**SUMMARY MINUTES**

**OF THE**

**OPHTHALMIC DEVICES PANEL MEETING**

**OPEN SESSION**

**August 1-2, 2002**

**Gaithersburg Hilton**

Gaithersburg, MD

OPHTHALMIC DEVICES PANEL ROSTER

AUGUST 1-2, 2002

###### Jayne S. Weiss, M.D. Chair

Arthur Bradley, Ph.D. Voting Member \*

Michael R. Grimmett, M.D. Voting Member

Alice Y. Matoba, M.D. Voting Member

Karen Bandeen-Roche, Ph.D. Consultant, deputized to vote

Mark A. Bullimore Consultant, deputized to vote

Stephen A. Burns, Ph.D. Consultant

Andrew J. Huang, M.D., M.P.H. Consultant, deputized to vote \*

Leo J. Maguire, M.D. Consultant, deputized to vote •

William D. Mathers, M.D. Consultant ₫

Cynthia Owsley, Ph.D. Consultant, deputized to vote

William H. Swanson, Ph.D. Consultant, deputized to vote

Glenda V. Such, M.Ed. Consumer Representative

Ronald E. McCarley Industry Representative

\* Primary reviewer for PMA P970043/S010

• Present on August 1, 2002 only

₫ Present on August 2, 2002 only

##### 

##### FOOD AND DRUG ADMINISTRATION (FDA) PARTICIPANTS

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

Jan C. Callaway Team Leader

Bruce A. Drum, Ph.D. Physicist

Malvina B. Eydelman, M.D. Medical Officer

Donna R. Lochner Chief, Intraocular and Corneal Implants Branch

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

Sara M. Thornton Panel Executive Secretary

David M. Whipple Deputy Director, Division of Ophthalmic and

Ear, Nose and Throat Devices

CALL TO ORDER - AUGUST 1, 2002

**Panel Chair, Jayne Weiss, M.D.,** called the meeting to order at 8:33
a.m.

**Panel Executive Secretary Sara Thornton** announced the confirmation
of Dr. Jayne Weiss as Panel Chair and noted that three newly appointed
voting members, Drs. Anne Coleman, Allen Ho, and Timothy McMahon, were
unable to attend. Ms. Thornton then read the conflict of interest
statement. Waivers had been granted to Drs. Mark Bullimore and Stephen
Burns for their interests in firms that may be affected by the panel's
recommendations. Dr. Burns' limited waiver allows him to participate in
the panel's deliberations, but he may not vote; Dr. Bullimore may
participate in the panel's deliberations and may vote. The Agency took
into consideration certain matters involving Drs. Arthur Bradley,
Michael Grimmett, and Jayne Weiss, who reported interests in firms at
issue in matters not related to the day's agenda; the Agency has
determined that they are allowed to participate fully in the panel's
deliberations. Panel consultants, Drs. Karen Bandeen-Roche, Mark
Bullimore, Andrew Huang, Leo Maguire, Cynthia Owsley, and William
Swanson, were appointed to temporary voting status.

# OPEN PUBLIC HEARING

**Ronald J. Link, executive director, Surgical Eyes, Inc.,** noted that
many patients experience complications from refractive surgery. If the
panel votes to approve a premarket approval application (PMA) for the
device, it should require (1) that clinical studies at multiple sites
across the United States be conducted on post-refractive eyes with a
minimum 1-month follow up; (2) that preexisting dry eye and large pupils
be listed as a contraindication or warning in the professional and
patient information booklets of any laser approved for laser in situ
keratomileusis (LASIK); and (3) that postapproval studies be conducted.
It is important to identify and disclose all pre- and postoperative risk
factors to both patients and doctors. In response to questions from
panel members. Mr. Link said that 1-month follow up should be adequate
for the studies he recommended and that the patient information booklets
and the information on the FDA Web site should match.

Ms. Thornton then read a letter into the record in which the writer
described the complications she experienced from refractive surgery and
urged the panel to list pupil size and dry eyes as a contraindication.

**David L. Shell, Arlington, VA,** described the dry eyes and
difficulties he has experienced since having LASIK 4 years ago. He is
blind 10 percent of the time because his eyes are closed due to pain. He
was not told of the high rate of dry eyes before his surgery and did not
have the information before the surgery to make an informed decision. He
recommended that PMA approval be conditioned on clinical studies of the
incidence of LASIK-induced dry eye. In addition, the percentage of
patients suffering dry eyes as a complication should be included in the
patient information booklet.

# OPEN COMMITTEE SESSION

**David M. Whipple, deputy director, Division of Ophthalmic and Ear,
Nose and Throat Devices,** noted that the director of the Office of
Device Evaluation, Dr. Bernard Statland, is leaving the FDA at the end
of August.

**James F. Saviola, O.D., chief, Vitreoretinal and Extraocular Devices
Branch,** presented an update on Branch activities. He noted that the
Branch had recently cleared a 510(k) application for the ChromaGen
Reading Aid Soft Contact Lens by Cantor & Silver Ltd. for correction of
refractive ametropia or to assist people who have reading discomfort not
related to binocular vision problems or uncorrected refractive error.
The clinical study did not support use of the lenses in treating
dyslexia or improving reading speed and was therefore not approved for
those uses. Dr. Saviola also noted that PMAs had been approved for the
Paragon CRT lens for overnight orthokeratology and the Menicon Z rigid
gas permeable lens for extended wear up to 30 days. Dr. Saviola
summarized the devices' indications for use.

**Donna** **Lochner, chief, Intraocular and Corneal Implants Branch,**
noted that the PMA for the Morcher capsular tension ring, previously
reviewed at the January 2002 panel meeting, is still under review by
FDA. The Agency has cleared the Ex-Press Miniature Glaucoma Implant,
Models R-30 and R-50.

**Everette T. Beers, Ph.D., chief, Diagnostic and Surgical Devices
Branch,** noted that three devices had been approved since the January
2002 panel meeting..PMA P010018s was approved on Apr;il 11, 2002, for
the Refractec ViewPoint CK or conductive keratoplasty system for the
temporary reduction of spherical hyperopia in patients who have 0.75 D
to 3.25 D of cycloplegic spherical hyperopia. On May 17, 2002, PMA
P970027/S002, Bausch & Lomb Technolas 217A excimer laser system for high
myopia with astigmatism was approved. The device is indicated for the
reduction or elimination of high myopia \< -12 D mean refractive
spherical equivalent (MRSE), where the sphere is \>-7 D and \< -10.99 D
and the astigmatism is \> 0.0D

and \< -3.5 D.

In addition, a Humanitarian Device Exemption (HDE),H000002, was approved
for the Custom Contoured Ablation Pattern method for the treatment of
certain patients with symptomatic decentered ablations from previous
laser surgery, as viewed on the Zeiss Humphrey topography unit.

**PMA P970043/S010**

# Sponsor Presentation

**Kathleen Chester, director, Regulatory Affairs,** noted that the
sponsor was requesting approval for the PMA for the CustomCornea™ Myopic
LASIK with the LADARVision™ 4000 System device as indicated for use in
Wavefront-Guided CustomCornea™ Laser In-Situ Keratomileusis (LASIK)
correction for the reduction or elimination of myopia up to --7.0 D with
less than --0.5 D of astigmatism at the spectacle plane in subjects who
are age 21 or older.

**George Pettit, M.D., Ph.D., vice president, chief scientist, Clinical
Outcomes Research,** defined wavefront-guided (WFG) custom ablation. The
system has two components: the wavefront system and the laser. He then
described wavefront sensing, which is a measurement of how the eye
functions as an integrated optical system that provides a detailed
refractive map within the pupil of the eye. Pettit provided technical
information on how the wavefront sensor operates, using numerous slides
to illustrate the differences between classical and wavefront vision
testing. Calculations of wavefront are based on Zernike polynomials.
Root-mean-square (RMS) wavefront error is the standard deviation of the
wavefront height; if the wavefront is perfectly flat, the RMS error is
zero.

Pettit then provided a detailed description of surgical wavefront
measurement; he noted that the daytime pupil center is measured before
dilation because the pupil center may shift with dilation. The wavefront
is measured five times; the outliers are discarded, and the remaining
three measurements are averaged to reach a final composite value. The
wavefront and geometry information are transferred electronically to the
treatment laser.

**Daniel Durrie, M.D., investigator, Hunkeler Eye Clinic, Kansas City,
MO,** summarized the safety data. He noted that only two eyes were lost
to follow up in the entire group. The safety cohort (*N* = 426 eyes) and
the effectiveness subsample (*N* = 139 eyes with spherical myopia) were
comparable in terms of demographics: They consisted mainly of Caucasian
patients who wore soft contact lenses. The only difference between the
two groups was that cylinder ranged from 0 to --0.50 in the spherical
myopia cohort and ranged from 0 to --4.00 in the entire group. Durrie
said that at 6-month follow up, 37 percent of the 426 eyes had gained 1
line or more in best spectacle-corrected visual acuity (BSCVA); no eyes
had a BSCVA worse than 20/32. All complications were resolved, except
for four eyes: One patient had epithelial ingrowth, and three
experienced ghosting. All patients who had adverse events had BSCVA of
20/16 or better. No adverse events occurred in the spherical myopia
group. Durrie summarized by stating that the device meets all
performance limits in the guidance document and demonstrates no
significant safety issues.

**Omar Hakim, M.D., investigator, TLC Canada,** presented effectiveness
data for the 139 eyes in the study that had spherical myopia. At 1-month
follow up, 97.1 percent were within 1 D of emmetropia; at 6 months, 95.7
percent of the eyes were within 1 D. Most eyes were ±1 D of emmetropia.
A small amount of undercorrection occurred; more than 90 percent of eyes
were within 0.5 D of the mean. The MRSE was very stable and surpassed
the standards outlined in the guidance document. Visual acuity also
exceeded those requirements. At 1 month, postoperative uncorrected
visual acuity (UCVA was equal to or better than preoperative BSCVA) for
59 percent of the patients and at 6 months, this figure was still
52.5%.. Patients were asked to list and grade symptoms following
surgery; those who noted that symptoms were worse were at --0.46 D to
--0.70 D. Therefore, improvement in the rate of undercorrection may help
alleviate symptoms in future. Patient satisfaction and quality of vision
both were high. Dr. Hakim summarized by saying that the device exceeds
all performance limits in the guidance document and demonstrates
refractive stability as defined in the guidance document.

Dr. Pettit then discussed the outcomes for the spherical myopia cohort.
For almost all aberrations, the rate was statistically significantly
higher postoperatively than preoperative; the finding is not surprising
because LASIK tends to increase higher order aberrations. The early
phase of the study had a contralateral control arm, in which patients
were randomly selected to have one eye treated conventionally and one
eye treated with the wavefront device. At 6 months, the conventionally
treated patients had higher rates of postoperative aberrations than the
wavefront group. The percentage of eyes with reduced magnitude of
aberrations after surgery was greater for the wavefront group.

**Stephen Brint, M.D., investigator, Brint Vision Correction Center,
Metarie, LA,** discussed the clinical implications of wavefront
correction. He noted that higher order aberrations, particularly
spherical aberration, may be substantially increased after conventional
LASIK. Increased higher order aberrations after conventional LASIK have
the pupil size--dependent effect of degrading retinal image quality and
visual performance. Correction of higher order aberrations with an
adaptive optics system improves visual acuity and contrast sensitivity.
In the Custom spherical myopia cohort the percentage of eyes with a
clinically significant gain in contrast sensitivity was two to threefold
greater than the percentage with a clinically

significant loss; with conventional treatment, no patients saw a gain
and some saw a loss. For all eyes, the wavefront device showed a trend
toward gain in both mesopic and photopic groups, whereas the trend with
conventional treatment was toward loss. Similarly, patients treated with

the wavefront device showed a gain in low-contrast acuity: At 3 months,
significantly less loss in low-contrast BSCVA occurred in the custom
group than in the conventional group.

Dr. Pettit summarized by stating that the wavefront device meets all
safety performance limits and exceeds all effectiveness performance
limits in the FDA guidance document. Compared with conventional
treatment, more eyes have a clinically significant gain than loss of
contrast sensitivity, and more eyes show a gain of greater than or equal
to one line of low-contrast BSCVA, rather than loss. Wavefront
device--treated eyes have a statistically significantly better mean
photopic contrast sensitivity, preservation of mesopic contrast
sensitivity at 3 months, and statistically significantly lower loss of
low-contrast BSCVA of greater than or equal to 1 line. In addition,
compared with conventional treatment, WFG LASIK produces significantly
fewer postoperative higher order aberrations, and significantly more
wavefront-treated eyes have a reduction in higher order aberrations from
the preoperative values.

Dr. Pettit then provided information in response to the panel reviewers'
and the FDA's questions.

# Panel Questions For the Sponsor

Dr. Weiss asked whether the patients who had one type of procedure on
each eye could notice a difference in vision in each eye, but Dr. Pettit
said the data were not available. Panel members asked for clarification
on the sample size, selection criteria, possible differences in pupil
size in the two cohorts, rates of higher order aberrations and
improvement in low-contrast visual acuity, implications of the higher
order aberrations for later cataract surgery, and rates of patient
satisfaction; sponsor representatives answered the questions to the
panel's satisfaction. Dr. Pettit noted that although higher order
aberrations are generally higher after LASIK surgery, with the wavefront
device, they are higher by an amount than less than that with
conventional surgery.

Dr. Huang observed that instead of reducing higher order aberrations,
the procedure seemed to be increasing them. Dr. Durrie replied that from
a clinical standpoint, the procedure is a step along the way; before, it
was not possible to measure aberrations before surgery. Some surgically
induced aberrations were predictable.

In response to Dr. Grimmett's comment that the patient satisfaction rate
was commendable (only 9 percent were dissatisfied), Dr. Pettit said that
the dissatisfied patients tended to be undercorrected. Because much hype
surrounds LASIK surgery, patient expectations tend to be a bit high.
Panel members concurred with Dr. Grimmett that the labeling should
address patient expectations and the possibility that correction may not
be 100 percent. Ronald McCarley, however, urged caution in making
labeling changes designed to "placate a small segment of the population"
because doing so may not affect how surgeons choose their patients. Dr.
Durrie noted that the manufacturers' claims are balanced by the data. A
patient who is --1.0 D has a less significant deficit than a patient who
is --4.0 D; the latter are more likely to be satisfied because they
start out with such a severe deficit.

Dr. Matoba commented that although the study has shown that the device
is safe, it is important to compare the wavefront device against
conventional treatment for patient symptoms and satisfaction. Patients'
expectations will affect the level of satisfaction.

# FDA PRESENTATION

**Jan Callaway, FDA review team leader,** provided a regulatory history
of the device. The original PMA was approved in November 1998, and the
sponsor is requesting approval to further expand the indication
statement. In the previously approved system, the ablation pattern was
based on manually entered manifest subjective refraction data for sphere
and cylinder. The new device uses information obtained from a wavefront
measurement device, transferring the data via computer to the laser.

**Bruce Drum, Ph.D., physicist,** focused on the panel questions. He
noted that the FDA has no clinical questions for the panel on the
device's safety or effectiveness, but it needs the panel's input on
issues specific to higher order aberration treatments, including
analysis and interpretation of the results, information needed to
support specific effectiveness claims, and labeling information. In
addition, the FDA has questions about the differences between the
wavefront-treated and the conventionally treated groups, about whether
Zernicke polynomials are the most effective way to look at higher order
aberrations, and about the criteria used to assess the stability of
aberration corrections.

**COMMITTEE DELIBERATIONS**

# Panel Primary Reviewers

**Dr. Andrew J. Huang** referred the panel to his written review. He
stated that although the new surgery can treat higher order aberrations,
whether the technology will work in practice is another matter
altogether. Vision is a dynamic process. Using wavefront technology to
correct at a given point may not be suitable for many patients, such as
those who need night vision. About 90 percent of aberrations are
low-order aberrations, and conventional LASIK is adequate for most
patients. If we can selectively use wavefront technology for patients
with higher order aberrations, the benefits can be justified. Huang said
that the sponsor's study was well conducted and complimented the company
on its data. He noted that the cohorts were small and asked the panel to
consider whether additional safety and effectiveness data were needed
before final approval. Dr. Huang pointed out that both the conventional
and the WFG LASIK groups experienced an increase in higher order
aberrations; the clinical significance of the difference is unknown.
About 20 percent of patients had decreased vision of greater than one
line, suggesting that no additional treatment was of benefit. In
addition, 10 percent of the patients said that their vision was worse
than before the operation. Finally, no data in the submission discuss
the long-term stability and effects of treatment.

**Dr. Arthur Bradley** discussed the devices' efficacy, stability,
safety, aberration correction, and labeling. He noted the tendency
toward undercorrection; even so, the data in the PMA exceed FDA
requirements. The outcome is stable, and the device exceeds FDA's safety
guidelines. WFG LASIK results in lower levels of higher order
aberrations than conventional LASIK does. This improved outcome may
account for the small differences seen in best corrected visual
performance when compared with the conventional cohort. It is important
to remember that WFG LASIK increases the level of higher order
aberrations relative to preoperative levels, but less than the increase
seen with conventional LASIK.

Labeling is the panel's greatest challenge. It must clearly state that
that WFG LASIK does not reduce the level of higher order monochromatic
aberrations relative to preoperative levels. Thus, in no way can it be
thought of as a procedure to correct higher order aberrations and render
supernormal vision. The sponsor can comfortably promote this process as
a new LASIK procedure that is an improvement over the previous
technology.

The sponsor uses the term "custom cornea," which is an appealing idea.
It is now possible to sculpt the cornea to correct for inherent optical
problems. Dr. Bradley challenged the sponsor to provide evidence that it
had achieved this outcome. One would expect the
preoperative/postoperative correlation to be zero if individual eye
aberrations were perfectly corrected. We need to know the test-retest
reliability to know how effective WFG LASIK is. The data leave us not
knowing whether a positive correlation is due to failure to correct
aberrations or only partial correction. Dr. Bradley noted that the
correlations between attempted and achieved corrections were \>0.5 for
third- order aberrations and were quite low for fourth-order
aberrations. The evidence suggests that WFG LASIK does a better job of
correcting third-order aberrations. Dr. Bradley emphasized that we do
not know all of the visual ramifications of monochromatic aberrations.
Vision is a polychromatic world, and it is possible that correcting
aberrations might compromise vision.

In summary, the WFG LASIK system has met the efficacy, stability, and
safety guidelines of the FDA. It appears to be an improvement over the
already approved system

**Panel Discussion of FDA Questions.**

**Question 1: What differences, if any, between custom and conventional
outcomes are clinically and/or functionally significant? What labeling
claims are supported by these differences?**

Dr. Bullimore said that the sponsor has shown convincingly that the
device can produce benefits. The labeling and patient information can
say that the demonstrated improvements in aberrations over conventional
LASIK may lead to a modest improvement in some aspects of patients'
vision. Dr. Matoba noted that all the patient booklet says is that the
surgery may reduce nearsightedness or eliminate the need for glasses. If
that is all the sponsor wants to say, there is no need to suggest that
the booklet say more. The panel agreed that it was likely that custom
corneal ablation has clinical or functionally significant outcomes over
conventional LASIK, but the evidence was not conclusive.

Ms. Such noted that although the wording in the patient booklet is
accurate, it may lead people to conclude that the device resolves
earlier problems with previous generations of LASIK. People may not
understand certain phrasing, such as "refractive error." The time that
is spent going over "the eye is like a camera," is helpful, but the
booklet then jumps into scientific language.

Dr. Owsley noted that no data are available on the surgery's effect on
instrumental activities of daily living (IADL), such as driving. IADL
problems are what patients are talking about. Dr. Grimmett said that no
data support higher functional performance (IADL) or satisfaction rates
in patients with customized versus conventional treatment. In addition,
although data suggest that the outcome is slightly better (e.g.,
improved contrast sensitivity), the relation to satisfaction or IADL is
unknown. There is a theoretical benefit to the performance measures.

The panel concurred that the patient brochure could say that WFG has
demonstrated slightly superior optical quality (reduced monochromatic
aberration) than conventional LADAR vision/LASIK and minor improvements
in visual acuity and contrast sensitivity relative to conventional LADAR
vision/LASIK. No data support improved functional performance.

Mr. McCarley stated that the labeling needs to make sure that it does
not render obsolete all products that do not have LADAR; the comparison
needs to be with conventional LADAR, not LASIK. A broad statement may
not be warranted.

Mr. Whipple stated that the FDA could wordsmith the labeling statement.

**Question 2: Are additional clinical data, analyses, or criteria needed
to evaluate the relative effectiveness of custom and conventional
treatments with regard to higher order aberrations and visual
function?**

Dr. Bandeen-Roche stated that there could be sources of bias with
respect to the cohort, such as practice effects. Ideally, she would like
to see data from randomized controlled studies. Perhaps matched analyses
could be conducted. Second, variability between sites needs to be
assessed: If substantial variation exists, it means that the assessments
are not valid.

The panel discussed limiting approval to treatment of people below --5.0
D, but ultimately agreed not to limit approval because it is known from
prior PMAs that predictability and effectiveness fall off at higher
ranges. No red flags are being raised at this point around higher
ranges. In addition, the number of patients beyond --5.0 D is quite
small.

Dr. Eydelman of the FDA noted that in previous approvals, the Agency has
not asked sponsors to have a statistically significant number of
patients in each dioptic range. Even though a small number of patients
are in a high range, no safety problems have emerged. Also, this PMA
represents a second generation of this device. If the panel has concerns
about optical quality, they can be handled in labeling.

Several panel members noted that they would like to see the symptom and
satisfaction data compared for conventionally treated patients versus
wavefront-treated patients.

**Question 3: What information about measurement, analysis, and
correction of higher order aberrations is needed in the labeling to
inform physicians and patients about safety of effectiveness of Custom
Cornea treatments?**

The panel agreed that the labeling should not imply that the procedure
will fix everything that is wrong with a patient's vision or with
current LASIK methods. The brochure should say that this kind of surgery
increases aberrations postoperatively less than conventional methods.
Dr. Bullimore suggested statements such as "WFG LASIK does not reduce
the level of higher order aberrations of the preoperative eye" and "WFG
LASIK cannot correct aberrations and provide supernormal vision." The
panel members suggested that FDA staff could fine tune

the wording. The panel also thought it was important to note that the
study was conducted primarily on Caucasian subjects age 65 or younger.

**Question 4: What additional stability criteria are needed for higher
order aberration treatments?**

Dr. Bradley noted that this is a potentially important point, but the
science is lagging. We know little about preoperative aberration
variability, so developing criteria for postoperative aberration is
difficult. Some panel members suggested that it would be reasonable to
have postmarket data that tracked changes in RMS values. The panel
concurred that a caveat in the data stating that no long-term data on
the safety and effectiveness are available would suffice. No additional
studies are required of the sponsor.

**Question 5: Should stability criteria be more stringent for
wavefront-based treatments than for conventional treatments?**

The panel concurred that certain data tables from the sponsor's study
(those that describe subjective symptoms, lines of loss, and changes in
low-contrast BSCVA) should be included in the patient information
booklet and that the booklet should state that vision becomes stable in
the first month, not in the first weeks. If the procedure is trying to
correct for small aberrations, the stability needs to be more stringent.
The stability of correction for spherical myopia is the primary outcome
determinant.

The panel spent additional time discussing the patient information
booklet. Dr. Matoba noted that the original format of the booklet had
already been improved for conventional treatment and asked whether it
was fair to make the sponsor list more problems with WFG LASIK when the
patient booklet for conventional LASIK will not have all that
information. The panel discussed whether the booklet for WFG should be
more detailed than the booklet for conventional treatment. Dr. Eydelman
noted that the booklet will have a separate section for the wavefront
device. Ms. Such said that the booklet has to incorporate new knowledge
and respond to consumer needs. She encouraged FDA to expand on the
effects without making too much of rare instances. Mr. McCarley noted
that the dry eye issue is not inherent to this application; if it is an
industry issue, this PMA should not be burdened. Dr. Bullimore suggested
that the panel needed to set a precedent and that perhaps the rest of
industry should update its patient and physician booklets. Panel members
stated that it is important to manage patient expectations and suggested
that the patient information booklet should state that a certain
proportion of patients will require glasses postsurgery.

# 

# OPEN PUBLIC HEARING

Mr. Link said that Surgical Eyes recommends that clinical trials be
attached to this PMA. The patient labeling and patient and professional
information booklets across all laser platforms need to be updated.
Zernicke polynomials only extend to 6 mm pupils---large pupils are a
contraindication. Information on spherical aberrations needs to be
translated into patient language.

# FDA COMMENTS

Mr. Whipple observed that labeling issues are challenging and that the
panel has given good guidance to FDA.

# SPONSOR COMMENTS

Dr. Pettit thanked the panel for its consideration.

# VOTE

Ms. Thornton read the voting options to panel. The panel voted 9-0
(unanimously) that the PMA was approvable with the following conditions:

1.  Issues related to clinical data

    -   Postoperative data should be provided to the FDA on symptoms and
        patient satisfaction comparing eyes treated with conventional
        LADARVision/LASIK compared to WFG LADARVision/LASIK treated
        eyes. The resulting comparison data should be included in the
        patient and physician labeling.

    -   A matched analysis of the study data comparing aberrations in
        conventional LADARVision/LASIK and WFG LASIK eyes

    -   Presentation of site to site variability in the aberration
        outcomes. A substantial variability would invalidate the
        reported confidence intervals and p values

2.  The labeling in the patient and physician information booklets
    should include the following statements:

-   WFG LASIK has demonstrated slightly superior optical quality
    (reduced monochromatic aberration) than conventional LADAR
    vision/LASIK. Minor improvements in visual acuity and contrast
    sensitivity relative to conventional LADAR vision/LASIK

-   The accuracy of the correction for myopia is still the primary
    determination of uncorrected image quality and vision.

```{=html}
<!-- -->
```
-   There is no data to support improved functional performance
    (activities of daily living such as reading, driving) or
    satisfaction rates in patients with WFG LASIK as compared to the
    conventional LADARVision/LASIK

-   Only a small number of eyes in the study had greater than --6.0 D
    refractive error (the sponsor is to provide the exact number).

-   Conventional LADARVision/LASIK demonstrated an increase in higher
    order aberrations of approximately 77 percent over preoperative
    levels, whereas WFG LASIK demonstrated an increase of approximately
    20 percent over preoperative levels.

-   No retreatment data are available.

-   The age and race of the study population and a demographic data
    table

-   Postoperatively a patient\'s eyes postoperatively should achieve
    stable vision after one month.

-   The exclusion criteria in the labeling should match the exclusion
    criteria in the protocol

> 3\. Tables describing the following data should be included in the
> patient and physician information booklets:

-   Change in BSCVA

-   Postoperative uncorrected visual acuity (UCVA) compared with
    preoperative best spectacle corrected visual acuity (BSCVA) or a
    statement that only 50% of patients saw well without glasses
    postoperatively as compared to their best preoperative spectacle
    correction.

-   The entire data table of subjective symptoms as presented in the
    body of the clinical study specifically including the categories of
    response ,i.e. significantly better, better, no change, worse,
    significantly worse.,

4.  The patient information booklet should include the following
    statements:

    -   Preexisting dry eye condition and/or large nighttime pupils may
        decrease satisfaction with the LASIK procedure. Advise that
        patients should discuss this issue with your physician.

-   The labeling should refer patients to the FDA LASIK Web site for
    more information.

5.  The physician information booklet should include

    -   A table giving the Change in Low Contrast Best Spectacle
        Corrected Visual Acuity of the safety cohort

    -   List pre-existing dry eye and large nighttime pupils as a
        contraindication.

In explaining their votes, panel members indicated that they had reached
consensus. Several panel members noted that little clinically
significant difference existed between this PMA and previous
submissions, and the sponsor had demonstrated safety and effectiveness
of the device. Dr. Matoba noted that she hoped that the FDA would take
into consideration the conditions that apply specifically to WFG LASIK
so that the device is not singled out to have more stringent labeling.
Ms. Such thanked the sponsor and the panel and said that the labeling
changes are an improvement, not a burden. Mr. McCarley said that FDA
should consider requiring all LASIK manufacturers to revise their
labeling.

# ADJOURNMENT

Dr. Weiss thanked the participants and adjourned the open session at
4:37 p.m.

**CALL TO ORDER - August 2, 2002**

**Panel Chair Jayne Weiss, M.D.,** called the meeting to order at 8:29
a.m. E.D.T.

**Panel Executive Secretary Sara Thornton** announced the confirmation
of the new panel chair, Dr. Jayne Weiss. Three newly appointed voting
members, Drs. Anne Coleman, Allen Ho, and Timothy McMahon, were unable
to attend. Ms. Thornton then read the conflict of interest statement.
Panel consultants Drs. Mark Bullimore and Stephen Burns had received
waivers for their interests in firms that could be affected by the
panel's recommendations and could participate fully in the panel's
deliberations. The Agency took into consideration certain matters
concerning Drs. Arthur Bradley, Michael Grimmett, and Jayne Weiss, who
reported interests in firms at issue regarding matters not related to
today's agenda; they could therefore participate fully in all
discussions. Ms. Thornton noted that guest speakers Drs. Henry
Edelhauser, Bernard McCarey, and Liliana Werner reported interests in
firms at issue.

**David M. Whipple, deputy director, Division of Ophthalmic and Ear,
Nose and Throat Devices,** thanked the panel for its discussion on
August 1, 2002, and noted that the Agency will use it in regulating the
marketing and labeling of the device.

# OPEN PUBLIC HEARING 

**John Vukich, M.D., Madison, WI,** presented data comparing LASIK
patients from his private practice and his investigational phakic
intraocular lenses (PIOLs) patients from Staar Surgical\'s Implantable
Contact Lens multicenter clinical trial. PIOLs offer an alternative to
LASIK. With LASIK, it is not uncommon for patients to lose two lines or
more of visual acuity; in his sample, not one PIOL patient lost two
lines or more. PIOL may be superior to corneal ablative procedures in
that patients prefer the quality of vision with PIOL. In the study,
wavefront analysis was used to assess optical quality and to compare
induced aberrations; significantly more coma and spherical aberration
was found in the LASIK group. Custom corneal ablation is not an option
for high myopia; it removes up to 20 microns of tissue per diopter and
is therefore limited to the diopter ranges that are already approved.
Few options are available to patients who have high myopia or other
patients for whom corneal ablation is inappropriate. A noncorneal
alternative is an important step forward.

Panel members asked Dr. Vukich questions on the risks and benefits of
PIOLs versus LASIK, which he answered to their satisfaction. He noted
that infection is a risk; one benefit is that PIOL provides the
opportunity to reverse offending treatment. In response to panel
questions, Dr. Vukich stated that PIOLs should be held to the same
standard as LASIK in terms of quality of vision. Small corrections can
be made on the corneal level rather than going back into the eye.

# OPEN COMMITTEE SESSION

# General Issues Discussion

**Donna** **Lochner, chief, Intraocular and Corneal Implants Branch,**
noted that the purpose of the meeting was for the panel to discuss
design elements for clinical studies of phakic intraocular lenses
(IOLs). The panel's recommendations will be used to further develop
FDA's guidance document for phakic IOLs/ refractive implants. The
panel's suggestions also will be taken into consideration by the
American National Standards Institute (ANSI) and International Standards
Organization (ISO) phakic IOL standards development committees.

**Bernard F. McCarey, Ph.D., Emory University Eye Center, Atlanta, GA,**
discussed issues in clinical specular microscopy. He first described the
types of equipment that are available and the major differences between
contact and noncontact microscopy. He then provided data on endothelial
cell density, which diminishes over time. Cell density follows a linear
regression line; at birth, a person has 3,000 to 4,000 cells per mm^2^;
by age 50, a person could have anywhere from 2,200 to 5,300 cells per
mm^2^. Surgical trauma affects cell density in the inferior, central,
and superior areas; density may not return to presurgery levels. In
addition, transient and chronic damage can occur from contact lens wear.
Dr. McCarey described four methods of determining cell density---the
comparison, frame, corner, and center methods---along with their
advantages and disadvantages. Finally, he summarized issues related to
the repeatability of cell density measurements. He offered suggestions
for clinical trials and listed issues related to clinical site training
that affect measurement of endothelial cell density.

**Henry F. Edelhauser, Ph.D., Emory University Eye Center, Atlanta,
GA,** stated that the purpose of his presentation was to provide the
panel with an understanding of the variability issues regarding specular
microscopy that may bias results. He provided examples of good and poor
photography to illustrate the variability in specular microscopy
photography. A good image has distinct cells, enables identification of
at least 150 cells, and groups cells in a uniform area. Dr. Edelhauser
noted that what may be a good image for clinical purposes may not be
acceptable for research. Dry eye, contact lens use, settings,
keratoconus, patient compliance, age, and the training of the
photographer all can affect image quality; certain conditions, such as
guttata, polymegethism, injury, and low cell density (i.e., huge cells)
increase the variability of images. To ensure consistency, it is best
for one person to conduct the image analysis. Finally, Dr. Edelhauser
summarized the consequences of under- or overcounting. Research has
found that Japanese and other populations of Asian patients have higher
cell density, which is an important issue for researchers. In the best
of hands, the precision of cell density counts is 1.5 percent. Sources
of variability include difficulty returning to the same location, poor
image quality, technician error, reader analysis, and equipment
calibration. Sites should not conduct their own analysis---a central
reading center should.

# 

# Panel Questions for Drs. McCarey and Edelhauser

Panel members asked many questions concerning the effects of contact
lenses on endothelial cell counts and whether patients should not wear
their contacts for a period before surgery. Dr. McCarey suggested that
not wearing lenses for 6 months would be ideal, but the topic is
complicated, given that recovery of cell density is so slow. Contact
lens wearers could benefit from this surgery, so they should not be
excluded; surgeons just need to be aware of the issues involving
endothelial cell counts. In addition, endothelial cell density not the
only indicator of corneal health. In research, however, it is best to
not start with patients who have low cell counts; a normal endothelial
cell population with some polymegethism is best.

Panel members also asked questions to clarify what constitutes a good
image and how much variability is due to the reader versus cell density.
Dr. Edelhauser said that one takes three images and uses the one that
has a uniform distribution of cells across the whole screen. If all
three images are good, the cell count for each image is averaged. Cell
density counts are less variable when a study takes place within a
single site.

Dr. McCarey suggested that for research purposes, it would be helpful to
do only unilateral PIOL surgery in order to obtain information from the
contralateral eye.

**Liliana Werner, M.D., Ph.D., director of research, Storm Eye
Institute, Charleston, SC,** presented an overview of issues related to
cataract formation after implantation of phakic posterior chamber IOLs.
She noted that two types of fibrocellular tissue attach to the lens---A
cells and E cells---and are related to different types of opacification.
She presented research findings on the evolution of IOLs, fixation and
sizing, surgical implantation, the relationship between cataract and
myopia, and cataractogenesis. Because anterior capsule trauma may lead
to crystalline lens opacities later, it is best if the lens is not
touched at all during surgery. A relation has been found between
cataract and myopia; Werner presented research findings that may explain
this relationship. Werner also listed several mechanisms of cataract
generation after phakic posterior chamber IOL procedures, including
anterior chamber reduction, increase of the aqueous flare, and
peripheral or central contact with the crystalline lens. Finally, Werner
presented three classification systems for cataracts and noted that
ideally, any system should indicate the location of the opacity and
provide an index for the degree of opacity and progression.

# Panel Questions for Dr. Werner

Panel members asked questions concerning appropriate intervals for
tracking cataract growth, the contribution of lens material to cataract
formation, and the effects of peripheral cataracts on night vision. Dr.
Werner said that the literature on all those topics is scant. Dr.
Mathers asked Dr. Werner about the best method for detecting small
amounts of visual impairment, and she suggested that perhaps both glare
testing and contrast sensitivity should be used.

# OPEN PUBLIC HEARING

No comments were made.

# FDA PRESENTATION

### *QUESTIONS FOR THE PANEL (see attached)*

### QUESTION 1 Endothelial Cell Density: Dr. Michael Grimmett, Lead Responder

Dr. Grimmett noted that the literature data have limitations: They are
mostly retrospective, are nonrandomized, are small, have poor follow up,
and do not report endothelial analyses (i.e., coefficients of variation
and hexagonality). PIOLs fall into two categories: anterior chamber and
posterior chamber. The two types have implications for endothelial cell
loss. Dr. Grimmett summarized the available cell loss data for different
types of PIOL. Data on the relationship of cell loss to IOL type will
help give guidance on clinical studies.

Dr. Grimmett presented normative endothelial cell loss data and data for
cell density loss following cataract surgery and penetrating
keratoplasty. He stressed that it is important to determine an
acceptable cell loss rate because it relates to how big sample sizes
must be.

For all phakic IOL studies, endothelial cell density measurements and
morphometric analyses are mandatory; corneal pachymetry is suggested.
Three years is probably a sufficient study duration for posterior
chamber phakic IOLs. Dr. Grimmett said that he favors 4-year studies for
higher risk factors, such as angle-supported IOLs, thicker anterior
chamber IOLs, shallower anterior chamber depth, and chronic anterior
chamber inflammation.

Finally, Dr. Grimmett recommended minimum endothelial cell density entry
requirements, derived from calculating backward from the average cell
density at age of death (based on actuarial data). He noted that if
1,500 cells/mm^2^ is the desired cell density at age of death, a 2.0
percent rate of annual loss is unacceptable. A loss rate of 0.9 percent
provides a better result. It is impossible to precisely determine
minimum entry requirements without knowing the exact rate of endothelial
cell loss per year for various types of phakic IOLs.

# Panel Discussion of Question 1

Panel members asked Dr. Grimmett's opinion on using a central reading
center for determining cell density; he replied that if a sponsor can
validate precision and validity and show that it produces results
equivalent to a reading center, use of a center should not be required.

Dr. Huang suggested that Dr Grimmett's endpoint was a bit strict because
surgery takes place 5 or 10 years before death; Dr. Grimmett replied
that he started with that endpoint, but the spreadsheet would not work.
He used the most conservative approach.

Concerning unilateral surgery, Dr. Grimmett felt that enrolling in a
3-year study and having to wait for surgery on the other eye is an
unreasonable burden to investigational patients. Historical data can
provide control benchmarks, and considering his recommendations for the
endothelial study design, fellow eye (non-operated) data are not
critical. Other panel members concurred.

###  QUESTION 2 Evaluation of the Natural Lens for Cataractogenesis 

### Dr. William Mathers, Lead Responder

*Response to Question 2, Part A:* Dr. Mathers stated that all PIOLs need
to be evaluated for changes in the lens. Even designs that would not
touch the lens could be a problem. Any perturbation is of interest. All
cataract processes need to be assessed; we have to look not just at the
lens but at the source of the problem, as in anterior chamber
inflammation. Flare needs to be measured as well.

*Response to Question 2, Part B: The clinical significance of a l*ens
opacity is subjective, and there is not good data available correlating
opacities and vision changes. Central opacification of the anterior
subcapsular area will not show up in standard visual acuity testing in a
dim room. Glare testing is the most relevant approach. We need to have
careful measurements of patients as they enter a study and a
standardized method of evaluating glare. High glare settings should be
used. Two or more lines of loss are a sufficient threshold. All lens
changes should be reported. As lenses are made that do not touch the
central crystalline lens, they may touch the periphery of the
crystalline lens, with cells migrating posteriorally. Inflammation that
occurs with the anterior chamber lens may affect the development of
nuclear sclerotic opacities and needs to be monitored.

*Response to Question 2, Part C:* No standard quantitative measures for
lens changes---meaning the visualization of the changes under the
anterior capsule---exist. The examination is light dependent.
High-resolution color photography is the best way to follow changes over
time. A scale has been developed (the LOCS system), but it can be
modified. Dr. Mathers recommended the use of digital photography.

*Response to Question 2, Part D: Evaluation of l*ens changes is less
objective than the endothelial cell study, for example. One study noted
some change in light transmittance that was not necessarily based on
cataract. Given that phakic IOLs will be implanted for a long time
period and given the possibility of chronic, subclinical inflammation;
at least 3 years of follow up would be necessary, and monitoring should
perhaps continue beyond that point.

# Panel Discussion of Question 2.

Dr. Weiss asked Dr. Mathers what he would call a clinically significant
cataract. He responded that it would involve the loss of a number of
lines of acuity, with much dependent on the measurement conditions.
Standard measures of vision are not adequate to pick up the changes. At
least two lines of loss by glare testing, or the loss of one line
without glare testing may be an appropriate cutoff. Contrast sensitivity
testing should also be considered.

Dr. Bradley commented that in glare testing, the pupil constricts so if
the cataract is central, it fills a larger portion of the pupil and
retinal image, increasing the visual effect. A peripheral cataract
covers a small proportion of the pupil. Therefore, the glare test may
not measure the true impact of a peripheral cataract. Addition of
cycloplegia to the glare test may be necessary to address this, perhaps
in a subset of patients.

### QUESTION 3. Contrast Sensitivity Substudy: Dr. Mark Bullimore, Lead Responder

*Response to Question 3, Parts A and B:* It is reasonable to set the
clinically significant decrease in contrast sensitivity at 0.3 log
units. He felt implied that 0.3 log units was parallel to two lines
acuity loss which represents adverse events or other unsatisfactory
outcome. He felt the loss should be at 2 or more spatial frequencies.
Dr. Bullimore said that the grading approach carries the opportunity for
bias. Saying the drop should be at two or more spatial frequencies is
reasonable. Letter charts should remain an option for sponsors.

**Panel Discussion of Question 3, Parts A and B**

The panel spent considerable time discussing issues related to measuring
changes in visual acuity and whether to use grading or letter charts.
Panel members noted that without knowing how much change would cause a
problem in functional performance, the question of the significance of a
0.3 log unit loss is difficult to answer.

Dr. Bradley noted that just because a product is new, it does not mean
that contrast sensitivity has to be measured. He supported use of
contrast sensitivity or contrast acuity to document whether any corneal
problems or lens opacities have degraded optical quality.

Dr. Owsley said that she knows of no convincing evidence showing that
letter tests are worse than grading tests in detecting visual deficits.
Many researchers who use letter tests are interested in obtaining
information about the entire shape of the function. Spatial frequency
testing is done in a variety of circumstances---before and after
surgery, and so forth. Sound arguments exist for doing all spatial
frequencies, but what information is it really providing that letter
testing would not provide?

Dr. Swanson noted that Dr. Bullimore's point is an important
consideration for sample size. Letter testing requires a smaller number
of trials. A multichoice forced choice (i.e., letter testing) is a
better option than a two-choice forced choice (i.e., grating). Letter
acuity is more suitable for gathering useful data in short time period.

Panel members concurred that letter charts are more appropriate for this
testing.

Dr. Bullimore stated that it would be useful if the guidance would allow
other tests to be considered. Several panel members noted the dearth of
evidence demonstrating that measuring spatial frequencies would matter
for the devices. Other panel members said that it was important to
measure the whole function. Dr. Whipple noted that a guidance document
always carries options for using other tests.

*Response to Question 3, Part C:* The panel concurred with Dr. Bullimore
that if a patient cannot read or see the highest contrast, it would have
to be scored as 0, not as missing data. If a person cannot see, it does
not constitute missing data. The panel also concurred that tests of
contrast sensitivity should have the best test--retest reliability
possible and should be brief.

# PANEL DISCUSSION ON REMAINING ISSUES

Panel members discussed the appropriate duration for studies before they
are presented to the panel; they were unanimous that 3 years was
appropriate. Dr. Bandeen-Roche noted that at least one, possibly two,
endothelial cell density evaluations should be scheduled between years 2
and 3. The panel concurred and noted that ongoing follow up for another
2 years would be appropriate.

The panel also discussed whether studies should use patients or eyes as
the independent entity. For LASIK studies, each eye has been the
independent entity, so 150 patients could represent 300 datapoints. Dr.
Bandeen-Roche noted that statistics could be used to account for the
fact that two eyes do not count the same as two people.

Dr. Weiss said that for IOLs, the first eye only was used in the primary
analyses; LASIK is an exception. Ms. Lochner noted that a correlation
factor between both eyes of a patient was not addressed in the guidance;
all calculations are based on the idea that one patient (first eye)
equals one entity. If FDA allowed one eye to equal one entity, it would
need to know how correlated eyes are for outcomes.

The panel discussed issues related to sample size and loss of
endothelial cell density and concurred that 300 subjects was
appropriate. Dr. Bradley noted that presenters had stated that a single
eye would have to have a 9 percent loss in cell density in order for
researchers to be able to confirm that a change had occurred. Dr.
Grimmett noted that with a cell loss of 1.9 percent per year, he would
be worried that patients would develop corneal edema and suggested that
the studies should be able to detect cell loss rates of 1.5 percent or
lower.

Dr. Bandeen-Roche noted that a sample of 300 and a 95 percent upper
confidence bound would permit a 1 percent adverse event rate, which does
not meet the 0 .001 standard proposed in the guidance. Instead, a sample
of 3,000 would be required. She said that the issue supports the
importance of collecting postmarket data and asked, "Can the panel live
with 5 percent of studies claiming an adverse event rate of 0.001 or
less when it is actually higher?"

The panel discussed whether patients with low myopia should be entered
into trials and concurred that it would be appropriate for IDEs to focus
on higher myopes first, then lower.

# ADJOURNMENT

Dr. Weiss thanked the panel members and FDA staff and adjourned the
panel meeting at

2:00 p.m.