National
Institutes of Health, had joined the division as the new chief of the
Ear, Nose, and Throat Branch.

**Everette T. Beers, Ph.D., Chief of the Diagnostic and Surgical Devices
Branch,** gave the branch update, stating that the branch had been busy
reviewing clinical trials and had approved two PMAs---PMA P930016/S14
for VISX for LASIK for mixed astigmatism of less than or equal to 6.00 D
in the spectacle plane and P980008/S5 for LaserSight for LASIK for
myopic astigmatism of --0.50 to less than -6.00 D SE and up to less than
or equal to 4.50 D cylinder.

**James F. Saviola, O.D., Chief of the Vitreoretinal and Extraocular
Devices Branch,** gave the branch update. He described two Ciba Focus
NIGHT & DAY soft contact lenses for correction of myopia and hyperopia
prescribed for daily or extended wear for up to 30 nights of continuous
wear that were reviewed at the July panel meeting and approved on
October 11, 2001 and gave their indications, precautions, and selected
study results. Dr. Saviola also described a supplement to PMA P980006
for the Bausch & Lomb (B&L) PureVision lenses approved on November 20,
2001 for daily or extended wear from 1 to 30 days between removals for
myopia and hyperopia at specified ranges and gave its precautions and
restrictions. He noted that the supplement had been scheduled for the
September 21 meeting for the panel to discuss the need for a postmarket
study and to review clinical data from a contralateral eye clinical
study. After cancellation of the September 21 panel meeting, it was
decided that the primary clinical issues in the PMA substantially
duplicated information previously reviewed by the panel. In lieu of a
full panel discussion, homework assignments from two additional panel
members were obtained. These corroborated the recommendations of the two
primary reviewers; all panel reviewers recommended that the supplement
be approved subject to a postapproval study to assess the long-term
rates of microbial keratitis and associated loss of vision.

Dr. Saviola described the approval restrictions on these two extended
wear lenses in the areas of advertising (including package inserts and
consumer information leaflets), labeling, and postapproval clinical
studies. Both the Ciba and the B & L studies will involve about 100
sentinel monitoring sites designed to provide data of 4,500-5,000
patient years of subjects wearing their one-month lenses during a
one-year period to give an early indication for risks in the real world
setting.

**PMA P010018---Refractec's ViewPoint Conductive Keratoplasty (CK)
System**

**Sponsor Presentation**

**Judy Gordon, DVM, regulatory consultant for Refractec,** introduced
the sponsor team.

**Jon Hayashida, O.D. and vice president for clinical affairs of
Refractec,** described methods for surgical correction of hyperopia and
collagen shrinkage via thermal keratoplasty through laser energy or
application of radio frequency energy. After a brief description of the
ViewPoint device, Dr. Hayashida provided an overview of the technology
involved in conductive keratoplasty (CK). He concluded that CK provides
a uniform footprint that leads to the success of the treatment and that
use of radio frequency in CK has clinical advantages based on its
mechanism of action.

**Marguerite McDonald, M.D., medical monitor and clinical
investigator,** presented clinical results. She outlined the protocol
and clinical investigators for the prospective, multicenter clinical
trial. Study design was consistent with FDA guidance for refractive
surgery laser and draft ANSI guidance for laser systems for corneal
reshaping and aimed for full correction of spherical hyperopia. Dr.
McDonald described eligibility criteria, noting that all treatments were
based on preoperative cycloplegic refraction spherical equivalent
(CRSE). Effectiveness parameters were improvement in uncorrected visual
acuity (UCVA), predictability, stability, and patient satisfaction.
Safety parameters were preservation of best spectacle corrected visual
acuity (BSCVA), induced cylinder, endothelial cell loss, patient
symptoms and complications and adverse events. Demographics, baseline
refractive characteristics, and preoperative refractive parameters by
diopter of all eyes enrolled were all consistent with other refractive
trials. Dr. McDonald stated that the nomogram was adjusted after an
analysis of the first 54 eyes, and that accountability of all eyes
enrolled up to 12 months was excellent. Safety and stability were based
on all eyes treated (400), effectiveness on eyes treated with the
current nomogram (363).

Dr. McDonald presented effectiveness results, stating that the key
effectiveness targets were met according to targets set by FDA. These
included improvement in UCVA to 20/40 or better in more than or equal to
85% of eyes with preoperative BSCVA of 20/20 or predictability of MRSE
within less than or equal to 0.50 D for 50% of eyes and within less than
or equal to 1.00D for 75% of eyes. Post operative stability was defined
by the change in MRSE over a 3 month interval of less than or equal to
1.00D for 95%, and mean rate of change in MRSE of less than or equal to
0.5D/year with an asymptote of zero, and a 95% confidence interval for
mean change in periods preceding and after stability is established to
include zero. A paired analysis of the eyes treated with the current
nomogram to see the percent of intended correction remaining found 94%
of intended correction in MRSE remained at 12 months, with 90% of
intended correction in CRSE remaining at 12 months. Proportion of
intended correction retained beyond 12 months was undetermined. Patient
satisfaction showed 31% and 46% of patients to be satisfied or very
satisfied at 12 months, which Dr. McDonald said was consistent with
other studies of hyperopia.

Dr. McDonald presented a summary of safety of all eyes treated at six,
nine, and 12 months according to FDA limits. Criteria for preservation
of BSCVA were loss of greater than two lines of BSCVA of less than 5%
(CK showed none at 12 months), loss of two lines of BSCVA (CK showed
less than 1% at 12 months), BSCVA of worse than 20/40 of less than 1%
(CK showed 0), BSCVA worse than 20/25 if 20/20 or better preoperatively
(CK showed 0), and increase of more than 2.00 D cylinder of less than 5%
(CK showed less than 1%).

**Peter Hersh, M.D., clinical investigator**, discussed safety limits
for induced cylinder, which were induced cylinder of more than 2.00 D in
less than 5% of eyes, induced cylinder of greater than 1.00 D reported
in labeling for all comparable products for hyperopia treatment, and
induced cylinder of more than or equal to 1.00 D reported at FDA's
request. He summarized that the CK results were below the FDA safety
limit of more than 2.00 D and that the frequency and magnitude of
induced cylinder diminish over time. When induced cylinder is present,
he said, there is on average one line less improvement in UCVA; UCVA
improves over time as induced cylinder resolves. There is no significant
effect on BSCVA.

**Dr. McDonald** discussed the safety parameter of endothelial cell
loss, which was targeted to be no more than 10% loss in cell density.
Results on all eyes in the substudy showed a less than one percent loss
in endothelial cell density over the course of follow-up in any region
and no polymegathism or polymorphism. She concluded that radio frequency
energy can be safely delivered to the cornea with no effect on the
endothelium.

A subjective questionnaire was administered at baseline, one, three,
six, nine, and 12 months to rate symptoms as moderate, marked, or
severe. Patient symptoms with a more than 5% increase from baseline to
month six, nine, or 12, were dryness, glare, halos, double vision,
fluctuation of vision, and variations in vision with change in lighting,
with the majority reported in the moderate category.

Safety parameters for complications and adverse events included adverse
events to occur in no more than 5% of eyes and any single adverse event
to occur in less than 1% of eyes. Complications for CK included
recurrent corneal erosions, later resolved, a foreign body sensation,
later resolved, pain in both eyes, later resolved, and double or ghost
images. Device/procedure-related adverse events included a corneal
perforation, no RF energy delivered during two treatments, which was
corrected and reviewed by FDA, and various clinical events including
transient intraocular pressure or mild iritis that resolved without
sequelae.

Dr. McDonald summarized the effectiveness results as showing UCVA
exceeding FDA targets, accuracy of achieved versus intended correction
exceeding FDA targets, 94% of intended correction remaining at 12
months, and no retreatments performed during the study. Safety results
showed that all performance limits identified in the study protocol and
FDA guidelines were met, that preservation of BSCVA was established,
that the incidence of induced cylinder met the FDA limit, that the
induced cylinder decreased in frequency and magnitude over time, with no
effect on BSCVA and minimal effect on UCVA, and that there was a very
low cumulative incidence of adverse events.

# Panel Questions for the Sponsor

Panel questions to the sponsors included the possible need for a
contraindication against device use with patients having implanted
electrical devices such as defibrillators and cochlear implants, concern
over the patient satisfaction levels, the issue of long-term stability
and permanence of the procedure, and the possible need for remedial
spectacles as results are stabilizing in the postoperative period.

# FDA Presentation

**Joel Glover, leader for the FDA review team,** thanked the sponsors,
the panel, and the FDA review team for their help in bringing the PMA to
panel.

**Sheryl Berman, M.D, Medical Officer,** thanked the sponsors for their
work. She listed six FDA questions, with accompanying summary tables of
data, on incidence of induced cylinder, adequacy of 12-month follow-up,
whether the refractive correction justifies the procedural risks, the
increased incidence of visual symptoms from preoperative levels, whether
the data support approval for the requested indication, and possible
labeling recommendations for panel review.

# Panel Questions for the FDA

#  The panel had no questions for the FDA.

# Additional Comments from the Sponsors

Sponsor representatives replied to the questions raised by the FDA. Dr.
Hersh stated that the rate of induced cylinder is within the current FDA
recommended guidance, diminishes over time, and has no significant
effect on BSCVA. On adequacy of available follow-up data, Dr. McDonald
stated that the available data provide reasonable assurance of safety
and efficacy and that sponsors are willing to update the data as further
results are available. Similarly, the sponsors thought the potential
risks were justified by the significant improvement in UCVA with no
serious adverse effects and no removal of tissue. While sponsors thought
the FDA's concerns were valid, they noted that such concerns were true
of all refractive procedures and that CK offered a viable alternative
with a comparable risk/benefit ratio. They discussed various possible
labeling changes as well.

# Committee Deliberations 

# *Primary Panel Reviews*

**Arthur Bradley, Ph.D.,** raised six issues in his review. He stated
that the data should have been presented in graph format and that the
original data should have been presented, rather than an analysis of how
the data met FDA criteria. Dr. Bradley also expressed concern that the
procedure appears to introduce huge variability in refractive error.
Similarly, he was concerned that extrapolation of the stability data
over a longer period would show the refractive error returning to
pre-procedural levels. He recommended a vector analysis be used in the
future to assess whether the procedure induced a random astigmatism or
one correlated more directly to treatment spots, and he also suggested a
scattergram be used to show interactions with other conditions. Finally,
Dr. Bradley urged that the patient consent document must present all
issues understandably, in particular the true nature of the procedure,
i.e., they weren\'t going to have a laser irradiating their eye but that
a sharp needle is going to be inserted into their eye up to 32 times,
and the likelihood, magnitude, and consequences of post-CK myopia and
astigmatism for such daily activities as driving.

**Michael R. Grimmett, M.D.,** noted that of the study population of
401, very few had reached the 24-month mark, making the data incomplete.
On safety, he expressed concern at the rate of BSCVA loss of greater
than or equal to two lines, noting that a 5% rate is not insignificant,
even if it decreases with time. He stated that the increase in
subjective symptoms such as glare, halos, double vision, fluctuation of
vision, variation of vision, and night driving problems suggests higher
order visual aberrations are induced. Also, the increase in variation of
vision and fluctuation of vision suggests refractive instability. He was
concerned about the increase in cylinder magnitude and recommended that
appropriate labeling should include specific data regarding cylinder
induction rates greater than or equal to 1.00, greater than or equal to
1.50 and greater than or equal to 2.00 diopters. Regarding the etiology
of the induced cylinder, he speculated that the high rate of induced
cylinder may be due to a combination of factors, e.g., inaccurate spot
placement, asymmetric energy uptake, non-perpendicular needle track, and
non-uniform needle depth. In light of his concerns about efficacy and
refractive instability based on increased variation and fluctuation of
vision, progressive declines in astigmatism magnitude, progressive
declines in overcorrections, progressive increases in mean MRSE, and a
continuous month-to-month refractive shift, Dr. Grimmett emphasized that
the seemingly transitory nature of this procedure should be communicated
to prospective patients, especially as there are no data on retreatment
outcomes. He listed seven material facts to be included in the informed
consent, saying that he was hard pressed to see that the prudent patient
would want this procedure but noting that the FDA's position on
temporary devices is that marginally effective devices can be approved
for temporary reduction of hyperopia and that such devices have received
approval. Dr. Grimmett thought it mandatory to emphasize the refractive
instability as shown by a progressive hyperopic shift and to note that
the duration of refractive drift is unknown, with the data insufficient
to prove whether the duration is stable or temporary. Dr. Grimmett
listed six recommendations for conditions of approval, with detailed
labeling changes.

**Jayne S. Weiss, M.D.,** stated her concern that the induction of axis
shift and astigmatism must be addressed in patient and physician
labeling because of the potential for causing subjective patient
complaints. She stated that the sponsor had provided reasonable
assurance of safety and efficacy at the 12-month point, but the panel
should discuss use of the word "temporary" in the indication for use to
best describe efficacy of CK and address concerns about regression. Dr.
Weiss thought the refractive correction obtained with the device did
justify the potential risks, although the labeling should be revised to
discuss possible complications and increased incidence of visual
symptoms from the preoperative levels. She recommended that the device
should be approved with conditions that the data be brought out to 24
months and the labeling amended according to several specific
recommendations.

**Dr. Rosenthal of the FDA** reminded the panel that each PMA must stand
on its own merits and that while references could be made to other PMAs,
no comparisons could be made.

# Panel Discussion of PMA P010018

# *FDA Questions to the Panel*

1)  What are the concerns regarding the incidence of induced cylinder
    with significant axis shift and its consequent effect on efficacy?

The panel expressed concern over not knowing the cause of induced
cylinder while acknowledging that unanswered questions do not preclude
approval of the procedure. The panel also expressed concern over the
UCVA loss associated with the procedure\'s variability, inaccuracy, and
shifts in cylinder axis. They advised that the labeling should state
clearly, in ways the patient can understand, that the study only
included patients with low initial levels of astigmatism and that
labeling should stratify the rate of induced cylinder by degrees of
induction and other variables.

2)  Is a 12-month follow-up sufficient to provide reasonable assurance
    of safety and efficacy? There are 21 eyes available at 24 months.
    Should data for these eyes also be required in the labeling?

The panel disagreed on this point, with some wanting the 24-month data
to be included for efficacy and others urging that approval be held
until more complete data are available to show stability. The majority
of members argued that the device could be approved based on 12-month
data if the effects are stated as temporary and that it was impossible
to predict what the 24-month data will ultimately show on stability.

3)  Does the refractive correction obtained with this device, in light
    of the rate of change of mean MRSE over time and the incidence of
    over- and undercorrection, justify the potential risks?

The majority of the panel thought the refractive correction obtained
with this device justified the potential risks since the safety risks
were minimal, despite the question of stability, although at least one
member argued that it was hard to assess if the benefit justified the
risk, given that the procedure itself actually increases variability and
produces clinically significant levels of myopia for significant numbers
of patients.

# *4) Are there concerns regarding the increased incidence of visual symptoms from pre-op levels?*

Again, some members of the panel thought that such visual symptoms were
a ubiquitous result with procedures of this sort and had been assessed
in an uncontrolled setting. Others expressed concern that patients did
not have these symptoms preoperatively but did have problems
postoperatively. It was recommended that a table be delineated in the
labeling listing symptoms pre and postoperatively.

# *Do the safety and efficacy data presented in this PMA support approval of this device for the requested indication? Is the requested indication appropriate as worded, based on the study outcome?*

The panel had an extensive discussion about the best way to indicate
that the procedure appears to produce a temporary and perhaps unstable
or changeable result over time. They recommended revising the requested
indication for use to read "CK treatment for temporary reduction of
spherical hyperopia in the range of..." in the first bullet and revising
the fourth bullet to state, "The magnitude of correction diminishes over
time."

5)  What are your recommendations for labeling regarding regression of
    effect, induction of cylinder, and incidence of visual symptoms? Are
    there additional labeling recommendations?

The list of labeling issues contained in Dr. Grimmett's review was read
here. He revised his 10^th^ suggestion to ask for data on spectacle or
contact lens dependence following the procedure. He deleted his 13^th^
recommendation in light of the newly revised indication. In addition,
panel members recommended that any implanted electrical device should be
a contraindication. The labeling should make patients aware that
overcorrection could be expected and that the recovery time to regular
vision will be lengthy. Expectations on immediate postoperative pain
should be clarified, as should the description of the actual procedure
given in the patient information.

# Open Public Hearing

There were no requests to address the panel.

# FDA Closing Comments

Dr. Rosenthal thanked the panel, and especially the primary reviewers,
for the discussion.

**Sponsor Closing Comments**

**Dr. Judy Gordon** thanked the panel and stated that the sponsor would
endeavor to convey the panel's suggestions in the labeling and patient
information brochures.

# Panel Vote

**Executive Secretary Sara Thornton** read the voting instructions and
options. A motion was made and seconded to recommend the PMA as
approvable subject to the following conditions:

1)  The indications are amended, with the first bullet reworded to state
    "CK treatment for the temporary reduction of spherical hyperopia in
    the range of..." The last two bullets (regarding diminution of
    magnitude of correction over time and proportion of intended
    correction retained) were eliminated. This condition carried by a
    vote of seven to three.

2)  Additions to the labeling should be made as listed by Dr. Grimmett,
    with the modification of BSCVA greater than two lines, corrections
    to number 10, and the elimination of number 13. In addition,
    implanted electric devices should be added as a contraindication,
    and it should be noted that the effect in patients with narrow
    angles is unknown. In the patient information, the procedure should
    be better described, including needle placement and deletion of the
    reference to gentle heating; it should be added that data beyond 12
    months are unavailable, and it should be stated that there is
    initial overcorrection and it may take six to nine months to reach
    the full results. This condition was carried by a vote of nine, with
    one abstention.

> 3\) The study should be completed to the 24-month interval with data
> submitted to the FDA for review. This condition was carried by a vote
> of nine, with one abstention.
>
> The vote to recommend the PMA as approvable subject to the above
> conditions was carried by a vote of nine to one. Those who voted for
> approval stated that they did so because the device can temporarily
> and unpredictably but clearly diminish hyperopia. The one member who
> opposed the motion stated that he thought the device was unreliable,
> inaccurate, and unstable.
>
> **Panel Chair Dr. Sugar** stated that he had enjoyed his time as a
> panel voting member working with the Center for Devices and
> Radiological Health and commended the FDA for doing what is best for
> all concerned under difficult circumstances. **Ms. Thornton** thanked
> Dr. Sugar for serving as Interim Chair and all new and returning panel
> members for their work.
>
> **Panel Chair Dr. Sugar** adjourned the Open Session at 3:50 p.m.**\
> **

I certify that I attended the Open Session of the Ophthalmic Devices
Advisory Panel Meeting on November 30, 2001, and that this summary
accurately reflects what transpired.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Sara M. Thornton

Executive Secretary

I approve the minutes of this meeting

as recorded in this summary.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Joel Sugar, M.D.

Interim Chair

Summary minutes prepared by

Aileen M. Moodie

Editorial Consultant

9821 Hollow Glen Pl.

Silver Spring, MD 20910