FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

OPHTHALMIC DEVICES PANEL

Thursday,

August 1, 2002

Salons A-C

Hilton Hotel Gaithersburg

620 Perry Parkway

Gaithersburg, Maryland

IN ATTENDANCE:

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

Stephen A. Burns, Ph.D., Consultant

Mark A. Bullimore, MCOptom, Ph.D.,

Consultant, deputized to vote

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

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

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

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Call to Order

Jayne S. Weiss, M.D.

Chair 7

Introductory Remarks, Conflict of Interest

Statement, and Appointment to Temporary

Voting Status

Sara M. Thornton

Executive Secretary 7

Open Public Hearing

Ronald J. Link

Surgical Eyes 13

Letter from LASIK Recipient

(Read by Sara M. Thornton) 21

David L. Shell

Arlington, VA 24

Open Committee Session

Jayne S. Weiss, M.D. 27

Division Update

David M. Whipple

Deputy Director

Division of Ophthalmic and Ear, Nose, and

Throat Devices 27

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Branch Updates

Vitreoretinal and Extraocular Devices Branch

James F. Saviola, O.D.

Chief 28

Intraocular and Corneal Implants Branch

Donna R. Lochner

Chief 33

Diagnostic and Surgical Devices Branch

Everette T. Beers, Ph.D.

Chief 34

PMA P970043/S010, CustomCornea Myopic

LASIK With the LADARVision 4000 System

Sponsor Presentation by Alcon

Kathleen Chester

Director, Regulatory Affairs 37

George Pettit, M.D., Ph.D.

Vice President and Chief Scientist,

Clinical Outcomes Research 38, 61, 72

Daniel Durrie, M.D.

Investigator

Hunkeler Eye Clinic, Inc.

Kansas City, MO 50

Omar Hakim, M.D.

Investigator

TLC Canada

Waterloo, Canada 55

Stephen Brint, M.D.

Investigator

Brint Vision Correction Center

Metairie, LA 65

Questions for the Sponsor 79

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FDA Presentation

Everette T. Beers, Ph.D. 127

Jan C. Callaway

Team Leader

Diagnostic and Surgical Devices Branch 127

Bruce A. Drum, Ph.D.

Vision Scientist and Physicist

Diagnostic and Surgical Devices Branch 129

Questions for FDA 134

Additional Comments from the Sponsor 135

Committee Deliberations

Primary Panel Reviewers

Andrew J. Huang, M.D. 137

Arthur Bradley, Ph.D. 142

Panel Discussion of PMA P870043/S010

and FDA Questions 156

Open Public Hearing

Ronald J. Link 245

Closing Comments by FDA 247

Closing Comments by the Sponsor 248

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Voting Options 250

Panel Discussion and Recommendation Taken by Vote 252

Polling of Panel Votes 289

Comments from Consumer and Industry Representatives

Glenda V. Such, M.Ed. 292

Ronald E. McCarley 293

Closing Comments

Jayne S. Weiss, M.D. 293

[P R O C E E D I N G S]{.underline} (8:35 a.m.)

DR. WEISS: I\'d like to call this meeting of the Ophthalmic Devices
Panel to order and we\'ll have introductory remarks from Sarah Thornton.

MS. THORNTON: Good morning and welcome to the 104th meeting of the
Ophthalmic Devices Panel.

Before we proceed with today\'s agenda, I have a few short announcements
as usual that I\'d like to make. I\'d like to remind everyone out there
as well as the panel and the FDA folks to sign in on the attendance
sheet in the registration area just outside the meeting room here.
Messages for panel members and FDA participants and information or
special needs should be directed through Ms. Annmarie Williams or Ms.
Jennifer Weber who are available in the registration area.

The phone number for calls to the meeting area is (301) 977-8900. In
consideration of the panel, the sponsor and the agency, we ask that
those of you with cell phones and pagers either turn them off or put
them on vibration mode while in this room.

Lastly, will all meeting participants please speak clearly into the
microphone, give your name clearly, until I get a signal from the
transcriber that he no longer needs your name, so that we will have an
accurate recording of your comments, please.

Now, at this time, I\'d like to announce the confirmation of the new
Ophthalmic Devices Panel Chair, Dr. Jayne Weiss. We also have three
newly appointed voting members, Drs. Anne Coleman, Allen Ho, and Timothy
McMahon, who are regrettably unable to be with us today. However, we
look forward to their attendance at future meetings.

I\'d also like to extend a special welcome and introduce to the public
and panel and FDA staff three panel consultants who are with us for the
first time today. Dr. Stephen Burns. Dr. Burns comes to us from Boston,
Massachusetts, where he is a senior scientist at the Schepens Eye
Research Institute and associate professor at the Harvard University.
Dr. Cynthia Owsley is from Birmingham, Alabama, where she is the
Professor of Ophthalmology at the School of Medicine and Co-Director of
the Center for Research on Applied Gerontology at the University of
Alabama. And Dr. William Swanson is a senior research scientist in the
Department of Clinical Sciences at the State University of New York,
College of Optometry, in New York City.

Welcome to you all. Hope you enjoy your day with us.

Will the remaining panel members take the time now to introduce
themselves, and I\'d like to begin with our industry rep.

MR. McCARLEY: My name\'s Rick McCarley. I\'m the industry rep. I\'m the
President and CEO of Ophtec in Boca Raton, Florida.

DR. BANDEEN-ROCHE: I\'m Karen Bandeen-Roche, Associate Professor of
Biostatistics at Johns Hopkins University.

DR. BULLIMORE: Mark Bullimore, Associate Professor, Ohio State
University.

MS. SUCH: I\'m Glenda Such, consumer representative, Director of
Computer Training Programs at Lighthouse International, New York City.

DR. MATOBA: I\'m Alice Matoba, Associate Professor of Ophthalmology,
Baylor College of Medicine.

DR. GRIMMETT: Michael Grimmett, Assistant Professor of Ophthalmology at
the University of Miami, School of Medicine.

DR. WEISS: Jayne Weiss, Professor of Ophthalmology and Pathology, Kresge
Eye Institute, Wayne State University, Detroit.

DR. BRADLEY: Arthur Bradley, Professor of Visual Science, Indiana
University.

DR. HUANG: Andrew Huang, Associate Professor of Ophthalmology,
University of Minnesota.

DR. MAGUIRE: Leo Maguire, Associate Professor of Ophthalmology, Mayo
Clinic.

MR. WHIPPLE: And I\'m Dave Whipple, Deputy Director of the Division of
Ophthalmic, Ear, Nose and Throat Devices.

MS. THORNTON: Thank you very much.

At this time, I\'d like to read the conflict of interest statement for
the meeting today.

\"The following announcement addresses conflict of interest issues
associated with this meeting and is made part of the record to preclude
even the appearance of an impropriety.

\"To determine if any conflict existed, the agency reviewed the
submitted agenda for this meeting and all financial interests reported
by the committee participants. The conflict of interest statutes
prohibit special government employees from participating in matters that
could affect their or their employer\'s financial interests. However,
the agency has determined that participation of certain members and
consultants, the need for whose services outweigh the potential conflict
of interest involved, is in the best interests of the government.

\"Therefore, waivers have been granted to Drs. Mark Bullimore and
Stephen Burns for their interest in firms that could potentially be
affected by the panel\'s recommendation. Dr. Bullimore\'s waiver
allowing him to participate fully in today\'s deliberations involves a
consulting arrangement with a competing technology firm. For this
unrelated consulting service, he receives less than \$10,000 a year. Dr.
Burns\' limited waiver allows him to participate in the panel discussion
but excludes him from voting. His interest involves a grant to his
employer with a competing firm funded for less than \$100,000 per year
for which he has involvement in data collection and interpretation.

\"Copies of these waivers may be obtained from the agency\'s Freedom of
Information Office, Room 12A-15 of the Parklawn Building.

\"We would like to note for the record that the agency took into
consideration other matters regarding Drs. Arthur Bradley, Michael
Grimmett, and Jayne Weiss. They reported interest in firms at issue but
in matters not related to today\'s agenda. The agency has determined
therefore that they may participate fully in all discussions.

\"In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participant should excuse him or herself from such
involvement and the exclusion will be noted for the record.

\"With respect to all other participants, we ask in the interest of
fairness that all persons making statements or presentations disclose
any current or previous financial involvement with any firm whose
products they may wish to comment upon.\"

I will read now the appointment to temporary voting status.

\"Pursuant to the authority granted under the Medical Devices Advisory
Committee Charter, dated October 27th, 1990, and as amended August 18th,
1999, I appoint the following individuals as voting members of the
Ophthalmic Devices Panel for this meeting on August 1st, 2002: Dr. Karen
Bandeen-Roche, Dr. Mark Bullimore, Dr. Andrew Huang, Dr. Leo Maguire,
Dr. Cynthia Owsley, Dr. William Swanson. For the record, these
individuals are special government employees and consultants to this
panel or other panels under the Medical Devices Advisory Committee. They
have undergone the customary conflict of interest review and have
reviewed the material to be considered at this meeting.\" Signed Dr.
David W. Feigal, Jr., Director of the Center for Devices and
Radiological Health, dated July 19th, 2002.

Thank you, Dr. Weiss.

DR. WEISS: Thank you, Sally.

We will now start the open public hearing. There are three individuals
who have requested to speak before us. I would appreciate when they
approach the podium, they should identify themselves and any financial
conflicts or potential conflicts, and we\'ll start with Mr. Ron Link. If
you could come to the podium and read your statement, please?

MR. LINK: Good morning.

My name\'s Ron Link. I\'m Executive Director of Surgical Eyes, Tampa,
Florida. I have no conflict of interests with regard to this meeting.

Well, good morning, Ophthalmic Devices Panel members and members of the
audience. I\'m here today to advocate on behalf of thousands of people
who have longstanding complications of refractive surgery. Together, we
can confront the challenge of rehabilitation of as many of these people
as possible. Surgical Eyes supports the advancement of wavefront
technology in that it may hold promise for the visual rehabilitation of
these patients who live with complications of LASIK and other refractive
surgeries. No less important is our mutual obligation that fewer
patients with complications be created.

I want to reference this slide of a recent survey that we did at
Surgical Eyes, only ran for a week, but I think the results are
compelling. This first slide were LASIK successes in the sense that they
had 20/40 or better UCVA. You can see significant quality of vision
issues and you expect much more in the excellent categories, but we see
that\'s not the case across different lighting conditions. Now, attempts
to improve that vision with contact lenses or glasses yielded slight
improvement. So what this tells me is that we need better technologies
to rehabilitate these folks. Now, people who were not corrected to 20/40
or better had even less good result with the attempts at correction.

These people and many others at Surgical Eyes may very well benefit from
laser and contact lens wavefront technology. If the panel votes for
approval on the PMA for this device, we ask that it do so with the
following conditions.

Number 1. Controlled studies on post-refractive eyes. Clinical studies
at multiple sites across the United States on post-refractive eyes with
a minimum one-month follow-up. Anecdotal reports from the estimated 200
global cases of wavefront-guided treatments on patients with
complications reveal that results are often immediate. Clinical studies
should not only include those with under-corrections or smaller
aberrations. Decentration, central islands, disparity between the
affected optical zone and pupil size, these and other complications
result in higher-order aberrations. We believe wavefront treatment on
such patients should first be performed in controlled circumstances by
surgeons who have the requisite skill and technical experience to
perform therapeutic studies on post-refractive eyes.

Controlled studies are necessary to prevent a rush by patients and
doctors alike to avail themselves of a new device in off-label use
without the necessary specific clinical protocols and data analysis to
evaluate the safety and effectiveness of a device on post-refractive
eyes. Should you vote for approval, such a condition attached to
today\'s PMA would be a win-win for all concerned.

Second. Professional use information and patient information booklets.
Preexisting dry eye should be listed as a contraindication warning in
the professional use information and patient information booklets of any
laser approved for LASIK brought before the FDA. The FDA\'s LASIK
website has a section entitled \"When is LASIK Not for Me?\" Under the
Other Risks section, it states, \"Dry eye. LASIK surgery tends to
aggravate this condition.\" Under another section entitled \"What Are
the Risks and How Can I Find the Right Doctor For Me?,\" it states,
\"Some people may develop severe dry eye syndrome. As a result of
surgery, your eye may not be able to produce enough tears to keep the
eye moist and comfortable. This condition may be permanent.\" This last
slide shows that dry eye is a significant factor of the 100 percent of
LASIK patients that are reported in this survey.

We believe that the information published by the FDA with regard to
lasers should be consistent with the information presented in laser
device professional use information and patient information booklets.
For the last approved LASIK device, dry eye syndrome was listed under
exclusion criteria for the PMA study data. If dry eyes are excluded from
PMA data, the same warning should be extended to the public.

The American Academy of Cataract and Refractive Surgery recently issued
LASIK Screening Guidelines for Patients on June 4th, 2002. Under the
less than ideal LASIK candidates listed have a history of dry eyes as
they may find that the condition worsens following surgery. We recommend
that these guidelines be consulted to update the information presented
in both professional use information and patient information booklets.

A similar argument can be made with regard to the issue of pupil size.
In any professional use information and patient information booklets
that we have read for this same laser device, the language is not
consistent. By way of example, with regard to the last FDA-approved
laser, it states in the professional use information that visual
performance could possibly be worsened by large pupil sizes or
decentered pupils. This sentence is not included in the Precautions
Section of the patient information booklet. The FDA website under \"When
Is LASIK Not For Me?,\" states under Other Risk Factors, \"Your doctor
should screen you for the following conditions or indicators of risk:
large pupils. Make sure this evaluation is done in a dark room.\"
Jumping ahead a bit, \"This can cause symptoms, such as glare, halos,
starbursts, and ghost images, double vision after surgery. In some
patients, these symptoms may be debilitating. For example, a patient may
no longer be able to drive a car at night or in certain weather
conditions, such as fog.\"

The overriding point is that the information put forth by the FDA on its
website and what it requires of manufacturers in professional use
information and patient information booklets should be consistent with
regard to dry eye, pupil size, and any other pre- or postoperative
information provided to the public. Degree of success for higher myopes
being yet just another example.

Also, we suggest that pictures be provided in patient information
booklets so that patients understand the visual manifestations of both
lower and higher-order aberrations in various lighting conditions,
particularly at night.

And lastly, post-approval studies. If required for contact lenses, by
way of example PMA for the CIBA Extended Wear Contact Lens, it is
logical to expect that the same for LASIK, PRK, LASIK, or any other
laser device used to perform these surgeries. Lastly, questionnaires
should be included to account for any potential adverse effects on
quality of life.

Surgical Eyes is cautiously optimistic that post-refractive patients
with complications may indeed benefit from controlled studies of the
wavefront device being presented here today. We support such
advancement. No less important is the identification and ready
disclosure of all pre- and postoperative risk factors to patients and
doctors alike.

Members of the panel and the audience, thank you for your time.

DR. WEISS: Thank you very much, Mr. Link, for your thoughtful comments.

I\'d ask the panel at this point if anyone has any questions for Mr.
Link. Dr. Bullimore?

DR. BULLIMORE: This is Mark Bullimore. I have a question for the FDA.

The PMA does not cover therapeutic use of the device. It just covers
primary LASIK, is that correct? I\'d like to add my thanks to the
chair\'s. I do appreciate your efforts at advocacy.

MR. LINK: Thank you.

DR. WEISS: Dr. Bradley?

DR. BRADLEY: Question for the speaker.

You are suggesting that the FDA mandate a one-month follow-up
post-surgical clinical study.

MR. LINK: On post-refractive eyes, yes.

DR. BRADLEY: Are you aware that those that we\'re studying today has
one-month, three-month, and six-month, and that\'s typically what we
see? I\'m wondering. Are you suggesting something different from that?

MR. LINK: Well, I think from the anecdotal reports that we\'ve heard of
global wavefront treatment, the results, the efficaciousness of the
procedure, is noticed immediately. So at a one-month period, from the
doctors that I\'ve spoken to who\'ve done the procedures, say that you
do see whether or not it\'s going to work. For instance, on a decentered
ablation or spherical aberrations. What we want to avoid is people
rushing to have it done and then there not being the necessary controls
to see if it actually works, and if the FDA were to vote for approval
with conditions, we would have data that could be shared openly and I
think it would be a good thing for all of us.

DR. WEISS: If there are no other questions, thank you, Mr. Link.

MR. LINK: Thank you.

MR. WHIPPLE: Jayne?

DR. WEISS: Yes, Dr. Whipple?

MR. WHIPPLE: Very quickly, for Mr. Link.

MR. LINK: Yes.

MR. WHIPPLE: You\'ve recommended some specific changes to the website
for updates on our FDA website.

MR. LINK: Well, I think by virtue of the fact that the patient
information booklets and the professional use information, it\'s my
understanding that what is present there is mandated by the FDA, and the
patient information booklets are to end up in the hands of the patients.
The information that is on the FDA website is actually more stringent
than what goes in the patient information booklets, and we believe it
should be consistent throughout all three forums.

MR. WHIPPLE: Periodically, obviously, we update our website and we\'ll
take into consideration what you\'ve said and see if there\'s any merit
to making any changes.

MR. LINK: Yes. If the information that\'s on the site ends up in the
booklets and the professional use information, that would be superb.

MR. WHIPPLE: Thank you.

MR. LINK: Thank you.

DR. WEISS: Thank you very much.

We have a letter from an additional person who was not able to appear
here today that Sarah Thornton will read to us.

MS. THORNTON: \"Dear FDA Panel Members: Unfortunately I was not able to
attend today\'s meeting in person. However, I would like to request that
this letter be read aloud on my behalf.

\"Two years ago, I had LASIK surgery. My initial uncorrected visual
acuity was 20/50, 20/20. I was therefore considered a LASIK success. The
reality is that as a result of having large pupils, I have debilitating
loss of night vision, ghosting, haloes, starbursts and loss of contrast
sensitivity. My eyes are extremely dry and burn constantly. Over time, I
experienced a loss of approximately 35 percent of the surgical effect.
Rigid gas permeable contact lenses are my best hope for visual
rehabilitation. Unfortunately, I am intolerant to hard lenses, probably
due to my dry eyes.

\"I wish I could describe to you the totality of what LASIK surgery has
done to my life. Driving at night is extremely difficult and dangerous
for me. I can no longer enjoy things that I used to take for granted,
such as going to the movies or dining in a dimly-lit restaurant. Now, I
see two or three smeared moons in the sky at night.

\"Today, you will be considering an application for wavefront customized
LASIK. I completely support the advancement of this technology that has
the potential to treat post-surgical eyes for the correction of induced
higher-order aberrations such as those I suffer from.

\"More importantly, however, I am asking the panel to condition this PMA
approval to include preexisting dry eyes in the contraindications and to
limit the approval of this device based on pupil size. The scoptic pupil
measurement should not exceed the effective optical zone. The transition
zone is not receiving the full refractive treatment and therefore should
not be included as part of the optical zone for this purpose.

\"Wavefront custom ablation is still LASIK surgery. In the words of Dr.
I. Howard Fine, past President of the American Society of Cataract and
Refractive Surgery, \'As we all know, LASIK transects the corneal
nerves, therefore inducing dry eyes in most patients.\' The size of the
optical zone in wavefront treatments is limited, just as in traditional
LASIK, by corneal thickness. Limiting the optical zone results in the
induction of spherical aberrations in patients whose pupils dilate
larger than the optical zone in low light. On Table 16 in the Summary of
Safety and Effectiveness Data for the approval of the LADARVision laser,
29.5 percent of the patients in the study reported halos that were worse
or significantly worse postoperatively. I believe these patients
reporting worse halos were primarily the patients with large pupils.

\"I know another woman with 8mm pupils who was treated on the
LADARVision system by one of the investigators for this PMA. She, too,
sees massive starbursts and halos at night, has dry eyes, regressed, and
is battling recurrent corneal erosions. She struggles with uncomfortable
hard contact lenses at times just to see her infant son\'s face clearly.
The surgeon was fully aware of her large pupils before he treated her.
Now, she is practically disabled at night.

\"Patients are making their decision to have this surgery based on a
barrage of advertising that doesn\'t disclose the risks or
contraindications. My informed consent did not mention dry eyes or large
pupils. Dr. Fine\'s statement shows that the industry is fully aware of
the magnitude of the dry eye problem. Why is it not taking preventive
action? The fact that 29.5 percent of patients were complaining of worse
halos proves the industry does not even consider night vision problems
as a complication, even though it can be incapacitating. This is a
medically unnecessary, elective procedure and therefore should be held
to higher standards.

\"It is not enough to simply put warnings in the patient labeling.
Surgeons do not always give patients a copy of the patient information
booklet. I was not given one. To protect patients, the FDA must limit
the device based on pupil size and dry eyes must be listed in the
contraindications.

\"Ladies and gentlemen on the panel, I believe that some good can come
from my terrible experience. Please help me make a difference for future
refractive surgery patients who don\'t know that dry eyes, glare and
halos are not simply minor side effects. They are life-altering
complications.

\"Thank you very much.\"

DR. WEISS: Thank you, Sally.

We will also have Mr. David Shell approach the podium and he would also
like to read a statement.

MR. SHELL: Members of the committee, I am David Shell, mechanical
engineer from Arlington, Virginia. I appreciate the opportunity to speak
here. The focus of my testimony will be on the inclusion of an incident
of LASIK-induced dry eye statistic and to the patient information
booklet for the medical device before us today.

Four years ago, I underwent LASIK. Since my surgery, I live in daily
misery from burning and stinging eyes induced by LASIK. Artificial tears
don\'t bring much relief. Eyedrops give only temporary relief and cause
greater visual distortion when used. My LASIK dry eye is not a minor
problem, as downplayed by some ophthalmologists. It\'s a disability. I
estimate that I am blind approximately 10 percent of the time due to my
eyes being closed because of the pain. At the time of my surgery, I was
told only a small number of patients experience a complication from this
procedure.

There is substantial evidence that shows this crippling side effect to
be relatively common. For example, an article in EyeWorld stated that
100 percent of patients have dry eye after LASIK. While most patients
improve, many do not. Numerous articles in industry magazines and
journals talk about how to manage LASIK dry eye. Internet websites, such
as www.surgicaleyes.org, discuss this issue frequently.

I know now that I did not have the information that would have assisted
me in making a fully informed decision. No one really knows the risk of
getting this debilitating condition in terms of percentage or the
information is just not getting out. Therefore, a person is unable to
make an informed decision about having this procedure. Should not this
type of data be available to the public? This type of data is no where
to be found in the patient information booklet.

My recommendations are as follows. Premarket approval for this medical
device should be contingent upon manufacturer conducting clinical
studies on the incident of LASIK-induced dry eye; data to be listed in
the manufacturer\'s patient information booklet in terms of percentage,
not just a casual mention that one could get dry eyes from this
procedure. We need a percentage.

Adoption of these recommendations will help increase public awareness
about this serious overlooked complication. I believe these
recommendations are fair and reasonable, easy to administer, and do not
impose an undue burden on the industry.

Before I conclude, I want to remind everyone that our eyes are very
precious. The standards for safety and effectiveness need to be very
high for an elective procedure on one\'s eyes. Personally, I don\'t
think they\'re high enough. I didn\'t need this surgery and ended up
with inheriting a lifetime of misery and pain. I\'m asking the committee
to make certain that any device that purports to correct a relatively
minor problem does not create crippling visual defects as a result.

Members of the committee, this concludes my testimony. Thank you very
much.

Also, I\'d like to add, if anyone wants to try some Dry Eyes, during the
break, I have a number of unused vials up here, and I\'d be happy to
give you one.

DR. WEISS: Thank you.

Does anyone have any questions for Mr. Shell?

(No response.)

DR. WEISS: Seeing no questions, thank you very much, Mr. Shell.

Are there any other participants who would like to come forward during
the open public hearing?

(No response.)

DR. WEISS: If not, that will end the open public hearing, and we will
move on to the open committee session and start with the FDA division
update.

Dr. Whipple?

MR. WHIPPLE: Thank you. It\'s Mr. Whipple, by the way. Thank you for the
promotion.

It\'s been some time since I\'ve had a chance to address this panel.
I\'m usually doing my thing behind the scenes and occasionally going up
to Ralph after the meeting or during the meeting and whispering things
in his ear, that kind of thing. But Ralph can\'t be with us today and
he\'s asked me to set in for him and I\'m glad to do that. He does send
his regards to everybody here and he wants to make sure you know that he
will be at the next panel meeting.

Now, as for division updates, the branch chiefs really have all the
important information to provide to you, so I won\'t steal their thunder
or step on their toes. But I do have one personnel piece of information
that I do want to present. The office director for Device Evaluation,
Dr. Bernie Statland, who is Ralph\'s boss, will be leaving the center at
the end of August, and on behalf of the division, I want to thank Dr.
Statland for his guidance and support in the past two years that he\'s
been our office director. We sure will miss his kind and gentle demeanor
and we do wish him well as he goes on to pursue a law degree at the
University of Minnesota, and as soon as we know who Ralph\'s new boss is
going to be, we\'ll let you know.

So that\'s all I have for now, and we can go on to the branch updates.

DR. WEISS: Thank you.

I think Dr. Saviola will be starting.

DR. SAVIOLA: Good morning, panel members.

I\'d like to update you today on one 510(k) clearance and two PMA
approvals. We recently cleared an application on May 9th, 20002, for the
ChromaGen Reading Aid Soft Contact Lens manufactured by Cantor and
Silver Limited of England. The indication includes the correction of
refractive ametropia as it would for a standard contact lens. It also
has a statement. \"In addition, the lenses may also be prescribed as a
colored filter for individuals who experience reading discomfort not
related to binocular vision problems or uncorrected refractive error.\"

This lens had previously obtained a marketing clearance in October of
2000 as an optical aid for people with red-green color deficiencies.
There was a small clinical study conducted that supported the use of the
lens as a colored filter to aid individuals who experience reading
discomfort. The 510(k) Summary of Safety and Effectiveness available on
our website provides a description of the clinical study, and for those
interested, the K number is K012132.

Current literature studies report inconsistent results concerning the
effect of colored filters on reading rate and comprehension and symptoms
of reading discomfort, along with rate of reading and reading
comprehension, can be strongly influenced by psychological factors. The
clinical data in our view did not support the use of the ChromaGen lens
in treating dyslexia or improving the general reading speed. Dyslexia is
a poorly defined anomaly with some controversy as to how it is
identified. Therefore, the lens is not cleared with the indication to
treat dyslexia or improve reading speed and the precaution statement was
added to the labeling to inform patients that results are variable due
to the subjective nature of visual discomfort and that not all patients
will experience success.

In our view, there is minimal risk associated with this device as
there\'s no indication to aid reading discomfort. The risk is comparable
to other tinted soft contact lens and while effectiveness is expected to
be variable, the lens may be beneficial for some people. We had issued a
homework assignment to a panel member on this project, and I want to
thank the panel for assistance in review of this submission.

The first PMA approval I want to inform the panel about is the Paragon
CRT and Quadra RG Lenses for overnight orthocaratology which we
discussed at the January 2002 panel meeting. These were approved on June
13th. Following the panel meeting, ODE issued an approvable letter which
the firm responded to. Following review of the additional clinical data
provided and interactive review of the draft product labeling, final
review was granted. The lenses are manufactured by Paragon Vision
Sciences of Mesa, Arizona, and the Paragon CRT designs are indicated for
overnight wear in a corneal refractive therapy fitting program for the
temporary reduction of myopia up to six diopters in eyes with
astigmatism of up to 1.75 diopters. The Paragon RG designs have
essentially the same indications as the CRT lenses, except the
pretreatment of myopia is up to three diopters in eyes with astigmatism
up to 1.5.

In order to address effectiveness concerns of the Quadra RG design used
overnight, a further analysis of existing data was conducted by
comparing the Quadra daily wear effectiveness data with the CRT
overnight data for a three-month time interval which was the duration of
the data we were studying. There are no statistically significant
differences in reduction of pretreatment refractive error, accuracy
stability or uncorrected visual acuity.

As to the age issue that was discussed during the panel meeting, among
the many recommendations by the advisory panel was the limitation to
those 18 years of age or older since limited data on this age group were
presented during the panel meeting. There was not an age restriction
included in the final approval by FDA since the company provided
additional data on adolescents between ages 12 to 17 who completed the
study, and they accounted for 11 percent of the completed dataset.

The primary effectiveness concern for this age group is their expected
progression of myopia. Although daily wear contact lens wear can reshape
the cornea or known as orthokeratology has been practiced since the
1960s, the long-term safety effects of overnight wear for reshaping the
cornea are not known for any age population and there\'s not been shown
any real long-term safety issues for daily wear orthokeratology.

And the last PMA update is for the Menicon Z, which is an RGP lens, that
was just approved in July, on July 12th, 2002, and this is a supplement
for P990018 for extended wear of an RGP up to 30 days of wear. This had
a prior daily wear approval in a variety of designs for indications for
myopia, hyperopia and presbyopia in both aphakic and non-aphakic
persons. In the extended wear version, it\'s approved in the spherical,
aspheric and non-prism ballast toric and non-prism ballast multifocal
lenses for again myopia, hyperopia and presbyopia, but it\'s only for
non-aphakic persons, and there\'s limitation on the power range of up to
+8 diopters for hyperopes.

Although this was not discussed at a panel meeting, we did solicit
homework assignments from three panel members in order to corroborate
the internal FDA clinical review. The panel reviews did not raise any
additional clinical issues that were unique to this device or different
from those identified in the internal review. All three homework
assignments recommended approval of the device for extended wear up to
30 days. The post-approval condition of conducting a clinical study was
placed upon this approval in the same manner as the previous two
silicone hydrogel lenses from CIBA and from Bausch & Lomb.

That concludes my remarks. Does anybody have any questions?

(No response.)

DR. WEISS: Thank you, Dr. Saviola.

Dr. Lochner will update us.

MS. LOCHNER: Again, thank you for that honorary medical degree.

DR. WEISS: I\'m giving out medical degrees left and right here today.
Step right up, Ms. Lochner.

MS. LOCHNER: All right. At the January 2002 meeting, the panel reviewed
P010059, the Morcher capsular tension ring, and recommended that the PMA
was approvable pending additional analyses of the clinical data. I would
like to advise you that this document is still being reviewed by FDA.
The issues that the panel discussed were related in a letter to the
sponsor and we are currently awaiting their responses.

Secondly, I\'d like to advise you that on March 26th, 2002, we cleared a
new glaucoma shunt from Optonol, Limited, K012852, the Ex-Press
Miniature Glaucoma Implant, Models R-30 and R-50, and this device is
different from previously cleared shunts in that it is a stainless steel
tube with a blunt needle-shaped penetrating tip at one end and a flat
angled flange at the distal end. It functions similarly in shunting
aqueous fluid from the anterior chamber into a conjunctival bleb and is
intended to reduce intraocular pressure in patients with glaucoma where
medical and conventional surgical treatments have failed.

That concludes my comments.

DR. WEISS: Thank you.

Are there any questions?

(No response.)

DR. WEISS: Thank you.

We\'ll go on to Dr. Beers.

DR. BEERS: Thank you.

We\'ve approved three devices since the last panel. A couple of months
ago, we approved the Bausch & Lomb PMA P990027 Supplement 2 for the
Technolas 217A for high myopia and that\'s up to MRSC of less than -12
with a sphere of less than 11. We also on April 11th, 2002, were
approved the Refractec PMA, P010018, for the ViewPoint CK or Conductive
Keratoplasty System. That was reviewed by this panel which recommended
that it was approvable on November 30th of 2001.

Based on the panel\'s recommendations, the indication for this device is
for the temporary reduction of spherical hyperopia in patients who have
.75 diopters to 3.25 diopters of psychoplegic spherical hyperopia, and
also added to the indications for use is the statement that the
magnitude of correction with this treatment diminishes over time in some
patients, with some patients retaining some or all of their intended
refractive correction.

The other device that we approved was approved on December 19th, 2002,
for the VISX Humanitarian Device Exemption, or HDE, H000002 for the
Customized Contoured Ablation Pattern Method for the treatment of
certain patients, and the indication is important here, for the
treatment of certain patients with symptomatic decentered ablations from
previous laser surgery as viewed on the Zeiss Humphrey topography unit.

Now, I\'m guessing that many of you don\'t know what an HDE is. An HDE
is an application that\'s similar to a PMA but is exempt from the
effectiveness requirements of PMA. An approved HDE authorizes marketing
of a humanitarian use device. The humanitarian use device is intended to
benefit patients in the treatment and diagnosis of diseases or
conditions that affect fewer than 4,000 individuals per year in the U.S.
So obviously given such a small patient base, it\'s difficult for these
types of devices to gain significant clinical trials to support safety
and effectiveness or certainly to support the effectiveness. So this is
a little bit different route for some of these.

It\'s important, though, to remember with these devices that the use of
the device at each institution is overseen by the IRB of that
institution and the IRB may make decisions on whether to use the device
on a case-by-case basis. So there are certain severe ‑‑ well, I
wouldn\'t say severe but there are certain limitations on the HDE that
you don\'t see with a PMA.

That concludes my presentation. Are there any questions?

DR. WEISS: Dr. Bullimore?

DR. BULLIMORE: Mark Bullimore. I have a question for Dr. Beers. It is
Dr. Beers.

You say the approval is limited to 4,000 cases per year. Is that the
actual approval or is that just ‑‑

DR. BEERS: That\'s in the Act. I mean, that\'s a limit.

DR. BULLIMORE: The FDA has no role or responsibility to monitor the
number of procedures that are done after approval?

DR. BEERS: They are monitored. The sponsor has to keep track of that.

DR. BULLIMORE: Okay. Thank you.

DR. WEISS: If there are no other questions, I\'d like to thank Dr.
Saviola, Ms. Lochner and Dr. Beers.

If there\'s no other information to be updated from the agency at this
point, we\'re going to move ahead to the discussion and review of PMA
Number P970043/S010.

I passed muster with Sally, so I must be doing okay.

We\'d like to inform the sponsor they have one hour, and I would like
each presenter when they come forward to identify themselves at the
beginning of the presentation, also to inform us of any financial
conflicts or potential conflicts.

MS. CHESTER: Good morning. I\'m Kathleen Chester, Director of Regulatory
Affairs for Alcon\'s Refractive Products, and today, we\'ll be
presenting the clinical results from the CustomCornea Myopic LASIK
Clinical Trial involving the commercially available LADARVision Laser
System.

The agenda for our presentation includes the following: I will give a
brief introduction. Dr. George Pettit from Alcon will provide an
overview of wavefront technology. Drs. Daniel Durrie and Omar Hakim, two
of our clinical investigators, will present a summary of our safety and
effectiveness results. Dr. Pettit will then discuss our wavefront
aberration clinical outcomes followed by Dr. Stephen Brint who will
discuss the clinical implications of wavefront correction based on our
clinical results. And finally, if time permits, we will respond to a
number of questions we received in advance from the panel.

This PMA supplement application requests an expansion of the existing
indications to include wavefront-guided custom cornea LASIK correction
of myopia of up to -7 diopters of sphere and less than -.5 diopters of
cylinder at the spectacle plane in the subjects who are 21 years of age
or older and with a documented stability of refraction.

Alcon is pursuing approval of spherical myopia only at this time. There
are no safety issues related to this decision. The decision is based on
the intent to provide the most effective astigmatic outcomes possible
with this new technology with minor adjustments in the algorithm before
seeking approval for the myopic astigmatism indication.

The study population consists of a safety cohort of 426 eyes in the
range of up to -7 diopters of sphere and up to -4 diopters of
astigmatism. The primary effectiveness cohort is comprised of a subset
of those eyes, of which there are 139, in the range of up to -7 diopters
of sphere and less than .5 diopters astigmatism.

Now, I\'d like to introduce Dr. George Pettit who will give you an
overview of wavefront technology.

DR. PETTIT: Good morning. I\'m the chief scientist at the Alcon Orlando
Technology Center and therefore I do have a financial interest in this
technology.

I\'d like to start with a very simple introduction to what is
wavefront-guided ablation. What are we talking about here? When we talk
about wavefront-guided customized treatment, our definition includes,
first, a quantitative measurement of both the lower and higher-order
aberrations ‑‑ i.e., those aberrations beyond simple sphere and cylinder
‑‑ that are present in the eye and transfer of that detailed aberration
data to an excimer laser which positions the treatment profile correctly
on the eye and calculates and delivers a specific ablation pattern
unique to each patient based on the preop aberrations. So it\'s
important to note that the ablation pattern is unique and is based on
the preop aberration measurement for each eye.

DR. WEISS: Dr. Bullimore, you\'re obscuring the view.

DR. BULLIMORE: I apologize.

DR. PETTIT: So the technology requirements in order to effect this type
of treatment, there\'s two components. First, we have to have a
wavefront system that\'s capable of measuring the higher-order
aberrations obviously accurately, quantifying the wavefront aberrations
in the patient, and we also need the wavefront device to accurately
register where exactly on the eye those wavefront aberrations came from.

The treatment laser we use employs an active high-tracking system to
stabilize the eye during the surgery, compensate for patient eye
movement, and allow us to deliver the customized ablation profile as
accurately as we can. We use a small Gaussian excimer beam to precisely
scope the subtle contours in the corneal surface and we use fairly
sophisticated software algorithms to convert the wavefront data into the
appropriate treatment profile.

So what is wavefront sensing? I\'d like to give just a very simple
introduction so we all know what we\'re talking about here. Simply put,
wavefront sensing is a measurement of how the eye operates as a
integrated optical system, and the wavefront device gives you a detailed
refractive map over the pupil of the eye. We think in simple terms of
how a theoretical perfect eye sees the world. When a simple perfect eye
looks at a far-off target, the light from each point in that target
enters the eye as a bundle of parallel rays. The wavefront is the
surface perpendicular to each of those rays. So in the case of a perfect
eye, the wavefront entering the eye from a distant target is a flat
wavefront and that flat wavefront is well focused down to a very small
spot back on the fovea.

Now, in the case of myopia, which is the indication we\'re considering
this morning, when a myope looks at a distant object, those parallel
light rays are not well focused on the retina. They\'re focused
somewhere in front of the retina, but by the time the light reaches the
retina, they\'re blurred out. A myope can see clearly if the target is
up close to the eye. So you imagine a nearby point source, the light
rays from that nearby source enter the eye as a diverging bundle. The
wavefront in that case is part of a spherical surface and that spherical
wavefront is then well focused down to a small spot on the retina.

When we perform classical vision testing, we\'re in a sense doing a
primitive form of wavefront sensing. We\'re asking what combination of
spherocylindrical lenses do we need to put in front of the eye so that
that flat wavefront from a distant source is as best focused as possible
back on the retina? The limitation of that, of course, is that there are
higher-order aberrations that are known to exist in the eye and these
cannot be characterized with simple spherocylindrical lenses. This is an
example of spherical aberration whereby the periphery of the eye is more
refracting, has more myopic power than the central part, and the rays
are blurred out in the retina. Another common example is coma and coma
can be simply thought of as one side of the pupil being slightly more
myopic than the average and the other side being more hyperopic than the
average. Again, it causes blurring, puts the light back on the retina,
and this can\'t be characterized well with simple lenses.

When we perform wavefront sensing using the Shack-Hartmann approach, we
take advantage of the fact that light is reversible. If we want to study
how light gets from Point A to Point B, being refracted at various
surfaces within the eye, we can instead measure how light travels from
Point B back to Point A. So what we do is we have the patient look into
the device and then we shine a narrow eyesafe probe beam into the eye
and illuminate a small patch back on the fovea. Some of that light is
scattered back out of the eye just like when you do flash photography
and you get a red eye effect and outside the eye, we now have a
reemitted wavefront which is just the time-reverse process of how the
myopic patient sees the world. So now we have that same spherical
surface but it\'s traveling out of the eye rather than into it.

So how do we measure what that wavefront looks like? Well ,inside our
wavefront sensing device, there\'s a group of relay optics, so that this
plane over here is imaged over here right at the entrance space of the
actual wavefront sensor. So whatever the wavefront is doing as it exits
the eye, it does again over here at the wavefront sensor itself. Now,
let\'s zoom in on the wavefront sensor. This slide shows a simple myopic
wavefront impinging on the wavefront sensor itself and I\'ve isolated
one lens lit up here. You\'re seeing part of the wavefront go through
that lens lit. There\'s an array of microlenses with a CCD camera screen
sitting at a fixed distance behind it and through one of those lenslets,
this piece of the wavefront is being focused to this camera screen at
this point here.

Now, if the wavefront was perfectly flat, that light would have traveled
straight through and then hit the screen over here. We want to measure
or actually describe what the wavefront looks like in some mathematical
term, W of X and Y, where X and Y are the transverse pupil coordinates,
and let\'s consider that single lenslet sitting at the location of Y
not. We know that the wavefront piece that went through that lenslet
traveled this distance to get back to the CCD camera and it\'s laterally
displayed from its ideal location by delta Y. From that information, we
can calculate the slope of the incident wavefront at that lenslet and by
doing this at a large number of points across this lenslet array, we\'re
actually able to rebuild the shape of the original wavefront.

This is an example of the CCD camera screen showing you a picture of the
focused light dots. The software in the wavefront device goes in and
finds the centers of all those dots, figures out how they\'re related to
one another, and more importantly which lenslet each one of them came
through them, and from this picture and the processing of the
information, we calculate the shape of the original wavefront.

Now, we have to have a set of mathematical tools to describe what does
the wavefront look like. It\'s going to be a complicated surface and we
need to describe it. We use what\'s called Zernike polynomials, which
are a convenient mathematical basis set for describing visual
aberrations. There\'s an infinite number of these. They come in orders
which are shown by the different layers in this pyramid. So there\'s an
infinite number of these going off to the bottom there and you can see
as you work your way down the pyramid, the orders become progressively
higher and the shapes become progressively more complex.

These second-level, second order aberrations are closely associated with
the conventional spherocylindrical errors in the eye, and then the
higher-order aberrations correspond to the lower layers in that pyramid.

Now, from the wavefront information, we can estimate the optical
performance of the eye. We can take the wavefront and calculate what\'s
called the point spread function which is an optical analysis of what a
distant point source would look like on the retina. So in the case of a
perfectly flat wavefront over a big pupil, that wavefront is focused on
the very tight spot, and this is a simulated optical image of what the
retinal image should look like when the patient looks at approximately
20/16 through through 20/10 lines on an eye chart. They\'re slightly
blurred out due to the effects of defraction, but this is about as well
as the optics can do for a 6.5mm pupil.

I\'ll just show you a couple more examples. This is myopia, that simple
spherical shape. The way to think about it, the wavefront of the eye is
down here and the wavefront\'s propagating up out of the eye. Myopia
causes, as you can see, blurring of the optical image on the retina. I
should point out that this does not take into account retinal effects or
neuroprocessing. We don\'t know exactly how well an eye cognitively
could see the eye chart, but this is a simulation of what the optics of
the eye produce on the retina.

I\'ll just show you one more. This is vertical coma, and you can see
that in this case, you actually can read all these letters, but there\'s
this sort of comet-like tail extending in the downward direction due to
the coma present in the eye.

In addition to being able to provide a detailed mathematical
description, we also want to have a simple single parameter to
characterize, well, just how distorted is this wavefront? So, we use
what\'s called the RMS error. You can hear this mentioned several times
this morning. The RMS error is simply the standard deviation of the
wavefront relative to that idealized flat profile. So, if the wavefront
is in fact perfectly flat, the RMS error is going to be zero, and as the
wavefront becomes more and more distorted, the RMS error becomes
progressively more positive. That\'s a very simple overview of wavefront
sensing, and there\'s a lot of details that I simply don\'t have time to
go into in this one hour.

So in a clinical wavefront sense, we need a little bit more equipment to
actually be able to measure a patient accurately, and so this slide
shows the principle optical components in our wavefront-sensing device.
The eye is sitting here looking into the instrument. We obviously have
to give the patient a target so they know where to look, and these are
myopic patients, so they don\'t see very well before surgery. So our
target has an adjustable focus mechanism to correct for the preoperative
myopia and actually to fog the eye slightly to try to minimize any
accommodation effect as the patient looks in there.

We have a video camera that\'s staring out at the eye that helps us
position the eye for the measurement and equally important, it helps us
record exactly how the eye was positioned and how it was rotated at the
instant that the wavefront data was taken. We\'ve already talked about
the probe beam and the wavefront-sensing pathways.

So how do we perform a surgical wavefront measurement? When a patient
comes into the clinic on the day of surgery, the first thing that
actually happens before they have any dilation applied to the eye is we
have them sit down at the wavefront sensor and we take a video snapshot,
so they look into the device and we use that video path to capture a
frozen picture of their eye under daytime illumination conditions, and
we do this because we want to record where their daytime natural pupil
center sits relative to their limbus. We do this by asking the clinician
to align two software reticles in the frozen video image, one to the
limbus and one to the pupil, and having done this, our software now
knows where the daytime pupil center is relative to the limbus and
that\'s going to be our anchor point later on.

The patient then goes off and has the eye dilated and in this trial, we
used a combination of tropicamide and phenylephrine. Immediately before
the wavefront measurement, the surgeon applies two ink marks using a
standard eye-marking pen to the sclera just outside the limbus. The
patient then sits down at the wavefront sensor. They\'re positioned
appropriately. They view the target. We fog the eye, and then we take
five repeat wavefront measurements in relatively quick succession. At
the instant that each of those wavefront measurements is taken, the
video image is frozen. So we have a frozen video image that\'s
synchronized with the wavefront capture, and we ask the technician in
that frozen image to align two reticles, one to the limbus, so that\'s
an elliptical reticle, and we also have a linear reticle that they\'re
supposed to draw through these applied ink marks, and with this
information and the wavefront data, we now know exactly where the
wavefront came from on the eye and the cyclotorsional angle of the eye
at the measurement time.

The five measurements are then automatically analyzed and the two
outliers are rejected based on a statistical analysis of the RMS errors.
The remaining three are then compared for consistency and then averaged
together to make a final composition wavefront and this is what we
actually base the surgery on. As a final sort of sanity check, we can
back calculate the effect of clinical prescription from the wavefront
data and compare that to what was measured at the foropter, and in this
trial, it\'s worth noting that we require both the sphere and cylinder
calculated from the wavefront had to agree within 1 diopter with what
was measured at the foropter.

The wavefront and the geometry information are then transferred
electronically to the treatment laser. Our treatment device again
employs a blind spot, relatively small, 193mm excimer laser, uses an
active eye-tracking system to stabilize the eye during the treatment,
and it\'s currently approved for all conventional treatment types of
refractive error.

The LADARVision treatment device actually takes the wavefront data and
calculates the appropriate ablation profile. The patient lies down, is
prepared for the surgery, and in the tracked image, once the patient and
the doctor are ready, in the tracked image of the eye, a single linked
reticle, a combination of the elliptical limbus reticle and the linear
cyclotorsional reticle, comes up in the tracked image screen and the
clinician then aligns these to the anatomical features on the eye and
that\'s how we register the ablation profile correctly both in position
and cyclotorsional angle.

The device requirements on the wavefront-sensing unit itself then.
First, it must record the natural pupil limbus geometry. It must measure
wavefronts up to at least the fourth Zernike order which is what we used
in this study, must be able to measure pupils in excess of 7mm in
diameter, obviously has to have a validated accuracy in wavefront
measurement performance, must record the geometry of the wavefront data
relative to the limbus and the cyclotorsion features, these are these
applied ink marks that I referred to, and it must be able to obviously
export the wavefront and the geometry data in a format compatible with
the LADARVision system.

I\'d now like to turn the podium over to Dr. Dan Durrie who\'s going to
summarize our safety data.

DR. DURRIE: Thank you very much.

It\'s a pleasure being here, and I\'m Dan Durrie, and I\'m one of the
investigators in this clinical trial, and I\'m a consultant for Alcon
and I\'m also a paid consultant for a competing technology.

I\'d like to review the safety criteria of this particular study that\'s
under question. First, I\'d like to clarify a little bit of the two
groups that we\'ll be talking about. The safety cohort includes 426 eyes
which includes the astigmatism cases that we\'re not asking for approval
for today but are included in the whole safety cohort. The primary
efficacy cohort as has been shown before is 139 eyes and were the ones
without significant astigmatism. This is based off the manifest
refraction, and as I go through this, I\'ll be showing any differences.

First, accountability is always important with any clinical trial and
this was excellent. It\'s always great to see a 100 percent down at the
bottom of the accountability chart. Unfortunately, there were two eyes
that were lost because of the death of a patient to colon cancer, but it
was a 100 percent of all patients who were available were accountable at
all visits. So therefore, we can have at every visit 139 eyes in the
spherical cohort and in the safety cohort of all the eyes is all the
eyes available except the two that were lost at the six-month visit.

As far as the demographics, and I will compare the two groups, they are
very similar. Between the two groups, the points of interest are the
fact that this was primarily a male study and as with most excimer laser
studies, it\'s predominantly Caucasian and also we note that most of
these patients were soft contact lens wearers. The age was in the upper
30s and similar between the two groups. Also as far as the amount of
correction that was attempted, the only difference between the two
groups really was the fact that there was the spherical group did not
have the cylinder as previously described but other than that, the
average amount of myopia and the range was similar in the two groups.

Now, again, I\'m going to talk about safety and this is the total group
with a 100 percent follow-up of those available. We\'re all familiar
with the guidance documents. We\'ve reviewed these studies before, and
if you\'re using the criteria in the lines lost of best-corrected
vision, we can see that this easily meets all the previously discussed
guidelines. There was one eye that did have vision that was less than
20/25 that was 20/25 preop and the three eyes that had loss of two lines
of best-corrected vision but no eyes that lost more than two lines.

Looking at the best-corrected data in a different way and overall lines
lost or gained as a clinician, we like to see the graph leaning to this
side from preop to postop which means that there is more lines gained
than lost, and as you can see at the six-month follow-up, 37 percent
gained one line or more and only 9.4 percent of patients lost any
vision. For most studies, these are fairly even and now with these newer
technologies, we\'re seeing the graph moving in that direction.

It also showed in looking at the best-corrected vision comparing preop
to postop and looking at the high level of vision correction of 20/12.5,
that we had a doubling of that in the study from preop to six-months
postop and 20/16 increased from preop to postop. So the best-corrected
vision overall was increased with this study.

In terms of complications and the way these are reported, they\'re
reported at any visit, any time. So that, the typical things we\'d see
with LASIK surgery, small amount of DLK, epithelial ingrowth, ghosting
images, and some corneal edema, and there were other findings that were
listed that were below the .2 rate that are listed at the bottom here.
Nothing out of the ordinary here for a LASIK trial or LASIk clinical.

Now, what happened to those patients who reported complications? All but
two eyes that had best-corrected vision of 20/20 or better and a 100
percent had 20/32 or better at the last visit. Also, all complications
resolved, except for four eyes, and these were one patient with
epithelial ingrowth and three patients with ghosting images. All the
reported DLK and epithelial ingrowth were Grade 1 or less at all of the
reporting visits.

In regards to adverse reactions, those related to the device, there was
recalcitrant DLK associated with blepharitis in two eyes of one patient
and there was one miscreated flap. The patient was exited from the study
and had successful recut LASIK surgery with a conventional laser. There
were also some unrelated to the procedure. There was one patient, I told
you before, that died of colon cancer and one patient that developed
multiple sclerosis during the procedure. There was one retinal horseshoe
tear which was felt to be unrelated to the procedure by the retinal
specialist. What happened to those patients, of all those patients who
had adverse reactions, a 100 percent of them were 20/16 or better at the
last reported visit, and other than the multiple sclerosis, all of the
other adverse reactions resolved.

In regards to intraocular pressure, corneal haze or other slit lamp
findings, there was nothing unusual in this study and there was nothing
that was out of the ordinary that we would expect. So the overall safety
of this study was extremely good.

Going to the spherical cohort, this is 139 eyes, just quickly showing
you that if we look at that group, there was all zeroes on the
parameters for the FDA guidance and no eyes had worse than 20/20 vision.
In regard to complications, it\'s the same distribution but slightly
less in this group, and there was no adverse reactions in the spherical
myopia group that we\'ll be discussing for efficacy.

Therefore, the safety criteria in this study meets or exceeds the
guidelines for loss of best-corrected vision, best-corrected vision
worse than 20/40 and induced cylinder and the incidence of adverse
reactions were overall, and there was no demonstrated significant safety
concerns.

I\'d like to introduce Dr. Omar Hakim who will be talking about efficacy
and this again to define is 139 eyes that are in the efficacy group.

Thank you.

DR. HAKIM: Thanks, Dan.

Hi. My name is Dr. Omar Hakim. I\'m Medical Director for TLC Laser Eye
Centers in Canada. I\'ve been performing laser refractive surgery since
1994 and custom ablation surgery since May of 2000, using a variety of
different platforms, and actually I had my own vision corrected with
LASIK in 1998. I am a consultant on Alcon\'s Refractive Medical Advisory
Board and travel expenses for this meeting were paid for by Alcon.

I\'ve been asked to present the effectiveness outcomes for the 139 eyes
in the study. Preoperably, these 139 eyes had up to 7 diopters of myopia
and less than half the diopter of astigmatism. First, we\'ll review the
manifest refraction spherical equivalent results and we\'ll see that
following surgery here on the left, that 83.5 percent of the eyes had an
MRSE within half a diopter of emmetropia at one-month postop and 74.8
percent at six months following surgery. Fully 97.1 percent of the eyes
were within 1 diopter of emmetropia at one month and almost 96 percent
at six months. Both of these groups clearly exceed the FDA Guidance
Document guidelines calling for 50 percent of patients to be within half
the diopter of emmetropia and 75 percent within 1 diopter of emmetropia.

This graph shows the attempted versus achieved correction at six months
of all 139 eyes and it really demonstrates the vast majority of eyes
fall within a 1 diopter bracket on each side of emmetropia shown by the
dashed line here. At the higher ranges of correction, there are three
eyes that fall outside the 1 diopter bracket. However, even at these
higher levels of myopia, excellent results were still reported with
uncorrected visual acuity of 20/25 or better in 92 percent of the eyes
between 5 and 5.99 diopters and 75 percent of the eyes above 6 diopters
or above. In fact, in this higher myopic group, 75 percent of the eyes
were still within half a diopter of emmetropia. However, overall, there
was a small amount of undercorrection as shown by this slide. When we
reexamined the results around this mean MRSE line of -0.37 diopters, we
see that actually more than 90 percent of eyes were within half a
diopter of this mean value, reflecting really a very high level of
precision and reproducibility of result.

This chart looks at the MRSE over time and shows excellent stability
from one-month postop with refractive MRSE of -0.27 diopters, -0.35 at
three months, and -0.37 diopters at six months. Again, the notable
precision of the MRSE is shown in the standard deviation values which
range from 0.34 diopters to 0.42 diopters of standard deviation. Of
course, surgeons routinely make adjustments in treatment based on
environmental factors, such as temperature and humidity, and
surgeon-specific or site-specific factors because we know these
influence the accuracy of our outcome in every-day surgery. The accuracy
of these results reflected in the fact that we had a mean
undercorrection of -0.37 diopters were limited by the study protocol
because it restricted clinicians from making these usual treatment
adjustments. This undercorrection could be dealt with by usual nomogram,
adjustments by the surgeon or could be incorporated into the software
and as commented on by Dr. Eydelman in her medical officer\'s review,
Alcon has already initiated a clinical evaluation of the minor software
adjustment to address this.

In terms of stability of MRSE, then we see that 100 percent of eyes
between the one- and three-month visits and three- and six-month visits
had less than 1 diopter change in MRSE, surpassing the FDA Guidance
Document guidelines. In fact, the mean change was only .07 diopters in
the one-to-three-month period and -0.3 diopters in the
three-to-six-month period, which translates into a mean change per month
of -0.035 diopters and in the three-to-six-month group of -0.01
diopters, really incredibly good stability.

This chart then shows the percentage of eyes achieving uncorrected
visual acuities of 20/20 on this side and 20/40 on the right side. We
see that 86.3 percent of eyes at one month had 20/20 uncorrected acuity
and 79.9 percent at six months had 20/20 acuity. Looking at 20/40, we
see that 99.3 percent of eyes had that acuity level at one month and
98.6 percent, almost 99 percent, at the six-month visit. Again, these
results exceed the FDA guidance calling for 85 percent of eyes to have
uncorrected acuity of 20/40 or greater.

It really should be noted that these excellent uncorrected acuity
results were obtained despite the mean undercorrection of -0.37 diopters
that we noted previously and a reduction in this undercorrection along
with the excellent precision of effect as shown by the MRSE results
should provide even better uncorrected visual acuity results with
nomogram adjustment, and in fact, at one month, 59 percent of eyes had
uncorrected visual acuity equal to or better than their preoperative
best spectacle-corrected acuity and at six months, this figure was still
52.5 percent.

In summary then, this study of CustomCornea Wavefront-Guided Ablation
has demonstrated uncorrected visual acuity results and accuracy and
stability of MRSE results that exceed those called for by the FDA
Guidance Document. Patients were also asked to grade any ocular or
visual symptoms. With regards to ocular symptoms, only 2.2 percent of
patients noted significantly worse dryness of their eyes and only 1.5
percent noted significantly worse burning or gritty sensation with their
eyes at six-month postoperatively, and in fact, many patients actually
noted they had significant decreases in symptoms, including significant,
for example, you look at dryness, 8.1 percent of patients said their
dryness of their eyes was actually significantly better following
surgery.

On evaluation of the visual symptoms, 2.9 percent of patients noted they
had significantly worse blurring of vision and 0.7 percent of patients
noted they had significantly worse night driving difficulty, double
vision or fluctuation of vision. What\'s interesting is that if we
looked at the mean MRSE on patients who said they were better or
significantly better, that ranged from .26 diopters to -0.36 diopters,
and in the group who noted that their symptoms were worse or
significantly worse, that range was -0.46 to -0.7 diopters. So that,
again, further improvements in undercorrection may further improve upon
this already-low level of symptoms.

As a surgeon, all these visual symptoms are important, but the most
concerning to me, you know, really the top three, glare, halos, and
night driving difficulties, and, you know, here we see that although the
numbers are small, more patients actually said their symptoms were
significantly better than significantly worse following surgery.

At three months following surgery then, 85 percent of patients said that
they were satisfied or extremely satisfied overall and at six months,
this was 79 percent. Again, the MRSE in patients who were satisfied or
extremely satisfied was -0.3 diopters and in the unsatisfied or
extremely unsatisfied group, that was -0.93 diopters, and again a
reduction in this undercorrection should shift the cohort towards even
higher patient satisfaction rates. Almost 90 percent of patients
described their quality of their vision as being equal, better or
significantly better following surgery at both the three- and six-month
intervals, and over 95 percent of patients at three months and 94
percent of patients at six months had no need for distance correction of
any kind.

So again, in summary, the study of CustomCornea Wavefront-Guided
Treatment has clearly exceeded the performance guidelines laid out in
the FDA Guidance Document in terms of uncorrected visual acuity and
accuracy and stability of postoperative manifest refractive outcome.

Dr. George Pettit\'s now going to return and discuss the wavefront and
higher-order aberration outcomes for the cohort.

Thanks, George.

DR. PETTIT: Now we\'re going to talk about the higher-order aberration
changes that we saw in this myopic cohort.

This slide summarizes the changes in the various higher-order
parameters. So the third- and fourth- order aberrations are considered
along the horizontal axis here. We\'re looking at the total higher-order
aberration content and then the individual content from the various
third- and fourth-order aberrations. The vertical axis indicates the
magnitude of the different wavefront parameters. The blue bar indicates
what they were preoperatively, so that\'s the starting baseline level,
and then the green, yellow, and red bars indicate the one-, three- and
six-month postop measurements on this cohort.

Now, I\'d like to just note there\'s 137 patients in this table. The
entire cohort was 139 eyes, but there were two eyes that missed one of
these wavefront measures at some interval. So, there\'s 137 eyes
considered here and that\'s why the N is slightly smaller. The little
asterisks indicate those changes that were statistically significant
between the preop and the six-month postop interval and you can see that
for almost all of the aberration parameters, they\'re actually slightly
higher by a statistically significant amount after surgery than before.
The trifoil is actually less after treatment but it\'s not a
statistically significant difference.

Now, I should just also mention this is based on a 6.5mm wavefront
analysis diameter. This isn\'t a surprising finding. It\'s well known
that LASIK tends to increase the higher-order aberrations. So an
important question to ask is how does this compare to conventional
surgery? We have a comparative conventional cohort. In the early phase
of this, our clinical trials, we ran a bilateral study where we had a
contralateral control arm. What I mean by that is that patients would
come in, if they met all of the entry criteria to be enrolled in the
study, they were randomly selected, so that one eye received
conventional treatment with our system and the other eye received
customized treatment. Again, the eyes were randomized.

Of that comparative arm, 50 eyes actually meet the criteria of being
myopic with less than half a diopter of cylinder. So we went back and
looked at all of the conventional patients that we treated in the early
phases of the study and found out that 50 eyes met the criteria for our
current conditions of approval, and you can see that the refractive
parameters for that conventional comparative group match up very, very
well with the primary Custom cohort. Those patients also had a treatment
optical zone of 6.5mm in diameter and we have wavefront data measured in
the same way available preoperatively as well as the one- and three- and
six-month postop intervals.

If we look at the aberrations in these two groups, the Custom shown by
the blue bars and the 50-eye conventional comparative cohort shown by
the red bars, preoperatively, the aberration content\'s relatively
similar between these two groups. There was a small but statistically
significant difference in the spherical aberration term but all other
parameters were well matched. That\'s not the case when we look six
months after surgery. Again, these asterisks indicate anything that
exceeded the P value for statistical significance of being less than .05
and you can see that the total higher order, coma, trifoil, spherical
aberration, and tetrafoil, are all significantly lower six months after
wavefront-guided treatment than six months after conventional surgery.
Secondary astigmatism term was also lower in the Custom eyes but that
wasn\'t a statistically significant difference.

Now, we\'ve tried to and we\'ve worked with the agency and tried to come
up with a way of describing what\'s the optical impact of the magnitude
of these differences in the higher-order aberrations, and this again is
an optical simulation of how a patient might see the eye chart under
best-corrected vision where the lower-order aberrations are removed. On
the left, they\'re left with the postop aberration mean for
wavefront-guided treatment, and on the right, they\'re left with the
mean values for conventional surgery, and you can see there\'s a modest
but definite difference with the optical quality being better in the
wavefront-guided approach.

Now, that\'s all based on mean values. We also looked at on an
individual patient basis what percentage of patients exhibited an actual
decrease in the higher-order aberration parameter after surgery as
compared to before, and so the different lines in this table indicate
the various ways of looking at the higher-order aberrations for third
and fourth order, and this middle column indicates the percentage of
wavefront-guided eyes that showed a reduction in that particular
parameter, and on the right-most column, we\'re looking at the
conventional eyes, and you can see that for most of these parameters,
much higher percentage of wavefront-guided patients actually showed a
decrease six months after treatment as before surgery and that\'s not
true in the conventional eye. The percentages are much lower.

I\'d like to now invite Dr. Steve Brint to come up and talk about the
clinical implications of the wavefront correction.

DR. BRINT: Thank you, Dr. Pettit.

I\'m Steve Brint from New Orleans, Louisiana. I\'m in private practice
and on the faculty of Tulane University. I likewise am a member of the
Alcon Medical Advisory Board. I\'ve been performing LASIK since 1991 and
am a LASIK patient myself, and I\'m also the Medical Monitor of a
competing laser technology and my expenses for this trip were also
compensated by the sponsor.

As clinicians, we know that prior studies of conventional LASIK in
general have shown that higher-order aberrations, particularly spherical
aberration which is frequently linked to poor night vision, occasionally
may be increased after conventional LASIK. These increased higher-order
aberrations after conventional LASIK are pupil-size dependent with
larger pupils showing decreased retinal image quality as measured by
point spread function and modulation transfer function and visual
performance as measured by the clinically useful contrast sensitivity
testing and low-contrast visual acuity testing.

David Williams\' group at the University of Rochester has done work in
this area and has shown that correction of these higher-order
aberrations using an adaptive optics system is able to improve the
visual acuity and especially the contrast sensitivity.

As Dr. Pettit just mentioned, we do have this comparative conventional
cohort of 50 spherical myopic eyes that was derived as he mentioned
which has comparable demographics and virtually identical preoperative
refractive error. Quality of vision in this group was used just as we
did in the wavefront-guided eyes using tests to determine the visual
performance under these low-contrast and mesopic situations. I think we
all realize as clinicians that we\'ve done a very good job of getting
good quantity at vision and now, as has been mentioned throughout the
morning, the goal is not only to improve the quantity but improve the
quality of vision for our patients.

So the contrast sensitivity testing was done using the VectorVision
Chart, the CSV1000, measured at 3, 12 and 18 cycles per degree. This was
done in both every-day full illumination to simulate a photopic
situation as well as in a room with total darkness, other than the light
coming from the eye chart, to simulate a mesopic light situation, and a
neutral density filter was placed in front of the eye which only
transmitted 3.16 percent of the light. We know that greater higher-order
aberrations are seen in these larger dark-adapted pupils as opposed to
the smaller light pupils.

Previous FDA studies have used a contrast sensitivity definition as a
clinically significant change of greater than 0.3 log units at two
levels from preoperative at two or more spatial frequencies, and this is
used to distinguish measurement noise from actual true sensitivity
change. What we saw in our spherical cohort as regards to percentage of
eyes with this clinically significant change of photopic contrast
sensitivity, here in the Custom group of spherical eyes, we see two to
three times gain as opposed to loss of contrast sensitivity and
clinically significant contrast sensitivity, and in the conventionally
treated eyes, we see actually at both the three- and six-month interval
no gain and some loss of this clinically significant photopic contrast
sensitivity.

The full eye larger cohort is nice in that it confirms what we saw
before with a tendency towards gain as opposed to loss in the
wavefront-treated eyes and loss as opposed to gain as treated in the
conventionally treated eyes.

Looking at photopic contrast sensitivity another way, at individual
spatial frequencies, we see conventionally treated eyes, no mean log
change in the lower spatial frequencies and significant loss in the
higher spatial frequencies. In the Custom group, however, we see gain
across the board at all log changes at all spatial frequencies and this
is statistically significant at the higher spatial frequencies of 12
cycles per degree and 18 cycles per degree, and this is confirmed
looking at the larger full eye group. In the conventional group, we see
across the board at all spatial frequencies a trend towards loss of
photopic contrast sensitivity as measured in log units and somewhat
modest gain in the Custom-treated eyes.

As regards the clinically important mesopic contrast sensitivity, the
large pupil at night time contrast sensitivity, important to our
patients in tasks such as driving at night, we see, also, two to three
times the number of eyes gaining clinically significant contrast
sensitivity in the Custom group, both early and at the late testing
intervals, while in the conventionally treated eyes, initially there\'s
more loss. However, there is recovery in the later interval which
simulates what we see in the six-month conventional group, what we see
in the Custom group at three months, suggesting that these customized
enjoy this improved mesopic contrast sensitivity throughout their
recovery period without going through the decreased period that our
conventional eyes have. This is confirmed once again in the all-eye
group with improved mesopic contrast sensitivity and decreased at three
months, recovers at six months, but once again is maintained throughout
the entire postoperative period in our Custom wavefront-treated eyes.

Looking at mesopic contrast sensitivity in our conventional eyes, we see
a modest gain at all spatial frequencies at six months. However, in the
Custom-treated eyes, we see a much larger gain in the Custom-treated
eyes as measured in log units over this period of time at six months at
all spatial frequencies, and this once again is confirmed when we look
at the larger cohort of all eyes wit these more difficult toric
prescriptions.

Low contrast visual acuity was measured using the ETDRS eye chart.
We\'re all familiar with the standard high contrast eye chart. You can
all see how extremely difficult it is to see this 10-percent low
contrast eye chart that was actually viewed in a room with ambient very
dim light, and it should be noted that even in our preoperative best
spectacle-corrected vision patients, only 8.6 percent of patients were
able to read the 20/20 line preoperatively.

Looking at the change in the low contrast best-corrected vision in our
spherical group, we see that there is more gain than loss at both the
early as well as the later time interval, more so than we see in the
conventional eye group, but more importantly, statistically significant,
we see that there is significantly less loss in the Custom eye group at
three months as compared to the conventional eye group, less loss of one
or more lines from preoperative value at 22 percent as opposed to 36
percent, and this approaches statistical significance. If we look at all
the eye group, we see that this is even more statistically significant
at both the early as well as later intervals, less loss of one or more
lines of low contrast vision as compared to what we\'re used to seeing
in our conventional eyes.

So in summary, of the Custom spherical eyes evaluated at the six-month
time gate, as looking at photopic contrast sensitivity, we had 2.2
percent gain as opposed to 0.7 percent loss with a mean gain at all
spatial frequencies. Looking at clinically important mesopic contrast
sensitivity, we had 15.3 percent gain as opposed to 5 percent loss, and
once again mean gain at all spatial frequencies, and with this extremely
difficult low contrast best-corrected vision, we had one or more lines
gained in 38.8 percent of the patients as compared to 20.9 percent loss.

So in conclusion, the Alcon CustomCornea System is unique in that it\'s
capable of measuring each of these aberrations measured by the
aberrometer and taking them and registering them to each other so that
we have a very accurate composite aberrometry reading of both the low-
and high-order aberrations of the entire optical system which we\'re
then able to match and link and transfer to the excimer laser, register
it perfectly to the treatment of the excimer laser, which then
calculates and delivers a specific ablation pattern unique for each
individual eye. The ablation pattern is uniquely determined from these
preoperative aberrations present in each individual eye.

Dr. Durrie has shown that wavefront-guided CustomCornea treatment easily
meets all the FDA guidance criteria for safety with exceptional
improvement of best spectacle-corrected vision, especially at the
extremely high levels of acuity, 20/12, 20/16. Dr. Hakim has shown that
the CustomCornea treatment exceeds all the effectiveness criteria as
established by the FDA with a very, very precise type standard deviation
around the mean. The Custom eyes have shown a consistent trend for more
eyes to have a clinically significant gain as opposed to loss of both
mesopic and especially photopic contrast sensitivity and more eyes have
shown a gain of one line or more of low contrast best-corrected vision
as opposed to loss.

Compared to these conventional eyes, the Custom eyes have a
statistically significantly better mean photopic contrast sensitivity
and as has been shown, we\'re able to preserve in the Custom eyes this
mesopic contrast sensitivity at three months which is lost in the
conventional eyes, although it does recover, but it allows the Custom
eyes to enjoy excellent mesopic contrast sensitivity throughout their
recovery period and there is a statistically significant lower loss of
low contrast best-corrected vision of one line or more.

We believe that wavefront-guided LASIK produces an eye that\'s optically
superior to conventional LASIK, and for our patients, this means
significantly less postoperative aberrations, as has just been shown in
Dr. Pettit\'s presentation, and in these Custom eyes, we\'ve seen a
significantly greater reduction in the higher-order aberrations of
virtually all of the specific types from preop as compared to what was
seen in the conventionally treated eyes.

So I think from a clinical point of view, this is something that, as has
been discussed this morning, is extremely important for improving the
visual quality of our patients and in the future for perhaps going back
and taking care of some of the problems as Mr. Link has previously
discussed.

I think we have a little bit of time left to answer some of the
questions that were specifically addressed by the panel. I\'ll turn the
podium back over to Dr. Pettit.

DR. PETTIT: Thank you, Dr. Brint.

By my watch, I have eight minutes, and I\'d like to just touch on some
of the questions that the FDA and you panel members have raised in
reviewing some of this material.

I\'d like to just start with Dr. Huang\'s review, and he noted that at
three and six months, after a CustomCornea, only 78 and 82 percent of
patients had a low contrast UCVA of 20/40 or better and only 5.8 percent
achieved a low contrast UCVA of 20/20 or better and expressed some
concern about that. We went back and looked at that data and found that
that\'s actually a fairly unremarkable ‑‑ this is a relatively difficult
test, and what I mean by that is if we look at the eyes preoperatively,
best-corrected visual acuity of 20/20 or better, only 8.6 percent of the
spherical eyes were able to see the 20/20 line on the eye chart. Three
months after surgery, 5.8 percent of our patients were able to see that
line, and at six months, it\'s 7.9 percent low contrast UCVA approaching
their preop BCVA. Low contrast UCVA of 20/40 or better is actually
slightly higher in the wavefront-guided-treated eyes at both three and
six months than it is in our comparative conventional group.

In Dr. Bradley\'s review, he raised a very interesting question, and
I\'m paraphrasing it slightly here. He\'s basically asking are we
correcting the aberrations that were in the eye before surgery? Are we
compensating for the treatment-induced aberrations or are we doing both?
Well, in all honesty, we are attempting to do both, so that the postop
aberrations are as small as possible.

When we began the wavefront development effort, our initial aim was
simply to treat the preop aberrations. However, in our early trials,
looking at the pre- and postop wavefront data, it became very clear that
the aberrations induced by the surgery were also very important and
some, not all, but some of these surgical effects were predictable, and
therefore our Custom ablation algorithm evolved from one that simply
calculated the profile directly from the wavefront data into one that
took the wavefront data but then made some adjustments to the
wavefront-based profile to compensate for predictable surgical effects.
I just want to stress that all 139 eyes in this cohort were treated at
the end of this process with a consistent algorithm.

Dr. Bradley went on to offer one analysis possibility that we could
perform. How do we know if we\'re treating the preop aberrations? He
suggested we look at the correlation between the aberrations before and
after surgery, and if successful, the wavefront-guided postop
aberrations should be uncorrelated with the preop eye-only aberrations.
We did that analysis, and the correlation coefficients are shown here.
This is looking at the individual higher-order third- and fourth-order
aberrations between preop and three months after surgery, preop and six
months after surgery, and you can see down here for two of these
fourth-order aberrations, there is a modest positive correlation
coefficient, somewhere in the .4 to .45 range, but in general, these
numbers are pretty small. Postop aberrations are not well correlated to
the preop aberrations. That\'s not ironclad proof that we\'re treating
the preop aberrations. I\'m going to come back to that in just a second
and say a little bit more.

How do we know that we\'re treating the surgically-induced aberrations?
Well, we looked to see if there were any significant correlations
between the lower-order aberration changes, the changes in the myopia,
and changes in the higher-order aberrations, and we found there were no
significant correlations between the lower- and the higher-order
aberration changes. We also looked to see if there\'s any correlation
between the clinical refraction changes and changes in the higher-order
aberrations, and again we found no correlation between the higher-order
aberrations and the refractive treatment effect. Neither of these
findings is true for conventional surgery, and we\'ve submitted a large
body of data to the FDA over time showing the trends we see for
conventional treatment. We don\'t see such coupling, so-called, effects
here.

What I\'m really trying to say is best summarized by this slide which I
showed earlier. This is looking at the higher-order aberrations six
months after surgery. The blue bars are the Custom outcomes, the red
bars are the conventional 50-eye outcome. The surgical predictable
effects that we include in the ablation algorithm involve only the
rotationally symmetric terms. So on this chart, that only involved the
spherical aberration term here. So the fact that we\'re having
significant success in limiting the spherical aberration, I believe, is
due to the fact that we\'re compensating for the surgical induction that
would otherwise occur, but these other higher-order aberrations are not
rotationally symmetric and there\'s no compensation mechanism folded
into the treatment profile to deliberately counter these. So the fact
that we see lower levels of these non-rotationally symmetric terms to
me, I think, is the best evidence that by including them in the preop
profile, we are effectively treating them, although not eliminating
them.

One of the questions that the FDA is posing to the panel is are any of
the differences between Custom and conventional outcomes clinically
and/or functionally significant? I think Dr. Brint very nicely
summarized what we think are the significant differences. Compared to
conventional surgery, wavefront-guided-treated eyes have significantly
lower postop higher-order aberrations, significantly higher percentage
of eyes with an actual reduction in various higher-order aberration
parameters relative to preop. They have a statistically significantly
better mean photopic contrast sensitivity and preservation of mesopic
contrast sensitivity at three months where we see a consistent dip in
the conventional treatments, and they have a statistically significant
lower loss of low contrast BCVA defined as one or more lines.

Part of Question Number 3 for the panel asked what information about the
measurement, analysis and correction of higher-order aberration is
needed to accurately inform physicians and prospective patients about
the safety and effectiveness? We\'ve worked with the agency to try to
come up with a simple means of describing the potential optical benefit
of doing this type of surgery. We\'re going back to that optical
simulation of what a high contrast chart would look like, and we come up
with a difference between wavefront-guided and conventional treatment
that corresponds approximately to about 2 diopters effective defocus
blur. Under low contrast conditions, this would be a different outcome
certainly.

DR. GRIMMETT: That would be .2.

DR. WEISS: Yes, I think you misspoke. I think you meant .2 rather than 2
diopters.

DR. PETTIT: I\'m sorry. Point 2 diopters. Absolutely. That would be very
nice.

(Laughter.)

DR. PETTIT: We\'re not there yet.

Question Number 4 for the panel talks about the refractive effects of
correcting the higher-order aberrations and states that these are
smaller than the effects of correcting the lower-order aberrations,
suggesting that relatively modest instabilities of sphere and cylinder
correction could disrupt the higher-order corrections.

There\'s two points I just want to touch on briefly here. Number 1. The
wavefront-treated outcomes have the same refractive stability as
conventional surgery. The higher-order aberrations in our wavefront
population are at least as stable as the aberrations in conventionally
treated eyes, and therefore we believe that modest versus large amounts
of these higher-order aberrations should be beneficial to patients in
the presence of refractive instability in the postoperative course.

Another final point is we looked at are the refractive instabilities
somehow linked to higher-order instabilities? In other words, if the
patient\'s myopia is changing in the postoperative interval, are the
higher-order aberrations changing in any corresponding fashion? No. That
should be defined as a correlation analysis looking at the higher-order
aberrations between three and six months, and we saw no significant
correlation, no correlation larger than .18, between the refractive
changes and the higher-order changes. We also looked at changes in the
lower-order aberrations as measured by wavefront device, compared those
to the higher-order aberration changes, and again saw no significant
correlations.

That actually concludes our presentation. Thank you very much for your
attention.

DR. WEISS: I\'d like to thank the sponsor for their presentation.

We will take a 10-minute break. I\'d ask everyone to be back here
promptly so we can start exactly in 10 minutes, and we\'ll proceed with
the meeting then.

Thank you.

(Recess.)

DR. WEISS: We will be starting now, if everyone is now seated. We\'re
going to proceed with, for the next half hour, with the panel questions
for the sponsor, and then we\'ll have the FDA presentation.

I would first like to ask the sponsor two questions. One. There was a
cohort in which one eye had conventional treatment and one eye had
customized treatment. Since a question the patients will ask is can I
notice any difference, aside from the numbers that we see, can the
patients notice any difference, were those patients asked which eye they
preferred, the customized corneal treatment eye or the conventional eye?

DR. PETTIT: We\'ll see if we can ‑‑ I\'m not sure. Right. That\'s right.
There are 50 eyes in the conventional arm of the study that meet the
spherical definition. There are actually only 19 eyes that were treated
conventionally in the spherical group. There were 19 patients that were
treated one eye conventional and one eye with the Custom algorithm. So
it\'s not 50 eyes. It\'s not 50 patients. It\'s only 19 where they
actually were treated one eye one way and one eye the other, and we\'ll
see if we can find information on those particular 19 eyes for you.

DR. WEISS: Okay. While we\'re waiting for that, I had a second question
on one of the higher-order aberrations, the tetrafoil. Does this behave
different than the other aberrations? For example, the conventional
group actually had a higher percentage of eyes, 28 percent of eyes in
the conventional group had a reduction in this particular higher-order
aberration as opposed to 22 percent in the Custom group. So the
conventional group had a greater percentage of people with reduction in
this particular type of aberration, and in addition, on Table 4, there
is a continued reduction in this aberration which is statistically
significant between three and six months. So it still is changing after
the \"eye\" has stabilized refractively.

So I was wondering why. Is this different than the others, and does this
treatment not treat this particular aberration, and if so, why not?

DR. PETTIT: Well, right. It\'s important to note that the average value,
looking across the groups, the average values for the tetrafoil
aberration were smaller in the wavefront-guided populations than they
were in the conventional, but there was a slightly higher percentage of
actually conventionally treated eyes that showed a reduction. So the
mean value was less looking across the entire group. Slightly higher
percentage of eyes, though, you\'re right, had a reduction in
aberration.

The simple answer is the higher-order aberrations, they all have
slightly different optical effects on image quality, and I think Dr.
Burns or Dr. Bradley can very objectively speak to which aberrations
potentially are the most detrimental. If I had to pick one that I
wouldn\'t worry as much about, it actually would be the tetrafoil as
opposed to some of the others. But certainly the panel members can speak
to that very eloquently.

DR. WEISS: Thank you.

Dr. Huang?

DR. HUANG: I have a follow-up question on the first question Dr. Weiss
raised.

There were only 50 patients had a treatment in one conventional and one
eye with the Custom treatment, but on the table presented by Dr. Brint
earlier this morning, there were several tables indicating that in all
eyes group, there were N equal to about 420 some odd eyes in the Custom
group and then in the conventional treatment, there were N equal to
about 130 some odd eyes.

Was there a mistake in terms of the tabulation or was that ‑‑

DR. PETTIT: No, there was no mistake.

Again, we\'re seeking approval just for the spherical cohort. So those
are eyes with less than half a diopter refractive cylinder. We\'ve
treated a much larger population of patients and contrast sensitivity.
We have data on the entire eye cohort which includes myopes and
astigmats. So if we include astigmatism, we have data on something like
426 wavefront eyes and 139 or something like conventional eyes.

For contrast sensitivity, which has historically been a safety parameter
and is done under best-corrected conditions, we presented that
information as supportive of the trends that we saw in the primary
cohort. So we have the primary cohort which is 139 Custom spherical eyes
as compared to 50 conventional spherical eyes, but then supportive data
on the larger body which includes astigmats and the Ns are larger for
that reason.

DR. HUANG: Thank you.

DR. WEISS: Dr. Matoba?

DR. MATOBA: In looking at your protocol, I didn\'t see any reference to
pupil sizes as either exclusion criteria or inclusion criteria. Is that
taken into account when you were entering these patients?

DR. PETTIT: I have to defer.

DR. MATOBA: And the reason I ask is because the 50 patients who had the
conventional ablation were done earlier in the study than the Custom
ablation patients in general, correct? And I wondered if there might be
a difference in the average pupil size between the two groups and that
may affect patient satisfaction or other visual tests.

DR. PETTIT: Okay. The entry criteria did not change over the course of
the study.

DR. MATOBA: If you didn\'t take pupil size into account, then how would
you know what they may have been in those patients that were entered?

DR. PETTIT: We can look at pupil size. Do you want to speak? Okay. Let
me make sure I have the question down exactly right. For this
conventional comparative group, did we control for pupil size or did we
have an analysis baseline?

DR. MATOBA: I\'m sorry. Go ahead.

DR. PETTIT: Well, I want to make sure I get it right. Did we analyze the
data based on pupil size to see if there was any statistically
significant difference in pupil size between those eyes and the
wavefront group?

DR. MATOBA: Well, my main question is could there have been a
significant difference in the average pupil size between the patients
who had Custom ablation versus people who had conventional ablation?

DR. PETTIT: Okay. So you\'re concerned that there might be a significant
difference in pupil size between the two groups?

DR. DURRIE: I can just comment from an investigator standpoint, is the
inclusion criteria were the same throughout the study, and the
conventional eyes were done fairly contemporary because initially we did
a group with the same algorithm. We did a group that had one eye with
conventional and the one eye with Custom. The reason that the number is
small is when we drop it down just to spherical cohort, then it gets us
down to only 50 eyes. So these were done at relatively the same time
period. It\'s not like one group was done three years ago and one group
was done a year ago, and the inclusion criteria regarding pupil size was
the same.

I think it is interesting, and I think it\'d be a good thing to look at,
is to actually analyze, since the aberrometer itself records pupil size,
so that data is available, and it would be a good thing to continue to
look at. I think with all these things, we\'re coming up with new things
we can look at because now we have a digital instrument that can
actually give us data that we haven\'t had before.

DR. WEISS: I\'m going to ask members of the panel, for the purpose of
the transcription, if they can identify themselves before they speak.
The sponsor. Excuse me.

Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Dr. Bandeen-Roche.

My question follows up on Dr. Weiss\'s first question and Dr. Huang\'s
question. I think it\'s coming up repeatedly. If you could just clarify
very explicitly this conventional cohort, you know, so they were
selected early on in the study. To what extent was randomization
involved in their selection versus the Custom eyes? Were they treated by
all of the same physicians who treated the Custom eyes? Were there any
differences with respect to this cohort that could be expected to
influence results, including practice effects, as the study went on? I
know there were some differences in temperature and humidity. Pupil size
has been raised, et cetera.

DR. PETTIT: Okay. I\'m going to ask Dr. Christy Stevens, our Clinical
Affairs Director, to come forward to talk about the inclusion criteria.

MS. THORNTON: Excuse me. I\'d like to emphasize to the sponsor, the
transcriber and summary writer have indicated that they would like very
much to have help from the sponsor group and give your identification
before you speak.

DR. STEVENS: Christy Stevens, Alcon.

The study started with a contralateral design with one eye Custom, one
eye conventional, and it was randomized as to which eye would be the
Custom treatment.

DR. WEISS: I wonder. Would you be able to get a little closer to the
microphone and speak a little slower? Thank you very much.

DR. STEVENS: Do you need me to repeat what I just said?

DR. WEISS: I think it would be best. Yes, please.

DR. STEVENS: Okay. It was a contralateral study design when it began.
One eye received Custom, one eye received conventional, and it was
randomized as to which eye received the Custom treatment.

When we started the study, we modified the Custom algorithm over the
course of the early part of the study. So in our Custom cohort that
you\'ve seen presented, it contains the final algorithm, only contains
the last algorithm, but we included all conventional eyes that were in
the beginning of the study because they were all treated the same way.

DR. BANDEEN-ROCHE: And I thought I heard a comment that only 19 of the
eyes were treated one eye one way and one eye the other. So who were the
others?

DR. STEVENS: There were 50 spherical conventional eyes total, of which
19 had an algorithm or current algorithm, the last algorithm in Custom,
that were also a spherical eye, and so yes, they were treated by the
same centers with the same study protocol.

DR. BANDEEN-ROCHE: Thank you.

DR. WEISS: Thank you.

Mr. McCarley?

MR. McCARLEY: I had just a question about what effects have you
considered or do you expect for a patient following cataract surgery? In
other words, the mean on these patients was 36 years, I think, and
assuming they\'re all phakic eyes, what happens when they\'re 70 or 75
and have cataract surgery? Would they be expected to go back and have a
reablation to address what had been corrected in their system, now that
one of the components is missing?

DR. PETTIT: Yes, that\'s a good question, and the honest answer is we
don\'t have any clinical data on patients that meet that criteria.

There is evidence in a young patient that the corneal aberrations are
somewhat balancing compared to the internal aberrations and that, you
know, obviously the situation\'s going to change very significantly when
you go in and do cataract surgery. I think it\'s important to mention,
though, that with our treatment, we are keeping the aberration magnitude
comparable to what it was before surgery. We\'re not grossly changing
the magnitude of the aberrations that were present in the eye
beforehand. We\'re keeping them more like they were before treatment. So
we don\'t anticipate that we\'re suddenly going to have all these new
problems when the patients come back for cataract surgery.

Now, to get the best possible optical quality after cataract surgery,
potentially sure, they might benefit by some kind of customized
correction on top of that, but we don\'t have any clinical data that
that\'s actually true.

DR. WEISS: Dr. Owsley and then Dr. Huang.

DR. OWSLEY: Thank you.

I just wanted to make sure I\'m understanding your low contrast acuity
data properly. It appears that whether we look at the sphere analysis or
the all eyes analysis, 20 percent or one in five patients experienced a
loss in low contrast acuity. I know that\'s different, lower than the
rate in the conventional surgery, but I just want to make sure I
understand. Twenty percent of the patients, one in five, experienced at
least a one line or greater loss?

DR. PETTIT: That is correct.

DR. OWSLEY: Thank you.

DR. WEISS: Dr. Huang, please.

DR. HUANG: I just want to ask. Since we set out to try to correct the
higher-order aberrations by this application, but the end result shows
that there were general increase of the higher-order aberrations, and I
don\'t know if the clinicians or the sponsor have any kind of comment
regarding the outcome.

DR. PETTIT: It is true that even after our wavefront-guided surgery,
that the higher-order aberrations are generally higher. They\'re higher
by an amount that\'s significantly much less than what we get with our
conventional surgery. We believe that\'s beneficial to the patient.

Our theoretical endpoint is to make them zero, and we clearly are not
achieving that yet, but by shooting for that as the theoretical target,
we are limiting what happens to them and that\'s where we are with the
current state of the technology.

DR. HUANG: But my point is, instead of reducing, now we are actually
increasing. So what\'s the future direction in that regard?

DR. DURRIE: Dan Durrie.

From a clinical standpoint, this is a step along the way because before
we weren\'t even measuring the patient\'s preoperative aberrations,
other than sphere and cylinder. Now we\'re finding other things that we
find clinically significant in the population now that the aberrometer
can measure.

As George said in his presentation about the progress, we found out then
that there was some surgically-induced aberrations and some of them were
predictable. I think as time goes on, we will learn more about the
surgically-induced aberrations and then may have to make compensations.
I think it\'s going to be important for all of us to start thinking
about how are we going to accomplish that from a regulatory standpoint
when you come up with the next new iteration, so it isn\'t so onerous
that the companies cannot pursue that, and it isn\'t too onerous from a
regulatory standpoint, and I think it\'s something that I know that
you\'re having a meeting tomorrow to talk about phakic eye welds, but
I\'d certainly like to have us continue to have a discussion between the
sponsors and the clinicians and the agency about once we get better,
what do we do then? Because I think this is a step along the way, but we
still would like to make that zero, and we\'re going to have to continue
to evaluate data in order to make that happen.

DR. WEISS: Dr. Burns, and then Dr. Bandeen-Roche.

DR. BURNS: Yes. Your sample had a very low percentage of Asians in it,
yet it\'s a high-refractive error group, and I just wondered if you had
a comment.

DR. PETTIT: I think the race distribution in the study was comparable to
that we\'ve seen in prior studies. Do we have any further comment? I
mean, there was no attempt to include or specifically recruit certain
patient populations or not. This is just the patients that came in, were
interested in being in the trial and met all of our inclusion criteria.

DR. WEISS: Dr. Roche?

DR. BANDEEN-ROCHE: Dr. Bandeen-Roche.

I have a question that goes to the fact that relatively few sites
participated in the study. So you provided the site distribution of all
eyes and it ranged from 36 percent in the provider who did the most to
about 10 percent in the provider who did the least.

Do you have the same distribution for the spherical eyes and also the
distribution of the conventional, the 50 conventional eyes by site?

DR. PETTIT: We\'ll see what we can dig up in that regard.

DR. BANDEEN-ROCHE: And finally, can you describe how the sites were
selected and what training, just very briefly, the extent of training
that the physicians received?

DR. PETTIT: The site selection criteria, we obviously were interested in
trying to get innovators in this field, high-volume/high-profile
refractive surgeons that were knowledgeable about new advances in
technology. I don\'t know that there was anything beyond that. It was as
simple as these doctors seemed to be very well qualified and were
interested in participating in the study, and we wanted to work with
them.

The training that they received, they obviously received some training
in how to use the wavefront device. The treatment aspects are very
similar to what they were already using for their conventional
LADARVision treatments. There was a slight difference in the fact that
they had to mark all patients before treatment as opposed to just
spherical patients in their conventional surgery, those little eye marks
they put on the eye, and then the reticle that came up during treatment,
the software image projected into the LADARVision tracked image screen
was slightly different, but the other aspects of the treatment were
really identical to what they\'d seen before.

We did spend some time going through them, the meaning of the wavefront
measurements and, you know, when their clinician brought them data, what
did that mean for that patient in terms of relative to the foropter, for
example?

DR. WEISS: Dr. Grimmett, and then Dr. Matoba.

DR. GRIMMETT: Dr. Michael Grimmett.

I just had an observation and would like to hear if you have a comment.
You may have none. There may be no answer.

I found it curious that despite a very comprehensive analysis and
sophisticated technology, that the patients that were unsatisfied or
extremely unsatisfied approximated 9 percent. It\'s notable that the
PERK study by comparison, using bear skins and stone knives, had an
11-percent dissatisfaction rate, and I found it curious that one in 10
patients are unsatisfied, despite a phenomenal amount of technology and
analysis, and I would like to commend you on a superb analysis and
presentation.

Do you have a comment why it\'s still one in 10 despite all the
sophisticated technology or is there no answer to that, sir?

DR. PETTIT: No. Well, I don\'t know everything. I didn\'t personally
speak to these patients. I think one factor was that they tended to be a
little bit undercorrected. The patients that were undercorrected on
average were less satisfied than the patients that were right on, and
again there\'s no latitude for the surgeon trying to optimize the
refractive outcome. We wanted everything done exactly the same way and
that led to a slight undercorrection, and the patients where that
undercorrection was more than the mean, they ended up more myopic than
the mean, they tended to be less satisfied.

I think, you know, in all honesty, in addition, there\'s a lot of hype
surrounding this procedure, and I think their expectation levels in some
cases was pretty high, but, you know, that\'s not scientific. That\'s
just an opinion.

DR. HAKIM: If I could just add to Dr. Pettit\'s comments, I mean, I
agree that ‑‑

DR. WEISS: Could you introduce yourself, please?

DR. HAKIM: Omar Hakim. Sorry. Omar Hakim.

I just want to add and really reinforce George\'s comments, you know,
about the undercorrection aspect of this. We weren\'t able to make any
adjustments as we normally do when we do surgery, and clearly there was
a difference in the patients who were satisfied versus dissatisfied with
their surgery, based on their residual refractive error, and the
expectation issue, I think, you know, is a very big issue. I literally
had patients coming back who were now seeing 20/16 uncorrected acuity
and wanted enhancements. So their expectations of the surgery clearly
were raised as well as in the minds of their own physicians who had
referred them. They were talking about supervision and the Popular
Science article last March, you know, talking about the ability to give
people, you know, better than 20/10 or 20/8 or 20/6 vision.

Clearly, what we really want to do is avoid problems, you know, like Ron
Link talked about this morning, is try to create better quality of
vision, and as Dan Durrie was saying, this is really a process in
evolution, but if I could have my surgery done again today and avoid the
induction of these higher-order aberrations that we create whenever we
do conventional surgery, that\'s what I would choose for myself and all
my patients.

DR. PETTIT: Just to follow up a little bit on an earlier question. This
is George Pettit from Alcon.

I think Dr. Matoba asked the question about the pupil sizes and were the
patients informed. Given this high-level expectation, it\'s important to
note that the optical zone was 6.5mm and we informed all patients
considering being in the trial that if their natural pupil was larger
than 6.5mm, even with this new technology, there was a potential risk
for them to have night vision symptoms. So we tried to bring their
expectations more in line.

DR. WEISS: Dr. Grimmett has a follow-up question.

DR. GRIMMETT: I have just a simple operational question.

Is this software that\'s going to be retrofitted to existing product
base, the LADARVision 4000s out there? Does this require a whole
investment in brand-new technology?

DR. PETTIT: No, from the LADARVision side, it\'s a simple software
upgrade.

DR. WEISS: Dr. Matoba?

DR. MATOBA: Alice Matoba.

I actually was going to refer to the same chart for the table on Patient
Satisfaction and also the previous page on Patient Symptoms. Do you have
these same data for the people who were treated with the conventional
laser?

DR. PETTIT: So the question is do we have the patient satisfaction
questionnaire-type data for the patients treated conventionally?

DR. MATOBA: And also symptoms at six months.

DR. PETTIT: And do we have data on the conventional patient symptoms at
six months? We\'ll see what we have in that regard.

DR. WEISS: Dr. Bradley was next, then Mr. McCarley, Dr. Swanson, and Dr.
Owsley.

DR. BRADLEY: Dr. Bradley.

I\'m just curious about the apparent huge discrepancy between what Ron
Link presented earlier today and the data on the symptoms presented by
the sponsor. For example, Ron Link indicated that dryness and double
vision are huge problems, and I think we have a couple of other people
indicating that, and I look at the data you just presented on dryness
where we have slightly more patients indicating worse dryness than those
indicating better, and we have a very small number indicating increased
double vision, about the same as those who are indicating decreased
double vision.

So from the sponsor\'s dataset, it appears that we don\'t have this very
large and disturbing incidence of dry eye and optical problems, such as
double vision, whereas Ron Link and a couple of the other presenters
indicated that these are very serious problems, and I wondered therefore
if we could clarify perhaps some inclusion criteria from the sponsor
because one wonders if Mr. Link\'s dataset is rather biased to those who
have the problems and somehow you have been able to effectively filter
these people out of your datasets. Yours are biased the other way.

I think it\'s very important to get a sense of that, particularly for
those people who are going to utilize this technology, and if you have
effectively avoided these problems by your patient selection criteria,
then this clearly should be included in the final labeling for this
device.

DR. PETTIT: Dr. Durrie, would you like to comment?

DR. DURRIE: Yes. I\'d really like to address that, and this is Dan
Durrie.

Ron\'s website, which is where he gets his data, are for people who\'ve
had surgery and by its own definition and its goal, it\'s for people who
have problems with refractive surgery, and I really appreciate the work
that he\'s done on helping us define of those patients who have problems
with refractive surgery, what are their problems, and obviously 25
percent of those problems are persistent dry eyes. But this is a very
selected group not only that\'s had refractive surgery but is
self-defined that they have problems and they\'re logging into the
website. So I think that\'s a defined group on that side.

On our side, I think that the only criteria that I think is significant
from my clinical experience is the average age of this group was 38
years old, and we know that the patients, if I did LASIK on an average
age of 55-year-olds, they\'d have more problems with dry eyes. So I
think that if there\'s a self-selection in this, there certainly wasn\'t
anything in the screening from the standpoint of we had healthy eyes,
there wasn\'t any tear film screening or any special testing, but I
think that you do have a healthy eye group that\'s screened for a
clinical trial that certainly is a healthy eye group and on the other
side, in the surgical eyes group, you have the group that basically is
having problems, and I think both those datasets are important.

I\'d like to also, because I did look this up during the discussion, is
if we take the 426 eyes that are available for analysis and run that
same grid, that total grid of symptoms, the numbers are essentially
identical. So here, you have ‑‑ which was requested really by the public
presenters ‑‑ a very good dataset with a 100-percent follow-up on 426
eyes that gives you an array of symptoms on how many patients were the
same, better or worse, and I think that could be a dataset for labeling
that could give you some good information with peer data because it does
have 100-percent follow-up and it was done under a controlled fashion.

DR. WEISS: Dr. Bradley has a follow-up.

DR. BRADLEY: From your reply, you seem to be saying you\'ve done nothing
special to avoid these dry eye or night vision, double vision problems.
Did I understand that correctly?

DR. DURRIE: In patient selection.

DR. BRADLEY: Second question, and this is really to ‑‑

DR. PETTIT: Dr. Bradley?

DR. BRADLEY: Yes?

DR. PETTIT: Could I just perhaps follow up? This is again fairly much
just conjecture on my part, but the patients that participated in this
study had to be willing to come back for many, many follow-up visits. So
perhaps we, without attempting to, screened for a more educated or, you
know, patients that really wanted this type of procedure and knew what
the risks were ahead of time, I don\'t know, but they weren\'t just your
standard patient coming in off the street that weren\'t going to have to
go through all these tests for six months.

DR. BRINT: I think my comment is similar to Dan\'s in that ‑‑

MS. THORNTON: Could you identify yourself?

DR. BRINT: Dr. Stephen Brint.

In this slightly younger group, in the 38- to 39-year-old group, it\'s a
little bit younger than we see in our typical LASIK population of the
over-40ish group, one thing, and then, two, relative to glare and halos,
obviously this is a symptom that this technology is attempting to
address, and as far as trying to screen out people already complaining
of this, there was none. As far as trying to screen out patients with
preoperative history of dry eye, in particular, there was none.

Also, I think that certainly now in contemporary LASIK surgery, we\'re
much more aware of the dry eye potential than we were as far as some of
the patients that Ron was referring to that are now appearing in his
database and that these patients were perhaps treated more aggressively
as we treat all patients more aggressively now for dry eyes, punctal
occlusion and other things much more aggressively routinely in our
every-day LASIK practices than we did several years ago.

DR. WEISS: I would just add one thing. On Table 34, if we include the
patients in the spherical cohort who are saying that their symptoms are
not only significantly worse but just plain worse, you actually have
about 32 percent saying the dryness was worse or significantly worse. So
it\'s still not trivial, and I think if we are looking at the worse
category, it significantly increases the number of complaints.

Did you have a follow-up question?

DR. BRADLEY: I did. On a related issue that was raised a few minutes ago
‑‑ that is, the rather high dissatisfaction rates amongst your patients
‑‑ I think Dr. Pettit indicated that this was probably due to the
residual myopia present in these patients.

It seems to me it would be worth establishing that as a fact or not. I
think some correlation analysis might allow you to do that and maybe
including something like that in the labeling because if indeed the
dissatisfaction is due to undercorrection, clearly that can be at least
remedied by wearing a spectacle or contact lens overcorrection, whereas
if dissatisfaction was due to some other uncorrectable problem, that\'s
a more serious dilemma and I think perhaps labeling should perhaps clear
that up.

DR. PETTIT: Yes. This is George Pettit again.

We have done some analysis. It is correlated, and we can pull that, if
you want, but there is definitely a link. It doesn\'t explain everybody
that\'s unsatisfied, but there\'s definitely a correlation there.

DR. HAKIM: Omar Hakim.

I just operated on a good friend of mine who\'s an optometrist, and when
he wanted to get his eyes done, he was about a -4, wanted to have his
eyes done about almost 10 months ago now, and was talking about having
conventional because he had seen the results that we had gotten with
conventional, the LADARVision, and I showed him some of the early
results that we had been presenting at some of the meetings on Custom.
He decided to have Custom, ended up, of course, mildly undercorrected in
one eye, about -75, and I just did a conventional retreatment on him, I
think it was last Friday or just this Friday past, and he noted an
immediate improvement in quality of his vision in that eye. So you know,
please do remember these patients have been enhanced. These are all
primary treatments, and I think with enhancements, you know, certainly
we can probably bring these people up and from what George is saying,
there is a correlation.

DR. WEISS: I would actually go back to the sponsor\'s own slides, on
page 22, that you indicate for better or significantly better, the mean
MRSE was -.26 to -.36, worse to significantly worse was -.46 to -.70. So
I don\'t know. I assume that\'s the data that you\'re referring to that
you\'ve shown us.

We\'re going to go on to questions by Mr. McCarley, Dr. Swanson, Dr.
Owsley, and Dr. Maguire.

MR. McCARLEY: This is Rick McCarley.

I just had, I guess, a comment on Dr. Grimmett\'s statement about the
comparison of the PERK dissatisfaction rates to this study\'s
dissatisfaction rates. The Ns are significantly different, as I
understand it. We have 139 patients in this and the PERK study was much
larger. So an error is certainly built in and not being considered, but
perhaps there are others in the room that have actually conducted
patient surveys or questionnaires, and I trust them on very large
numbers, but anything less than 10,000, I think you have, you know,
problems built in, like did they get a parking place close to the door?

I guess I would caution the panel as to whether we should be making
labeling changes to placate certain small segments of the population
believing that that\'s going to change necessarily how a surgeon would
pick the patient after they\'ve already been educated on which patients
should be included. In other words, if a surgeon performs surgery on a
patient they should not have, the outcome\'s going to be the same
whether or not they told the patient. The question is will the patient
make a different decision? I\'ve spoken with patients myself who
probably would have gone ahead with the decision because they didn\'t
understand the total consequences. So I guess it\'s just a comment. I\'m
not sure we can label ourselves out of this. Certainly more education
and more experience with this will give us a better idea of where it
goes.

DR. WEISS: Dr. Swanson?

DR. SWANSON: Bill Swanson.

You\'ve been very forthcoming. It\'s a lot of data analyses. One of the
things that you did that was useful was to look at the clinically
significant change, and then there\'s mentioned like in the summary that
contrast sensitivity more had a clinically significant improvement than
loss. However, those numbers are very small, and if you do confidence
intervals for percentages, you can get some sense or some other type of
statistical measure, are they actually different? It\'s easy to say 4
percent is twice as big as 2 percent, but then the question arises, is
that data statistically any different or could it be because of the
small sample size?

DR. PETTIT: We have not done a more detailed analysis than the simple P
values and whatnot that you saw there. So we can do that. We don\'t have
that data right handy.

DR. WEISS: Dr. Owsley?

DR. OWSLEY: Cynthia Owsley.

Many of your analyses were on basically change scores before and after
surgery, whether it was referring to acuity or wavefront or whatever.
However, your measures that really are components of health-related
quality of life, it seems that your analyses, unless I missed something,
focused on postsurgery only, and your change score was by inference of
asking people whether there have been significant changes and they\'re
answering in a subjective way.

I\'m wondering if you did any of your symptom lists or quality of vision
instruments before surgery and whether the change data has ever been
looked at.

DR. PETTIT: We\'re bringing Dr. Stevens again to address that.

DR. STEVENS: Christy Stevens, Alcon.

There\'s a preop questionnaire data in the PMA and it\'s rated on the
scale from none to severe. Postoperatively, the patients were asked to
specifically rate their change, significantly worse, significantly
better. They were not asked to rate them on a scale from none to severe
postoperatively.

DR. OWSLEY: So the same instruments were not used pre and post, if I
understand you correctly.

DR. STEVENS: That\'s correct.

DR. WEISS: Dr. Maguire?

DR. MAGUIRE: Dr. Maguire.

Dr. Durrie said earlier that this is a step on the way to improvement,
and it appears, and correct me if I\'m wrong, that this is probably the
seventh step in your algorithm where you\'ve approached the panel, is
that correct?

DR. PETTIT: Seventh iteration of our Custom treatment algorithm.

DR. MAGUIRE: Seventh iteration, and it appears that you made a judgment
to bring spherical correction before the panel but not astigmatic. What
fell short in your non-spherical group that caused you to hold back?
Just a second. To give you a rationale behind that, as you said earlier,
marketing is 85-percent confusion and 15-percent commission, and so
there\'s been a lot of that around in this particular technology, and as
it\'s already been mentioned, people do have high expectations.

So the question that comes in mind as a clinician is, when has there
been enough step occurred, and should the step be bigger? So I\'d be
interested to know what your criteria were for not stepping forward with
your astigmatic group but stepping forward for your spherical group.

DR. WEISS: I would like to just direct this to Mr. Whipple because this
is information that the sponsor does not want to approval for, and I
would like to know whether this is appropriate for them to have to
answer this question or address this question or not.

MR. WHIPPLE: I think they can make the judgment. If they feel like
answering it, they can.

DR. WEISS: Okay. It\'s in your court.

DR. PETTIT: No, I\'m happy to answer the question.

The honest answer is that in the astigmatic cohort, we did meet all the
safety parameters as Dr. Durrie indicated, and we were effective, but in
an honest assessment, we were not as effective as our conventional
surgery in the treatment of astigmatism. We found out the trends that
explained that and we decided we can fix this. Why don\'t we fix this
and get the best possible astigmatic outcome before we pursue astigmatic
approval, and it was a judgment call just on our part.

DR. MAGUIRE: And I thank you for that honest answer, and then in
follow-up on that, then as I look at the basic clinical data for your
spherical cohort, what it appears is by the small numbers and the higher
myopic range, that there\'s more scattering results and there\'s a very
small sample and so that in, you know, the mean is kind of pushed
towards emmetropia by the large number of lower corrections placed in
there, and looking at the chart in the medical officer\'s review on page
30, it does appear that there gets to be more scatter when you get above
-5, and you\'ve already talked about patient dissatisfaction increasing
with undercorrection, and we\'ve also discussed that the marketing
issues that have led to high patient expectations.

So how did you decide that in this group above -4, that was acceptable
as compared to the astigmatic group?

DR. PETTIT: Well, in general, even at the high end of the range, we have
relatively good outcomes in terms of BCVA numbers. The scatter is higher
at the high end and that\'s what we see with all of our refractive
surgical procedures. So again, it was a judgment call, that in general
that group did well with more scatter and some patients that were more
undercorrected than they were at the lower ranges.

DR. MAGUIRE: But would you agree that a patient coming in with high
expectations may be more likely to be disappointed if their spherical
correction was greater than -4 preoperatively?

DR. PETTIT: I actually would invite our clinicians to comment on that as
well. They have more likelihood of being undercorrected after surgery.
The accuracy is less when you get to the higher end, and we would need
to communicate to them to try to set their expectation realistically.

DR. MAGUIRE: So you would agree that that would be a very appropriate
thing to put in the labeling and to give particular emphasis to it with
this particular submission because of the claim for higher levels of
superior vision. We\'re not just correcting emmetropia but we\'re
promising superb optical resolution of emmetropia.

DR. HAKIM: This is Dr. Omar Hakim.

You know, I would like to add, you know, maybe sort of retracing some of
the ground that I went through in some of the slides that even in that
higher myopic group that you referred to, Dr. Maguire, above -5 and -6,
that, you know, again 92 percent of patients between -5 and -5.99 had
uncorrected visual acuity of 20/25 and above -6 still 75 percent of
patients had uncorrected acuity of 20/25, and overall in that -5 and up
group, fully 75 percent of patients were within plus or minus a half
diopter of emmetropia. So you know, while there was more scatter, you
know, I definitely agree with you, as we see even with conventional
surgeries or any type of platform, you know, those are numbers that as a
clinician I would consider very acceptable.

DR. MAGUIRE: I agree with you totally. I find it totally acceptable,
too, but I think the labeling must reflect the higher expectation of the
patient regarding this, that this isn\'t conventional and we\'re not
supposed to be as encouraging conventional ideas. We\'re supposed to be
using ideas that are promising to the patient, that are a significant
step ahead where we have to make it clear that it\'s just a moderate
step ahead on the way to the ideal.

DR. DURRIE: This is Dan Durrie.

I think that there is a balance here, and Leo, I think you\'re getting
at a very important thing, is that, if the indications for use and the
claims that are being ‑‑ I mean, if you all decide that the claim of
superior vision is something that is going to be tied to this, then
those claims will be balanced out by the data that at the higher level,
less people will meet those claims.

On the other hand, you have to really look at this as an elective
surgery that somebody\'s undergoing and the patient who is a -1 has a
less significant visual handicap than the patient who\'s a -6 triope. So
if I apply this to my practice, the happiest patients that I have are
the patients in the higher level, even if they have more symptoms of
night glare because their disability of their myopia and the lower-order
aberrations were so much greater.

So I think we\'ve got to be a little cautious here because, you know,
you say it in such a way that if we are claiming superior vision and
marketing at that level, that\'s one thing. I think we should be
cautious on both sides of that, too. So balancing that, I wouldn\'t want
to go out and just say that higher myopes are less satisfied with
refractive surgery, Custom or not Custom. That certainly is not true,
but the situation is is that it is harder to sink a long putt than a
short putt, and I think we\'ve seen that in all of the clinical trials
and this is just typical of it.

DR. WEISS: Dr. Maguire, did you have any follow-up questions?

DR. MAGUIRE: That ends it.

I just wanted to say, I realize this is a dilemma, and wisdom\'s the
ability to make a decision when you\'re faced with a dilemma, and
reasonable people can disagree on what\'s wise. All I\'m saying is, I\'m
looking at this not from a physician standpoint, I\'m looking at it from
a patient standpoint, taking into consideration what I\'ve heard from
the sponsor which is that the higher myopes are more dissatisfied and
that there\'s at least a sense, maybe it\'s not backed up by data, that
the patients that are undercorrected tend to be more dissatisfied
perhaps because they have a higher level of expectation with this
particular technology than they would with conventional and somehow that
spirit that we all agree on has to find its way into labeling to avoid
patient dissatisfaction from unmet high expectations.

DR. WEISS: I think the panel then can address it in labeling as far as
putting more information in the patient insert than might be there at
the present time.

I would like to start to wrap up this portion. I know Dr. Swanson had a
question. Oh, now we have small questions as opposed to large questions.

(Laughter.)

DR. WEISS: I know Dr. Burns had a question. You have a large question.
Can you make that a smaller question? Is it an important question? While
you cogitate over that question, why don\'t we start with Dr. Swanson?

DR. SWANSON: Well, actually, I think you were going to comment on the
percentages.

DR. WEISS: Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Why don\'t you go?

DR. SWANSON: The 75 percent that you\'ve referred to several times is a
sample of core people. One of them was outside that. So although that
technically is 75 percent, the percentage that could be from a large
population is very large and that was the general point I was making
about confidence intervals, and I think at that point ‑‑

DR. WEISS: Can you speak a little closer to the mike?

DR. SWANSON: Okay. That was a general point I was making on confidence
intervals. You can say the number\'s 75 percent, but statistically, it
could be anywhere from 40 percent to 100 percent, 99 percent, but I
think you were going to comment on that.

DR. BANDEEN-ROCHE: Well, I did have a follow-up. I mean, you just made
one of the points exactly and then a slightly more technical but maybe
as important point is whether the statistical significance that you
quoted in your presentation was for the whole sample of eyes. Did it
account for correlation between eyes in any way? Do those results hold
up if they\'re only done on the primary eye?

DR. PETTIT: The statistical significance, I\'m sorry, in terms of which
parameters?

DR. BANDEEN-ROCHE: The clinical findings of, for instance, slightly
better contrast sensitivity in the Custom cohort compared to the
conventional cohort. I believe your presentation at the end said that
some of those clinical comparisons were significantly in favor of the
Custom group. No confidence intervals were provided, they ultimately
should be, but my question is did those statements of statistical
significance incorporate the correlation between eyes in any way? Do
they hold up when they\'re only done on the primary eye or am I mistaken
all together? Was there no significance at all?

DR. PETTIT: There were statistically significant differences, and we did
try to note those, but with regard to if we break it down by primary eye
and whatnot, we haven\'t done that analysis.

DR. BANDEEN-ROCHE: And then, my very brief just to finish off my
questions, in terms of your correlational response to Dr. Bradley\'s
presentation forthcoming, I noticed that those were for the 6.5mm
diameter. Did you do those on the 5mm diameter as well and what was
the ‑‑

DR. PETTIT: They were comparable.

DR. BANDEEN-ROCHE: They were comparable?

DR. PETTIT: Yes. The numbers weren\'t exactly the same, but they were
definitely very close.

DR. WEISS: Dr. Burns?

DR. BURNS: Yes. You talk about the difference for the undercorrection.

MS. THORNTON: Could you speak into the microphone, please?

DR. BURNS: I\'m wondering if, when you talk about touching up the
surgery, you\'re thinking in terms of now having less surgically-induced
aberrations and whether you\'re going to try to deal with that on the
touch-up or just do the spherical correction in the algorithm, and do
you think that?

DR. PETTIT: Well, we\'re actually discussing with the agency the best
way to address this in the commercial embodiment and also going forward.
The data that I presented, the important thing to me was that with this
algorithm, there\'s no ‑‑ some people call it coupling. When you try to
treat a lower-order aberration, you actually induce wrong amounts of the
higher-order aberration, and by showing that there was no significant
coupling between the lower- and higher-order terms, you could envision,
if we took out that .37 diopter on average defocus error, we aren\'t
going to suddenly have lots more coma or lots more spherical aberration.
So giving some adjustability or changing the target by a small amount,
we\'re not going to totally disrupt the higher-order differences that
we\'ve seen. Does that answer your question?

DR. WEISS: A moderately phrased and lengthy question by Dr. Bullimore.

DR. BULLIMORE: Thank you, Madam Chairman. This is Mark Bullimore.

I would like to commend the sponsor on an excellent job. One of the
dissatisfying things, though, about the data is that from this initial
cohort of over 400 eyes, we\'re now presented with an efficacy cohort of
a little over 100, a comparison cohort of 50 of which, if I\'m not
misquoting the sponsor, fewer than 20 were treated with the most
up-to-date algorithm, is that correct?

DR. PETTIT: Can I clarify that for you?

DR. BULLIMORE: Yes, please do for us.

DR. PETTIT: Okay. And I apologize. I know this is a little bit
complicated.

DR. BULLIMORE: That\'s fine.

DR. PETTIT: Over the course of the trial or in the early parts of the
trial, we were enrolling patients and randomizing, one eye Custom, one
eye conventional. Now, the conventional surgery was a 6.5mm optical zone
using the latest conventional algorithm, and that persisted throughout
the entire trial. So all those patients were treated exactly the same.

The Custom algorithm evolved up to Level 7, as you indicated, and then
all the 139 patients were treated with that in the Custom eye with that
same algorithm. So the data that you have for the primary cohort, there
were no adjustments, no site adjustability, nothing. They were all
treated exactly the same with the single algorithm.

For comparison, looking at all the conventional eyes that we had
enrolled in the contralateral arm of the study, we found that there were
50 eyes that met the inclusion criteria to be defined as spherical. So
then, if you look at those two groups, on the Venn diagram, where do
those patients intersect? It turns out that there are 19 patients that
were treated conventionally in one eye and with Algorithm 7 in the
Custom eye. That\'s a very small sample set and the only reason we bring
it up is that based on some reviews back and forth with the FDA, we did
narrow it down because that\'s a pretty powerful group to look for
differences. It\'s a small number, I concede, but we saw exactly the
same wavefront trends and whatnot that we did in the much larger groups.

So it\'s small but it\'s a pretty good little set to look at to support
what you find in the big set.

DR. BULLIMORE: Yes, I think there\'s a number of challenges that the
panel\'s going to face later, but I want to sort of at least get them on
the table during this session where you are essentially available to
answer questions.

I think your data have shown reasonably compellingly or fairly
compellingly that ‑‑

DR. PETTIT: Thank you.

DR. BULLIMORE: Let me tell you what you\'ve shown first.

(Laughter.)

DR. BULLIMORE: That the aberrations in your Custom algorithm are lower
than they are in the conventional algorithm and that\'s a given. But in
terms of what\'s communicated to the patient in terms of their vision
expectations, they\'re still higher than they are preoperatively and
that\'s something that somehow needs to be captured in the claims
labeling, whatever, that we handle later.

There\'s a couple of contradictions in your data and they may be
reasonably easy to explain, given the brainpower or horsepower around
the table here. Aberrations are worse postoperatively than they are
preoperatively, but there seems to be some modest or subtle improvement
in the low contrast acuity and the contrast sensitivity data and that\'s
something that again we have to somehow reconcile, even though the
optics are getting worse but not as worse as they are with conventional,
there seems to be some modest improvement in vision.

So those are the issues I\'m wrestling with internally, are how to get
that information out appropriately, and I\'ve been looking through your
patient information booklets and your physician booklets and you\'ve
done an admirable job.

DR. PETTIT: Thank you.

DR. BULLIMORE: But it\'s going to be awfully confusing to people because
your information booklet is covering a range of procedures, a range of
lasers, a range of algorithms, and even if these booklets make it to the
patient, the chances of them getting the right message is going to be
difficult.

DR. PETTIT: I\'m George Pettit with the sponsor again.

It\'s in our best interests to try to communicate realistically to the
patients what\'s going to happen. We don\'t want unhappy postop patients
certainly. So we look forward to your input and trying to present that
in the best way we can.

The modest improvements in some of the low contrast, the BCVA and the
contrast sensitivity that we see, Dr. Bradley in his review noted that
and suggested two factors that may be contributing to those findings.
Number 1. There is a slight magnification difference because the
patients are best corrected before and after surgery, but they don\'t
have nearly the degree of myopia after treatment, and the other thing is
simply that they\'re familiar with the test. Maybe there\'s some aspect
of it that they learned how to do better. So you know, I can\'t
optically explain why we\'re seeing statistically significant
improvements after treatment where we\'re increasing the higher-order
aberrations, but in looking at the Custom versus conventional, I think
the differences are still somewhat valid because whatever those, the
learning effect or the magnification difference, that happens in both
sets of eyes. So you know, where is the absolute level? There is
definitely some uncertainty and so we don\'t quite understand what\'s
really going on there.

In other studies, contrast sensitivity with conventional LASIK, contrast
sensitivity dips and it tends to come back near baseline and that\'s
just for conventional treatment with our system or with other systems in
published studies. So that\'s a real effect that\'s out there, but the
fact that we see a difference and at least in the early time course, a
fairly significant difference between the two populations, we think, is
encouraging and supportive of the notion that Custom is better.

DR. WEISS: I just want to ask one simple question and then we\'re really
running over and so we\'re going to close off the question session and
this is simplistically. Are these people any happier than the people who
have conventional treatment? You have 19 people and I sort of phrased
that in a more scientific form. Did you ask the people? Did you do a
survey? But if you didn\'t do a survey of the clinicians before us, what
is your perception? Do these people notice the difference?

DR. PETTIT: Dan, before you all answer, can I just say? We\'re not going
to be able to dig up the data on those specific 19 patients in any
reasonable time frame this morning.

DR. WEISS: Okay. That\'s fine. Then perceptually, does a patient notice
if they\'ve had this customized treatment versus if they had
conventional treatment?

DR. DURRIE: Very difficult to answer, and I want to tell you why,
because this residual myopia issue kind of clouds it because one thing
we know as we go back to look at the patients who had quality night
driving problems dissatisfaction, those are the ones that have residual
myopia.

DR. WEISS: What about if you took out the ones with residual myopia?
Eliminate those residual myopia. The remaining 10 people you\'ve got,
are they any happier?

DR. BRINT: It\'s three. Three people.

DR. DURRIE: Yes, I think it just gets so small, and it\'s one of those
things where I\'ve asked the same question because it\'s obviously one
of the things I want to know what to tell my patients. So it\'s the
first question you asked today and it\'s the one that we\'re ‑‑

DR. WEISS: Well, of course, this is the basic question because
otherwise, what are we talking about? Otherwise it\'s just numbers.

DR. DURRIE: Well, I think the contrast sensitivity and low contrast
acuity is very important to me because I\'ve been studying contrast
sensitivity for quite awhile. I\'ve done a lot of clinical trials on a
lot of different devices, and I\'ve always seen that we were losing
contrast sensitivity.

DR. WEISS: I\'m going to just, in the interest of time, go back to if a
patient doesn\'t notice it, it might be important, but ultimately the
patient\'s going to decide if this was worthwhile or not.

DR. DURRIE: And that\'s what I was getting at, is that, this is what
I\'m hearing from patients, you know, is that their quality of vision is
better. I know that that\'s a soft thing, but this is what I\'m hearing.
We can get everybody out of glasses but now working on quality and as
we\'re looking at these new technologies, I think that\'s where we\'re
heading up the scale, but I do not have the statistics because the
sample sizes are too small to answer the question.

DR. WEISS: I\'m just asking you your perception is of those number of
people who ended up not undercorrected, their customized eye, they
preferred to their not customized eye or we don\'t know that?

DR. DURRIE: I can\'t answer that.

DR. BRINT: Steve Brint.

I think you\'re asking for an anecdotal answer, and I\'ll give you an
anecdotal answer.

DR. WEISS: If that\'s all I can get, that\'s better than nothing.

DR. BRINT: I did 19 of the eyes. Again, this includes the astigmatic
group and I don\'t know how many of those ended up in the spherical-only
group. Nineteen eyes in the contralateral study, so that one eye had the
Custom and one eye had the traditional, and I just sort of know from
looking at the data that I had, my site had the smallest amount of
undercorrection, and I strongly feel that the patients that had the
custom ablation appreciate the improved quality of vision, and a lot of
those, I don\'t know exactly how many, but when we look at those
patients that had improved best-corrected vision to 20/12 or 20/16, some
of those are in my patient group and I definitely feel that they can
appreciate the improved quality of vision, the sharpness and, you know,
I hear anecdotally things, I have bionic eyes and this sort of thing.

So I think it\'s a real phenomenon and as we\'re able to go back and
manually find the method of tweaking that nomogram or adjustment to have
the lasers specifically tailored for each of our individual sites and
humidity and temperature conditions and these things as we normally do,
that this is going to become even a very much more real phenomenon.

DR. HAKIM: Omar Hakim.

Among the patients i treated were three optometrists and an
ophthalmologist\'s wife, and all of those physicians had referred a high
volume of patients and had noted that the patients who were having
Custom found the quality of their vision better and that\'s why they
chose to proceed with Custom, and sort of, I guess, going back to the
question of how about the people with higher degree of myopia, and I
would argue that even if there is this slight trend to undercorrection
that we should be able to adjust, as Dr. Brint, Dr. Durrie pointed out,
that the induction of higher-order aberrations is more significant in
that population of patients. So it becomes even more important to me to
be able to apply this technology to a patient who\'s a -5 or a -6 than
it does to a patient who\'s a -1 or a -2 where the induction of the
higher-order aberration is going to be less because of the amount of
surgery that you\'re doing.

So thanks.

DR. WEISS: Dr. Matoba wanted to make one brief comment without any
response from the sponsor.

DR. MATOBA: No response. This is my comment, which is that your study
has shown that this is clearly a safe procedure and that through your
objective parameters, it\'s superior to conventional ablation, but the
question is, what does it mean for the patient, and it seems like
patient satisfaction and postop symptoms do become important, but if you
look at page 22, you\'ve given symptoms that the patients have postop
for custom ablation, and I asked previously for the same data to be
given for conventional treatment so we can look at numbers rather than
anecdotal information about the degree of complaints that you got about
glare, halos and night driving, et cetera, and then on page 23, patient
satisfaction, you give it to us for custom ablation. We don\'t have it
for conventional ablation. I\'d like to see that so we can compare.

Now, the problem with that is that you have patients enrolled in your
custom ablation who had extremely high expectations and so you didn\'t
control preoperatively for the level of expectation and that is going to
skew your patient satisfaction, but still I would like to see that
information for conventional to compare to your custom ablation
patients.

DR. WEISS: If you can answer in one sentence or less, if you have it
available? Actually, do you have any of this available or can it become
available today?

DR. PETTIT: No.

DR. WEISS: No. Okay.

DR. PETTIT: But we\'d be happy to provide it.

DR. WEISS: When it becomes available at another time but not at today\'s
meeting.

Okay. I\'d like to thank the sponsor very much for an excellent
presentation and for their helpful answers.

We\'re going to go on to the FDA presentation. The FDA will come up to
the podium now.

Dr. Beers, will you begin?

DR. BEERS: I\'m Everette Beers, Chief of the Diagnostic and Surgical
Devices Branch of the Division of Ophthalmic and EMT Devices.

I\'m going to turn this over to Jan Callaway, the team leader, but
before I do, I wanted to really say thank you, Jan and the rest of the
team, for getting this together and to panel so quickly and also to the
cooperation from the sponsor for meeting some very tight deadlines.

Jan?

MS. CALLAWAY: On November 2nd, 1998, an original PMA application,
P970043, the LADARVision Excimer Laser System, received approval for its
argon fluoride excimer laser. The device was intended for use in
photorefractive keratectomy, PRK, to correct mild to moderate myopia
with astigmatism. On May 9th, 2000, the laser was approved for the
expanded indication of laser-assisted in situ keratomileusis, LASIK, for
myopia with or without astigmatism, and on September 22nd, 2000, for
LASIK for hyperopic astigmatism and mixed astigmatism. The laser uses a
small diameter pulsed ultraviolet laser beam to reshape the cornea and
incorporates an infrared eye-tracking system.

In Supplement 10, the sponsor\'s requesting approval to further expand
the indication statement for wavefront-guided LASIK correction for the
reduction or elimination of myopia up to 7 diopters with less than .5
diopters of astigmatism at the spectacle plane. In the clinical studies
supporting this application, the method by which the planned ablation
pattern is determined has been modified, not the ablation technology.
The pulse energy, firing rate, influence distribution at the treatment
plane, and eye-tracking hardware and software are the same as for
conventional LASIK treatments. In the previously approved system, the
ablation pattern was based upon manually entered manifest subjective
refraction data for sphere and cylinder. The CustomCornea ablative
shaping algorithm utilizes information that is obtained from a wavefront
measurement device. Wavefront sensing provides a detailed refractive
map, including sphere, cylinder, and higher-order aberrations, unique
for each eye. A computer file containing this information is transferred
to the treatment laser. The ablation profile is calculated directly from
wavefront data.

The FDA team responsible for Supplement 10 included Dr. Bruce Drum, Dr.
Malvina Eydelman, Dr. Gene Hilmantel, Dr. Dexiu Shi, Dr. Marwood Ediger,
Dr. Lilly Yue, Dr. Jean Toth-Allen, Ms. Mary Lou Davis and myself. Dr.
Drum will not present the areas in which your input is being requested.

DR. DRUM: Thank you, Jan.

Since we\'ve just gone over the submission in substantial detail and
we\'ve gotten an excellent presentation from the sponsor, I\'m not going
to go into specifics with regard to the study itself, but I\'ll mainly
concentrate on questions that we have that we would like the panel to
address.

Jan has just named the review team, and I\'ll go right to the
introduction. Dr. Eydelman\'s clinical review did not come up with
specific clinical questions for the panel. The data appear to be
satisfactory with regard to basic safety and effectiveness, but this is
the first submission of its kind for trying to correct higher-order
aberrations, and so we have several issues that we would like to have
the panel address with respect to any special information that would be
required to evaluate the results of higher-order aberration treatment,
and for the most part, these will involve perhaps special analyses or
information that may be helpful in determining the proper labeling.

First, we\'ve already gone over this, the comparison study, but I\'d
like to remind the panel of the study and the issues that were involved
in it, and the comparison of the results showed that the Custom eyes
were slightly better than the conventional eyes in a number of aspects.
The higher-order aberrations increased less for the Custom eyes than for
the conventional eyes, and there were absolute reductions in aberrations
for a higher percentage of Custom eyes versus the conventional eyes and
that may be an area that would be beneficial to investigate further.
That would be information that patients might find useful in deciding
whether to have the procedure.

As George has already told you, we\'ve tried to find a way to evaluate
the higher-order aberrations that was interpretable in terms of more
people might be familiar with and relating the improvement of vision to
the equivalent spherical blur, and there was a little less than a
quarter of a diopter effective reduction according to the procedure that
they\'ve worked out.

Relative to preop, the postop contrast sensitivity was higher for Custom
eyes than for conventional eyes only by a small amount on average, and
so basically what I\'d like to ask the panel, what differences between
Custom and conventional outcomes are clinically under functionally
significant, given that the differences are typically small, and what
labeling claims would be supported by these differences? Also, are any
additional clinical data or analyses or criteria needed to evaluate the
relative effectiveness of Custom and conventional treatments?

I won\'t dwell on this. George has already given you a very clear
presentation of how higher-order aberrations are analyzed. One thing I
might mention, you can do RMS analyses of the overall correction or on a
term-by-term basis, and I guess the question there is is that an
adequate way to look at the effectiveness of reducing higher-order
aberrations or might we need some other additional methods?

Just some thoughts about the analysis of higher-order aberrations. The
functional significance is not always evident, but if you look at the
pictures of various Zernike terms of the higher-order aberrations, you
see different spatial patterns, that you have coma and you have
spherical aberration and then you have these other terms with little
scallops around the edge, and it\'s not always clear, it\'s not clear at
least to the general populous, what those mean in terms of vision. So if
there\'s a way that we can make that clearer or find out which
aberrations to pay attention to that would be helpful. Different Zernike
terms are the same. RMS may have different visual effects. That\'s been
alluded to earlier. Elimination of all aberrations may not be optimal.
There\'s evidence that some positive spherical aberration may be
beneficial for equivalent defocus or for accommodation or other visually
important functions.

It would it be beneficial to ask for an analysis of vision not assuming
that a zero aberration is optimal? There\'s also positive and negative
spherical aberration. Would it be valuable to separate the analysis of
how the spherical aberration is changing? Zernike parameters depend on
pupil size. When you do a Zernike analysis of higher-order aberrations,
the coordinate system is defined by the limits of the pupil. So if you
have a 4mm pupil, all of your Zernike terms are defined on a 4mm space.
If you have a 7mm pupil, they\'re defined on a 7mm diameter and the same
term will mean a different thing, and is there a way to take that into
account when we\'re evaluating the effects of correcting aberrations
assuming that certain pupil size ‑‑ when the pupil actually is taking on
a whole range of sizes in real life?

The last point. Can higher-order aberrations be compared to equivalent
defocus? We\'ve made a first step with the sponsor at trying to find a
way to relate higher-order aberrations to defocus, but you might have
some suggestions about how that could be improved. So the basic question
here is what information about measurement analysis and correction of
higher-order aberrations is needed in the labeling to inform physicians
and patients about the safety and effectiveness of CustomCornea
treatments?

One additional specific area that has already been addressed to some
extent is stability, refractive stability. We have a list of criteria by
which we define refractive stability for sphere and cylinder. I won\'t
read them all, but basically it\'s just making sure that the change of
refraction goes at least towards zero over time or that the rate of
change goes toward zero and that it ends up close to your target.

But most of these criteria, they don\'t directly address the kinds of
changes that are probably going to take place in higher-order
aberrations. In other words, if your higher-order aberrations are
changing, standard stability criteria will not detect that. You may need
special analyses, such as looking at changes in RMS over time, and that
raises a question of whether a reduction in RMS is adequate to define
stability or whether there may be changes taking place that RMS analysis
in insensitive to.

George Pettit has already given an answer to the question of whether the
stability of sphere and cylinder may interact with the stability of
higher-order aberrations and concluded that they were not helpful, but
I\'m not sure that we should take that as a final answer because he
based that on a correlation analysis of a fairly small number of eyes.
So I\'d still appreciate your input about whether we need to relook at
our stability criteria in the case of a higher-order aberration
treatment.

I guess that\'s all I have for now. I have some additional slides with
individual questions on them for when the panel is making a decision.

Thank you.

DR. WEISS: Are there any questions from the panel for Dr. Drum or any
other members of the agency on the presentation?

Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Just one clarifying question about the RMS. When you
get term-by-term RMS, is that essentially equivalent to the absolute
Zernike coefficient or does it also include information about the basis
functions?

DR. DRUM: Well, I can\'t give you a really confident answer here, we
have people that are more expert than I am on the Zernike analysis, but
it seems to me that if you look at the RMS of an individual Zernike
term, the shape of that term is defined. So a reduction in RMS for that
term would probably be a fairly strong indication that that variability
or that the size of that term is reduced.

Having said that, though, Zernike analysis is a polynomial expansion,
and so all these terms are just picking out the part of the variation
that fits the shape of that term, and they\'re all approximations and so
you can\'t get a really good description of what\'s going on without
looking at more terms. But perhaps Steve or Arthur would have a more
intelligent answer.

DR. WEISS: I think we probably can deal with that in deliberations, and
if there are no other questions, I want to thank you, Dr. Drum, for your
presentation and thank the FDA for such a clear review.

We have five minutes for additional comments from the sponsor, if they
would like to make them, they can come up to the podium, and then we
will break for lunch.

Does the sponsor have any comments they would like to make? I take that
as a maybe, a firm maybe. That\'s a yes.

DR. PETTIT: Just real quick.

We were able to pull one answer to one question that was asked earlier.
For the spherical eyes in the Custom cohort, the mean pupil mesopic
pupil diameter was 5.63mm with a standard deviation of .89, and for the
comparative 50-eye conventional cohort, it was 5.78 plus or minus .081.

DR. WEISS: Can you repeat that again?

DR. PETTIT: Okay. The mean pupil diameter for our primary cohort was
5.63 in the Custom eye and 5.78 in the conventional eyes, and the
standard deviations were .89 and .81 for those two groups, just to
answer a question that came up earlier.

DR. WEISS: Fine. No questions on our side. Questions on their side?

DR. BULLIMORE: Can you just remind us what the optical diameter is,
optical zone diameter?

DR. PETTIT: In all treatments, the optical zone diameter was 6.5mm.

DR. WEISS: If there are no other questions from the sponsor, Sally
Thornton has two announcements.

MS. THORNTON: I have just two things. There is a FedEx package at the
registration desk for a Helen Laurielle, L-A-U-R-I-E-L-L-E, of Staar
Surgical, and the panel members and the FDA staff have reservations at
the Tack Room of the hotel restaurant.

DR. WEISS: Important announcements as we\'re going to break for lunch.
So I have 12:00 now. I would ask everyone to be seated and ready to go
at 1:00.

(Whereupon, at 12:00 p.m., the meeting was recessed for lunch, to
reconvene at 1:00 p.m.)

[AFTERNOON SESSION]{.underline} (1:02 p.m.)

DR. WEISS: Could the members of the panel please be seated?

MS. THORNTON: Before we start, I\'m doing what you told me to do, I have
an announcement I\'d like to make to the panel, the sponsor, and the
FDA, who may be wanting to speak in the microphone. The transcriber and
summary writer and the audio folks have asked me to ask you to please do
not be any farther away from the head of the microphone than four
inches. It can\'t capture it if you don\'t get within that short space
and please speak directly into it. They can\'t get it when it\'s like
this. They can\'t get it when it\'s like that either. So I\'d just like
you to be aware of this, so that we can get an accurate transcription
and make their job a lot easier. They can\'t turn up the audio but so
far or it\'ll start to squeal. So please help them with this.

Thank you.

DR. WEISS: Okay. Well, we will begin again at this point with the
committee deliberations and the primary panel reviews. We\'re going to
start with Dr. Andrew Huang for his review.

Thank you.

DR. HUANG: Good afternoon, ladies and gentlemen. I\'m sure by now the
members of the panel and the sponsor should have my written review. So
I\'m not going to repeat what I have written, but basically I would like
to address to the public as well as the panel of the members, the
members of the panel, that there are some philosophical points as well
as some specific questions.

First, as we all know, the existing refractive surgery, such as LASIK or
PRK, can treat sphere and cylinder, and it doesn\'t really treat
higher-order aberrations. However, with this new wavefront technology,
we can now measure these high-order aberrations and begin to treat them.

Nonetheless, whether this technology will work in practice is another
question all together. As we all know, vision is really a dynamic
process. The patient will have dynamic variations and a patient may have
a different accommodative state throughout the day and throughout the
week, and using a wavefront technology to correct the vision at one
given point, as indicated by the sponsor, may not be adequate for those
patients, especially for those people that need night vision or the
patient performing the task in the dark.

There\'s a common statement that we often heard for this kind of
patient. That is, is 20/20 for 10 to 20 years better than 20/15 for two
to five years using that new technology?

Suffice it to say that about 90 percent of all aberrations are low-order
aberrations. Either they are sphere or cylindrical, such as myopia,
hyperopia, or astigmatism, and I believe the conventional or the
existing LASIK is probably adequate for most of these patients.

There are up to about 10 percent of the patients have much higher-order
aberrations and these patients probably will benefit greatly from the
use of this wavefront technology. So therefore, using this technology
will enable us to pick up these specific aberrations and to treat them
accordingly with confidence and also ensure the safety as well as the
quality of vision.

For patients with good preexisting low refractive error or good preop
vision, they may already have their very, very minimum aberrations and
potential benefits of the Custom wavefront-guided surgery probably will
be very, very small. They do not necessarily need better supervision and
the wavefront technology at best is probably for us to ensure the safety
as well as the quality of their vision. However, if we can selectively
use the technology to select the patients with specific amounts of
higher-order aberrations and treat them accordingly, the benefit of
custom ablation probably can be further justified.

Specifically for the sponsor and also for the public, I found the study
is very well conducted and the sponsor should be commended for their
efforts for this accountability of their entire dataset.

However, the small cohort has been discussed earlier today. There are
only 179 patients and specifically that in the 70-data cohort, there
were only 19 patients ranged from zero to -1 diopter and nine patients
went from -6 to -7 out of these 426 eyes. For the effectiveness data,
out of 139 eyes, there were only one eye in the group of zero to -1
diopter and four eyes in the -6 to -7 diopters. So I found this small
number of data is unacceptable or insufficient for this review.

There\'s also a general trend towards undercorrection, and we have
discussed earlier and also answered by the sponsor regarding the future
management of this treatment, but I would like to raise the question to
the panel members, if we should need further data before we recommend
final approval?

The third point is that in both groups, the conventional treatment
versus the CustomCornea treatment group, showed a reduction of total
aberrations. As expected, both groups substantially reduced the preop
low- order aberrations. Nonetheless, high-order aberrations were
generally increased and we have discussed this earlier today. The
CustomCornea did not result in less overall higher-order aberrations
than the conventional treatment. Specifically, the spherical aberrations
is only increased by 22 percent in the CustomCornea and by about 80
percent in the conventional LASIK, and I\'m not aware of the clinical
significance of this kind of difference.

The fourth point is that the inverse correlation was the low contrast
best-corrected visual acuity and the total higher-order aberrations was
at best modest. The correlation coefficients was less than .5. There was
no strong evidence suggesting that the higher-order aberrations were
further corrected with sustaining effect on the major improvement by
CustomCornea.

Specifically, about 20 percent of the patients had decreased vision
greater than one line in their best-corrected visual acuity, suggesting
that no additional treatment was really benefit from this CustomCornea.

The fifth point is that the patients on postoperative questionnaires,
there were 40 items raised. There were seven of them, 10 percent or
greater of the patients, answer was worse or significantly worse than
their preoperative finding. I found it was significantly higher
percentage of the dissatisfied patient in this cohort and maybe
preoperative and postoperative counseling should be included in this
type of clinical study.

And finally, I would like to emphasize there is no data in this current
submission that on the long-term stability beyond six months and
there\'s also no follow-up on the retreatment, even though there was
some anecdotal data. So therefore, the long-term effect and the
necessity of retreatment cannot be ascertained in this proposal.

Thank you.

DR. WEISS: Thank you, Dr. Huang.

We will have our second panel reviewer, Dr. Bradley, speak.

DR. BRADLEY: Thank you.

I\'d perhaps reiterate what some of the other panel members have already
said today, and that is the presentation by the sponsor and the data
provided by the sponsor were really excellent in my opinion and that
helped with the review of this PMA.

I\'m going to cover several issues here, start out with the standard
ones that we on the panel are concerned about, efficacy, stability,
safety, and using standard criteria for these, before really getting
into the specific issue associated with the current technology and that
is one of aberration correction and obviously the challenging issue of
how to label this product.

As most of us in the room are aware, the level of understanding of the
optics of aberrations and the visual ramifications of these aberrations
is imperfect and the level of expertise in this room is high. For the
average physician, the average patient, this is going to be a huge
challenge and one that the FDA and the sponsor and the panel must come
to some conclusion on.

By the way, there\'s something else going on today, and that is I\'m a
Mac user, and the question is can a Mac user effectively use a PC?
There\'s an ad on TV at the moment that says that PC users can convert
to Macs quite easily. So this is a test of whether a Mac user can
convert to a PC. So let\'s see what happens. Let\'s try that button.
Great.

I put this slide in because I think it\'s very important to get an
overall picture of what\'s going on here. First of all, there are really
two innovations here and they have been blended into one as the
discussion has gone so far today, and I wanted to separate them out.
First off, the current wavefront-guided LASIK procedure is employed what
I call our projective optical measure to control the laser ablation.
This is unique in that previous approaches have always been to employ
subjective refraction, and it\'s worth pointing out that prior to this
technology, typical objective measures of optical status of the eye, for
example, autorefractors, are used only as approximations, later to be
refined by subjective refraction. So going straight to guiding the laser
using an objective device is really novel in and of itself, irrespective
of the fact that they\'re trying to correct high-order aberrations.
They\'re using this to try and correct regular sphere and cyl, and I
think that\'s an innovation to be fully aware of.

Second, of course, is that in this particular device, they\'re trying to
go beyond correction of sphere and cyl to correct the higher-order as
they\'re known aberrations. This poses a unique challenge again, not
because there\'s anything uniquely different about a higher-order
aberration versus a lower-order aberration, but primarily because the
higher-order aberrations are much, much smaller. So the challenge here
is can they correct very small aberrations, very small imperfections in
the optics of the eye, rather than the larger myopias or hyperopias that
they\'re typically trying to correct? So I think those are two types of
innovations here and both are worthy of our appreciation.

The efficacy. A couple of criteria we always examine for efficacy.
Basically, this is a procedure to correct refractive error. That\'s why
the patients are in there. How well does it do? Obviously the way to
examine that is to look at the postprocedure refractive error
distribution, and I\'ve always preferred to see the data in this format
as provided by the sponsor and we saw it this morning. This is a
scattergram of post versus pre refractive error in terms of spherical
equivalent, and this is meant to be the Y equals X line. That is,
achieved versus attempted. I\'m sorry. This is achieved versus
attempted, and the data should fall along this line, solid line in the
middle, if the achieved equals the attempted, and these people will end
up emmetropia. I think the attempted was to correct for emmetropia.

This distribution looks good, if not better, than many we\'ve seen
before, many published in the literature for other lasers, other
procedures. I just highlighted a couple of these outliers up here who
have been between 5.5 and 6.5 diopters of myopia, clearly undercorrected
by up to about 2 diopters, it appears, and again that\'s been commented
on already today. By and large, this dataset looks as good, if not
better, than what we\'ve seen before.

The FDA actually set some standards for this or some guidelines. They
wanted to know how many eyes have less than or equal to half a diopter
refractive error post-LASIK. The FDA requires at least 50 percent, and
in this PMA, we see 75 percent. Likewise, for 1 diopter of post-LASIK
refractive error, the FDA requires that at least 75 percent achieve
this, and in this PMA, it\'s almost 100 percent, up to 96 percent. So
that looks very good. It clearly meets the FDA guidelines, comfortably
meets them.

Other effectiveness criteria is the post-LASIK uncorrected visual
acuity, and as we all know, this will correlate highly with the
post-LASIK refractive error, and the FDA sets a standard here that 85
percent must have an acuity better or equal to 20/40. It turns out 99
percent of these patients had that. The sponsor also provided us with
this criteria. What percent of the patients had better or equal to 20/20
acuity? It turns out 80 percent of these had that. Remember this is
uncorrected, and I think those 80 percent probably consider the
procedure to be effective.

Issue of stability is always there, primarily sort of a historical
concern in that this sort of regression that was very large in the early
procedures, slowly regressions are becoming smaller and smaller, and
this is the classic sort of plot. This is the refractive error pre is
the mean. This is post at one month, post at three months, post at six
months. The difference between the three- and six-month data is
basically three-hundredths of a diopter. Essentially, it achieved
perfect stability in terms of the mean.

We\'re always interested, though, about outliers as opposed to just the
mean, and the FDA actually has some guidelines on that. They want less
than 5 percent to drift by more than 1 diopter and between the
three-month and six-month, and it turns out none of them did in this
particular PMA. So again, I think they\'ve established stability quite
nicely.

Safety issues. There are lots of people in the room far more qualified
than myself to assess adverse outcomes and other types of what I might
term pathological outcomes that would be safety issues. I\'ve
concentrated here on what I consider to be the general overall safety
guideline and that is best spectacle-corrected visual acuity, the idea
being is that if the optics subsequent to the procedure are in good
shape, you ought to be able to correct this patient to have very good
acuity. So this is our benchmark safety criteria, and again the FDA has
certain guidelines for this. They want postop, the best-corrected, how
many patients are going to be allowed to be worse than 20/40. The FDA
guideline is only 1 percent. There was zero in this PMA. Also, the FDA
says, well, how many can lose greater than two lines? They allow 5
percent. Turns out it was less than .5 percent in this PMA. So they\'re
exceeding the FDA guideline by a factor of 10.

Some other data which I thought were quite important on this issue, the
best spectacle-corrected visual acuity preop, what proportion of the
eyes had better than or equal to 20/20 acuity? It\'s 99.3. Postop, 99.5.
Basically the same. Interestingly, postop, best spectacle-corrected
visual acuity, better than or equal to 20/25, was every single eye, and
so with this criteria, clearly the PMA has demonstrated safety.

Now, let\'s move on to aberrations. This is a tricky area. So let\'s
just summarize a couple of points. The wavefront-guided LASIK results in
lower levels of higher-order aberrations than conventional LASIK. This
was the comparison cohort that we saw. Some concern about the sample
size here, but clearly when you compare the conventional against
wavefront-guided, wavefront-guided eyes ended up with lower levels of
higher-order aberrations than the conventional LASIK. This improved
outcome of wavefront-guided LASIK may and is likely to account for the
small differences seen in best-corrected visual performance when
compared to the conventional cohort.

Some question has been raised this morning about, well, how significant
is this reduction in higher-order aberrations, and I\'m not sure that
the scientific literature can answer that question, and the sponsor\'s
data may have to suffice to answer this, and what we saw this morning is
that there were these slight improvements in the best-corrected visual
performance of the wavefront-guided LASIK group compared to the
conventional cohort, and again that is probably a reflection of the fact
that the higher-order aberrations were lower in this wavefront-guided
group. Very important thing to point, though, Number 3, wavefront-guided
LASIK procedure increased the level of higher-order aberrations relative
to the preop levels. This is an extremely important point to keep in
mind. So I think those are the three main points that I\'d like to make
about aberrations.

Let\'s move on to labeling, and I personally think this is the greatest
challenge for us today, and I\'m not sure I have any clear conclusions
in my own mind at this point. So let\'s see how the afternoon goes.

Number 1. I think it must be clearly stated that wavefront-guided LASIK
does not reduce the level of higher-order monochromatic aberrations
relative to preop. Thus, in no way can wavefront-guided LASIK be thought
of as a procedure to correct higher-order aberrations and render
super-normal vision. This is an extremely important point.

Number 2. I do believe, though, the sponsor can comfortable promote this
new procedure as a new LASIK procedure that is an improvement, albeit
slight, over previous conventional LASIK, and I think those are issues
that need to be addressed in labeling.

More on labeling. Now we get into really the subtleties, and I say that
to, let\'s say, we\'re stepping down on the importance of the issue, but
I think this is an important one. The sponsor in the PMA uses the term
\"CustomCornea\" and I think the idea is a very attractive one, the idea
being that as a patient, you go in to have your eye examined and using
the wavefront measurement device, they are able to identify that your
eye has a certain level of aberration and that includes myopia,
astigmatism, spherical aberration, coma, and a variety of other terms,
and it is now possible to sculpt the cornea to correct for your inherent
optical problems, and therefore they\'re creating a Custom cornea to
correct for the optical problems of your whole eye. It\'s a very, very
attractive idea, and as the sponsor knows, in my original review, I
challenged them to present some evidence that they had really achieved
this.

Now, this challenge would never have originated if the post-LASIK
aberration levels were lower than the pre, and if that were the case, we
would have to conclude that they had corrected some, if not all, of the
existing aberrations in the eye. However, as we now know, the postop
monochromatic aberrations are actually larger than the preop. So it
becomes a slightly tricky issue to establish whether or not the inherent
aberrations of the eye have indeed been corrected. So given that
complication about trying to ascertain whether or not the aberrations of
the eye have been corrected, a discussion really revolves around some
correlational analysis, and there are two types of correlational
analysis that can be done and the sponsor has done this.

One is pre versus post correlation, the idea being a very, very simple
one, that if one had corrected the inherent aberrations of an eye, the
aberrations that exist postop would be unrelated to the aberrations that
exist preop. They would not correlate and that\'s what I said here. The
pre versus post correlation you expect to be zero if individual
aberrations, individual eye aberrations are perfectly corrected. You
expect it, however, to be a correlation of one if they are left
uncorrected. That is, if you have a certain level of aberration pre, you
would have it post, and so we\'d expect the correlation of one.

Interesting thing is that that correlation of one would only be expected
if there is no variability in the measurements. That is, there\'s no
test/retest variability.

If there is test/retest variability, then this correlation of one would
drop to somewhere between zero and one. That is, in the end,
correlations between zero and one could be due to partial correction of
the inherent aberrations of the eye or simply due to test/retest
variability, and it turns out that\'s where the data lie, and the
largest correlations were observed here for the oblique secondary
astigmatism, R was .46 for spherical aberration, it was .45, and this is
just a scattergram showing the oblique secondary astigmatism, and
there\'s the regression through the data, and again if the aberrations
had not been corrected, but there was test/retest variability, we would
expect a positive correlation with an R of less than 1.

So we\'re left not knowing whether this correlation, this positive
correlation is due to either a failure to correct the aberrations of the
eye or is simply, yes, due to a failure to correct the aberrations of
the eye or only partial correction, and in order to assess that, we
really need to examine the test/retest variability to know how effective
the CustomCornea correction is, and I would certainly defer to our
statistician to assess how we formally do this, but I think that can be
done.

The second correlation or analysis that the sponsor performed, which I
think was really quite instructive, and that is to correlate the
intended aberration change versus the achieved aberration change. Now,
the question here is very simple. If you\'ve achieved what you intended,
you can get a very good correlation, expected correlation of plus one,
if the CustomCornea is perfect and there is no test/retest variability
and an R of zero if it is completely ineffective.

Well, it turns out that you get an R of greater than .5 for the third
order coma and trifoil aberrations, indicating that the intended was
highly correlated with the achieved, indicating that some successful
correction has occurred. Interestingly, the fourth-order aberrations,
the Rs tended to be quite low, less than .5, indicating perhaps that
they have not been effectively corrected. One interesting comparison can
be made, if you compare what I\'ve just shown you, and that is intended
versus the achieved change, if that R is less than the pre versus post
R, then I think we have evidence that the correction has not been
achieved, and it turns out that was the case for Z4 zero and Z4 -2.
Again, the statistician might be able to comment on that. So I think the
evidence that wavefront-guided LASIK does a better job of correcting
third-order than fourth is definitely there and there is some question
of whether it corrects the fourth-order aberrations at all.

The final point, I think, visual benefits for correcting higher-order
aberrations. This is a tricky one, very tricky one. It\'s tricky in the
sense that science is a bit behind the sponsor in this case. We don\'t
know all of the visual ramifications of monochromatic aberrations. Those
data are now being collected in my lab and in other labs. So we\'re sort
of at the cutting edge of our scientific knowledge here, going a bit
beyond it really.

A couple of points. Wavefront-guided LASIK is designed to correct
monochromatic aberrations, but vision is in a polychromatic world. This
is a very important point. So even if you correct all the monochromatic
aberrations, you do not have perfect vision because you have chromatic
aberrations. Just to put things in a bit of a perspective, Thibos and
colleagues looked at a large sample, looked at higher-order
monochromatic aberrations and found that they gave an RMS that is less
than a quarter of a diopter. So the effects in dioptric terms, just like
the sponsor has suggested, are less than a quarter of a diopter. That\'s
sort of an equivalent based upon RMS, and I think Dr. Drum questioned
whether an RMS comparison is appropriate.

Yoon and Williams recently published very nice data where they used
wavefront correction in the lab, not on the cornea, they used an optical
device to do this, and I\'ve said perfectly correcting for higher-order
aberrations. When they did this, again correcting monochromatic
aberrations, but they\'re in a polychromatic world, they still found an
improvement in visual acuity by a factor of 1.4 which is .15 log units
or 1.5 lines on a logMAR chart, should convert a 20/20 to a 20/14, and
this is basically the best you can possibly expect to achieve by
correcting monochromatic aberrations.

It\'s also worth pointing out there are some possible concerns that
correcting monochromatic aberrations might compromise vision. This is
again sort of at the edge of what we know here, but there has been some
indication that aberrations are valuable in helping us control
accommodation and certainly if you examine laser safety standards, these
are based upon point spread functions in the eye that are spread out
because of aberrations and therefore the actual flux density at the peak
of the point spread function is reduced. If you correct the aberrations,
these flux densities will go up because the point spread function will
become smaller. So there\'s some general concerns about that.

I\'ll skip over that. Just in summary, the wavefront-guided LASIK system
that we\'re examining here has met the efficacy, stability, and safety
guidelines used by the FDA, and it appears to be an improvement over the
already-approved conventional LADAR System. So I think in that sense,
that is a pretty clear result. The questions regarding labeling, how
well does the wavefront-guided system actually correct the monochromatic
aberrations of individual eyes? This is still unclear to me, and again
the sponsor and all of us really face the difficult challenge of
communicating the potential visual benefits of introducing less
higher-order aberrations.

Thank you very much.

DR. WEISS: Thank you very much, Dr. Bradley.

Dr. Bandeen-Roche, did you want to comment on any of the statistics that
were referred to?

DR. BANDEEN-ROCHE: This is Dr. Bandeen-Roche.

My overall comment would be that I agree with Dr. Bradley\'s
presentation. I find his discussion of the statistics to be sound.
Certainly his point about the correlation being dependent both on the
strength of the actual relationship measured without any error and of
the degree of test/retest reliability is right on, and there are
statistics that can at least model the degree of attenuation in the
relationship from the true relationship if one does know the test/retest
reliability.

Then finally, in terms of the point of the correlation between intended
and achieved with respect to the fourth-order being less than the
correlation between pre and post RMS, I would certainly agree that it\'s
inconsistent to cite one as evidence for no relationship and the other
for evidence of a relationship, given that the directionality is reverse
than what you would expect if that were true.

DR. WEISS: Thank you.

We\'re going to proceed with the panel discussion of this PMA, and I
would suggest that we go through the FDA questions one by one. Thank you
very much, Dr. Drum, if you\'d be so kind as to show us the question,
and we can begin the discussion on those. We\'ll be starting with
Question Number 1.

DR. DRUM: Let me see if I can open this.

DR. WEISS: Perhaps I can read this while we\'re getting it on the board
and we can start the discussion.

The first question, which is on page 5 of the handout from the FDA, is
what differences (if any) between Custom and conventional outcomes are
clinically and/or functionally significant? What labeling claims are
supported by these differences?\" So what differences are clinically
significant between Custom and conventional outcomes?

Would anyone like to start the discussion of this?

DR. BULLIMORE: I\'ll take a shot. Mark Bullimore.

Just to reiterate what Dr. Bradley said, I think the sponsor has shown
fairly convincingly that the objectively measured aberrations with the
Custom algorithm device are significantly less than those obtained with
conventional LASIK. The caveat, of course, is that both procedures
increase the level of aberrations over and above what you would expect
preoperatively.

DR. WEISS: How would you address the question functionally significant?

DR. BULLIMORE: I was hoping somebody else would address that. I mean, if
you want me to put something into words, I would say that in the
labeling and patient information booklet, that these demonstrated
improvements in the aberrations over conventional LASIK may lead to a
modest improvement in some aspects of patient\'s vision.

DR. WEISS: Sufficiently nebulous.

DR. BULLIMORE: Thank you. That\'s high praise.

DR. DURRIE: Are you running for office next?

Dr. Matoba?

DR. MATOBA: This patient information booklet that\'s in our ‑‑ is this
the updated version of the patient information booklet? Because all it
says here is under \"What Are the Benefits of CustomCornea LASIK?,\" all
it says is, \"CustomCornea LASIK surgery may reduce overall
nearsightedness. CustomCornea LASIK may also reduce or eliminate the
need to wear glasses or contact lenses to see clearly.\" Is that all
you\'re going to claim then?

DR. WEISS: Someone from the sponsor can approach the podium and perhaps
give a succinct answer. It\'s actually quite a simple question. The
insert we have for patient information, is that the final insert that
was given to the FDA, and obviously we can ascribe some changes that we
would suggest, but I think Dr. Matoba wanted to make sure that there
wasn\'t anything more updated in terms of what you were going to convey
to the patient.

DR. MATOBA: Because if that\'s all they want to say, I don\'t think we
necessarily have to suggest that they say more.

DR. WEISS: Yes, please?

DR. PETTIT: Okay. The version that you have, I understand, was before
the latest round of response to deficiencies, and I guess we were
waiting for feedback from the agency and from the panel as to what would
be appropriate beyond those very simple remarks to put in there.

DR. WEISS: Fine. Thank you very much.

So we have Dr. Bullimore suggesting that we put in further comments
elucidating the potential advantages and Dr. Matoba suggests perhaps we
should leave things as it is in the present insert.

Dr. Bullimore?

DR. BULLIMORE: And a philosophical question for the panel is whether we
think there should be an attempt to describe and demonstrate to a
patient what the benefits might be and include fancy diagrams and
simulated eye charts or whether, you know, we should steer the agency
and the sponsor towards some simple statements about, you know, proven
superior optical quality that may lead to some modest benefits, visual
benefits in certain conditions.

I mean, we can go either way, I see it. We can keep it very nebulous, I
think that was your word you used to describe my previous statement, or
we could make the suggestion that, you know, there\'s a couple of
chapters out of an optics and vision science textbook included in the
patient information booklet.

DR. WEISS: You know, I\'m going to ask actually just a simple question
to the panel just in terms of polling panel members. If you could raise
your hand, if you believe that CustomCornea ablation has a clinically
and/or functionally significant improved outcome over conventional
LASIK? Why don\'t we start there? And then after that, we can decide how
we might pen that.

The members of the panel, who here, if you could raise your hand, if you
feel from the data presented that Custom ablation has a clinically or
functionally significantly improved outcome over conventional treatment?

(Show of hands.)

DR. MATOBA: I think it may, but I don\'t think we\'ve got ‑‑

DR. WEISS: Well, let\'s just vote this and discuss it.

DR. BULLIMORE: Is this a straight yes or no?

DR. WEISS: Just a straight yes or no. Just sort of a bottom line.
You\'re a maybe. We can do a maybe if you want to, but let\'s just do
the yeses right now.

(Show of hands.)

DR. WEISS: So we have three yeses. Okay. Four yeses, and consumer and
industry can voice their opinion as far as this goes.

How many would vote maybe?

(Show of hands.)

DR. WEISS: Okay. We\'ve got six maybes.

MS. THORNTON: Five.

DR. WEISS: We have five maybes, and how many feel that it has no
benefit? How many are nos?

(Show of hands.)

DR. WEISS: One no, and we\'ve got a total here of 10. Okay. So that
might indicate why there might be some discussion on this one. So
basically, four of us at this point in the discussion feel that there is
definitely a significant improvement and five are not sure and one does
not think there\'s a significant improvement and clinical or functional,
clinical or functional as opposed to anything else. So then, the next
question would be then how to scribe that opinion.

Dr. Grimmett?

DR. GRIMMETT: Michael Grimmett.

Just reiterating a point Dr. Matoba made earlier, in the absence of
seeing the comparison data, for example, on the symptom charts between
CustomCornea and conventional patients, I\'m really unable to answer the
question regarding is there any clinical or functional? Certainly from a
patient\'s perspective, I would want to know that. That\'s why I can\'t
say for certain with the question clinically or functionally is it
better, notwithstanding the data that we\'ve seen regarding contrast
sensitivity and these other measures that we see some improvement over
conventional LASIK. I don\'t know if it makes a clinical difference. I
don\'t believe I\'ve seen the data that convinces me of that.

DR. WEISS: Dr. Bradley, and then Dr. Maguire.

DR. BRADLEY: Just a general comment that as optical quality gets better,
at that point, one can only improve things by small increments. At that
point, the opportunity for dramatic visual improvement is basically
eliminated. So posing the question using traditional clinically
significant or functionally significant terms may not be appropriate
when we get into wavefront correction because we are dealing with very
subtle effects and we\'re looking for small improvements that may only
be observable when you look at population means, but for each individual
patient and what\'s the clinical significance of, let\'s say, half a
line improvement in acuity, I think we\'d all argue probably very
little, but if that\'s what the procedure does, then it is a significant
improvement.

Can you argue that it\'s clinically or functionally significant? I think
that\'s the point.

DR. WEISS: I think we would probably want to get the opinion of the
consumer rep, but I personally would believe that it would be important
to convey that to the patient to counter any claims of super-human
normal animalistic eagle vision, et cetera.

(Laughter.)

DR. WEISS: So Glenda?

Ms. Such, do you have any opinion from a consumer standpoint, what do
you think the consumer would want to know or have conveyed to them when
they\'re trying to decide whether they should have customized treatment?

MS. SUCH: Actually, I\'ve got quite a lot to say, only because I\'m
sitting here and have a version of it up right now and am reading
through, and because this is the next, well, seventh generation of this
particular thing, that a person who\'s coming in new to this, not having
been in Version 1 through 6, that the patient who\'s getting this is
going to, by the wording in the pamphlet I\'m seeing so far, is going to
feel as though this is the new, the improved, and is resolving all the
issues that were causing the symptoms or causing the bad effects before.

There\'s a lot of wordage in the particular pamphlet that we have
that\'s talking about, you know, what exactly is causing the problem
with the vision and all this stuff. When I first started reading this, I
thought, wow, the sponsor really deserves a lot of credit for this
because it\'s really educating people, and then there\'s like this
quantum jump to because of the eye movement and there\'s eye movements
in every single person that they did, there was 100 percent of the
people had eye movements, and then there was another jump, you know, to
say that this would resolve this and this would then be able to make
sure this didn\'t happen anymore, and that type of wording, although
accurate, is going to lead people to think that, oh, well, you know, I
know people that had this surgery. They had some problems, but it was
probably because of that, and you are faced with people who are thinking
that this is going to give them the ability to not have to wear glasses
again or any form of glasses, and I\'m seeing people that that\'s not
true on just in my work experience, seeing people, and they have been
given the impression that they are going to get results so they don\'t
have to wear any eyewear at all, and you know, there\'s some phrasing in
here that because we\'re all in the field, we\'re so used to hearing the
words that we get caught up and everybody knows what they mean.

I mean, refractive error is such a common phrase among us, that it was
like duh, but in the same sense, most people when you say to them, you
know, that it\'s going to make it so perhaps if the surgery has a little
problem, that you might have a slight increase in your refractive error
and you may have to have a little difference in your glasses, they
don\'t really know what that means. They don\'t mean that the reason
that they got this surgery in the first place was because they felt that
glasses were too thick and now they\'re going to have even thicker
glasses.

There\'s phrasing like that that\'s within here that\'s a little bit
concerning to me. The time that\'s spent in going over, you know, that
the eye is like a camera with a film, I always liked that for most
consumers because most consumers are not as high end as we are in
knowing about things and need analogies, but you know, it suddenly does
this jump again. It does a jump into the scientific. If you\'re going to
start that way, finish that way, and I think that, you know, you need to
be honest about that this is a cosmetic surgery that is going to allow
you to perhaps not have to wear glasses, and if you do have to wear
glasses, that they may be less, you know. They may not have to be as
strong, and I think some of the wordings, I was deeply moved by some of
the people that talked about, you know, issues around dry eyes, that
there\'s phrasing all through here that\'s not thorough.

DR. WEISS: Actually, some of that, we will get to when we talk about
additional labeling.

MS. SUCH: Okay.

DR. WEISS: What I\'d like to do right now is confine this to the first
question, which is specifically, whether the differences in the outcomes
in this particular laser are clinically or functionally significant. So
from a patient standpoint, do you think any of the data that you\'ve
been shown today demonstrates to you that there are certain things that
are clinically or functionally significant, and if so, which are these
and what do you think a patient would want to know about?

MS. SUCH: I don\'t think ‑‑ clinically, yes. I think that a patient
should know that if we get some more data that actually supports what
has been proposed today, that it works better clinically, that they
would want to know that this would enable the surgeon to be able to do
this more effectively.

I think functionally, it\'s not saying a lot of difference. It\'s saying
that there\'s some difference, but I don\'t necessarily see that it\'s
produced a significant difference functionally.

DR. WEISS: Okay. Thank you.

Dr. Maguire?

DR. MAGUIRE: One obvious important clinical outcome is the level of
uncorrected visual acuity after the first event, and as Dr. Huang has
said and I concur and I think most of the other people here concur,
there\'s insufficient numbers in the higher levels of myopia that are
being requested for approval to say that this is as accurate and has
just as minimal scatter as for lower levels, and the reason that\'s
important are a few.

Number 1.

DR. WEISS: Actually, I think that\'s going to go to Question, perhaps,
Number 2. I still want to confine ourselves to the benefit of this over
conventional. We\'re going to get to ‑‑ we can discuss in a little bit
whether the range ‑‑

DR. MAGUIRE: Right. I agree and I understand what you\'re saying, but
describing the higher-order aberration correction, it\'s kind of
building a church. You have the basic lower-order aberrations are the
basic portion of the building, and then the higher-order aberrations,
that\'s the steeple on the top, and if you have a bad foundation, then
higher-order aberration correction doesn\'t really make a whole lot of
difference functionally.

DR. WEISS: Then what I\'d like to do is, I think you\'re speaking about
above -5?

DR. MAGUIRE: Yes.

DR. WEISS: What I\'d like to do, Leo, is at a little bit later down the
line, discuss the above -5 but get back, let\'s say, to the ‑‑ we can
even discuss less than -5 and that category where we\'re satisfied with
the postop uncorrected and best-corrected visual results.

Do you feel that there is an advantage, clinical or functional, of
customized over traditional?

DR. MAGUIRE: If the data shows that now. What it looks like is there\'s
a much higher level of subjective packings in the lower levels of
correction.

DR. WEISS: We\'re going to have Dr. Owsley speak, then Dr. Bradley, then
Dr. Burns, then Dr. Bullimore, then Dr. Bandeen-Roche.

Okay. Dr. Owsley?

DR. OWSLEY: I just want to go back to, I guess, emphasize my own
perspective that we can\'t really answer this question from the
patient\'s point of view because one of my colleagues on the panel has
already mentioned, we don\'t have the relevant patient report data to
answer that question.

The other way you get patient-centered functional information is by
looking at visual performance measures, and we don\'t have those either
in this study. So from the patient\'s perspective, I don\'t think we can
answer that question because the data aren\'t available.

DR. WEISS: What I would suggest is what could be put in the patient
insert, if the panel wanted, is something to the effect that there\'s no
evidence of a higher satisfaction rate in patients with customized
treatment versus conventional treatment.

Mr. Whipple?

MR. WHIPPLE: Yes. Jayne, very quickly, just as guidance, when we\'re
talking about labeling claims in that patient booklet.

DR. WEISS: Yes.

MR. WHIPPLE: Much of that will also spill over into advertising and
promotion as well. So just kind of keep that in mind when you\'re
talking about how you might craft words or something like that.

DR. WEISS: The other thing, and I\'ll defer to you, is if the data is
available at a later point from the sponsor, we could pen something like
that until such time as the sponsor gives us the data showing that there
is a higher satisfaction or that there was better visual performance in
those that they treated conventionally, excuse me, those they treated
with customized treatment and then I assume the patient insert could be
changed appropriately to reflect that.

MR. WHIPPLE: Yes, and that is an option for this panel.

DR. WEISS: So that, it doesn\'t have to be available this exact moment,
but unfortunately the panel has only to go by the data that we have here
presently.

Dr. Bradley?

DR. BRADLEY: Yes, I was really going to repose the question to Dr.
Owsley, and it seemed to me there are two types of data that could be
applied to this question, one being the performance data that we have,
low contrast acuity, high contrast acuity, contrast sensitivity,
photopic and mesopic, and we have that comparison data between the
Custom LASIK and the conventional LASIK.

What we do not have is the subjective reports in a comparison between
Custom and traditional and that\'s what I think people are asking for.
So I\'m going to bring us back to the data that we do have which is the
performance data.

DR. OWSLEY: Can I just clarify? I\'m using the word \"performance\" in a
different way. What the sponsor has done is measure visual function.
Okay. Visual performance data would be data from the performance of
visual IADLs, like a big one that comes before panel all the time, I
know, is driving.

DR. BRADLEY: Yes.

DR. OWSLEY: So we don\'t have that kind of data, and it\'s often those
types of instrumental activity of daily living problems that patients
are talking about when they say they have visual problems. They\'re not
talking about how they performed on the grating test or the letter
acuity chart. So I just want to clarify my remarks that it\'s that kind
of functional data we don\'t have and we most certainly have the
psychophysical data.

DR. BRADLEY: So that\'s what I was going to ask your opinion on because
we have those data. The sponsor has shown that with the Custom
procedure, contrast sensitivities are higher relative to conventional.
The various acuity measures tended to be slightly better with Custom
versus conventional.

Now, if presumably it would be possible to ascertain whether those
differences were statistically different, significantly different, if
that were the case, would it be reasonable for the sponsor to put in
labeling that improvement in vision is likely? How would it be possible
to accurately and meaningfully communicate these data to the patient in
the patient information?

DR. OWSLEY: Well, I can speak to the issue of driving. The contrast
sensitivity differences you see with the conventional technique and the
Custom technique are contrast sensitivity levels that are not in the
level of contrast sensitivity impairment that would impair driving
performance. So I don\'t think you\'re in the danger zone. So it\'d be
more an issue of whether just sort of personal preference, but there\'s
no data that suggests that contrast sensitivity levels in either of
these two groups would put somebody at risk, say, for crash involvement
or avoiding obstacles on the road, and I suspect the same thing could be
said about reading, that we\'re talking about contrast sensitivity
levels that are so high, that you\'re not going to get a big hit to
reading and reading and driving are really the two IADLs that people
mention most of the time when you ask them about visual IADLs.

DR. WEISS: Dr. Huang?

DR. HUANG: I just want to be a little bit different from my fellow
members, but I just feel that in that issue on the table is really the
technology and also that in the current safety and quality of the
vision, I don\'t feel that, you know, it\'s FDA or sponsor\'s
responsibility to say this is indeed revolutionary or this is
super-vision, you know, this is a new creation of the laser surgery.

I think our responsibility should be based on the data to review to see
if the claim is appropriate and to see if it\'s safe for the lay public.
So I would like to, you know, focus our discussion based on the data
rather than asking for more, especially in the subjective data, you
know. I feel that, you know, intrinsically, that LASIK patients, there
are millions of patients already have a LASIK surgery. So that LASIK
surgery is somewhat known already, and I do not feel that it\'s our
responsibility or our obligation to go back to check on if the new
technology ‑‑ basically what we are reviewing is just Custom software,
if it\'s improving. We are not improving our microkeratome. We are not
improving our surgeons\' technique. We are not improving on any of the
other parameters.

So I feel that, you know, subjective symptoms itself, you know, if we
need, we can use the reference population. We don\'t really need to go
back to another, you know, study because otherwise we have to go back to
ask for data for visual performance. We have to ask for then is the
visual performance of the patient after the surgery, are they really
better than the patient without surgery or the myopic patients more or
less likely to have a visual performance, you know, than the hyperopic
patient, and I think we are opening up a Pandora\'s box, you know, of
the questions that we probably would never be able to answer.

The key question here is that if this technology can reduce the
higher-order aberrations, obviously the answer is not there yet, but on
the other hand, is it safe or is the quality of vision better? In my
opinion, the answer is yes.

DR. WEISS: Dr. Burns?

DR. BURNS: Yes, I just wanted to comment on why I\'m firmly in the maybe
category, also, is that, we need to keep in mind that the level of
aberration differences we\'re seeing are things that will develop over
the next 10 years. In other words, your aberrations increase with age,
and so a lot of these variations we just can\'t know the answer right
now to what the long-term differences are. So I don\'t feel confident
saying yes, but I sure don\'t want to say no.

DR. WEISS: I guess that\'s a maybe.

Dr. Bullimore?

DR. BULLIMORE: Well, as someone who\'s maybe in the firmly camp, it\'s
interesting that Dr. Grimmett and I voted on opposite sides, but we were
actually in violent agreement on this one. I think we would both agree
that the aberrations are improved or less destroyed or whatever word you
want to use. We\'re questioning whether there\'s visual benefit as
assessed with the contrast test, and I\'m firmly with him on the issue
that there\'s been no demonstration that whether you think about it in
terms of satisfaction, whether you think about it in terms of symptoms
or activities of daily living, as Dr. Owsley likes to refer to them,
there\'s any benefit been demonstrated by the sponsor.

I think we could probably pretty quickly reach consensus on that and
work on crafting some verbiage that would capture those sentiments for
the agency.

DR. WEISS: That sounds good.

Then we\'re going to have one last comment on this question and then
maybe we can start some crafting.

Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: I keep thinking about validation, and this goes to
Dr. Bullimore\'s comment about the high-tech images that might appear in
the literature or Dr. Bradley\'s point about the first innovation. That
is, the objective measurement of vision. Are there validation measures,
validation data to support that such objectively measured vision
actually does appear better to the patient or whether the simulated
charts correspond in any reasonable way to what the patient might see?

DR. WEISS: In relationship to Dr. Bullimore\'s comment about symptoms
and satisfaction and the absence of data, the same sort of statement
could be used in the patient insert which is that there\'s no evidence
that the postop symptoms are decreased or that there\'s a higher
satisfaction rate, but I\'ll leave it to the panel to start the
crafting, if they would prefer another approach.

So Dr. Bullimore, did you want to start? I guess not from that look.

DR. BULLIMORE: I mean, let me give you a couple of little sound bites.

DR. WEISS: That means five seconds or less.

DR. BULLIMORE: Optically, you know, demonstratable optical benefits.
Subtle visual differences.

DR. WEISS: Okay. Sound bites without verbs. Okay. So we\'ll add verbs.

DR. BULLIMORE: Okay.

(Laughter.)

DR. WEISS: Both Dr. Grimmett and I do verbs. Can you repeat the first
one?

DR. BULLIMORE: Do you do them together or independently?

DR. WEISS: Separate verbs.

DR. BULLIMORE: Separate verbs.

And the thing I think we can all agree on is no benefit in terms of
patient satisfaction, functional performance, or ‑‑

DR. WEISS: I don\'t know if you could say functional performance. Well,
can you say it, because the contrast ‑‑ I think we should include the ‑‑

DR. BULLIMORE: Well, I mean, I\'m using functional in the Dr. Owsley
sense of the word rather than the contrast sensitivity sense of the
word, and this is where I think it\'s so important to get the verbs and
the nouns and the adjectives right.

DR. WEISS: So, you did the adjectives or the nouns. Maybe we want
someone to do the verbs separately.

DR. BULLIMORE: Dr. Owsley.

DR. OWSLEY: Are you trying to write this so the patient understands it?

DR. WEISS: Well, first, we\'re going to try to come up with a sentence
and then we\'ll go on from there.

DR. BULLIMORE: I\'d like to buy a vowel.

DR. WEISS: We don\'t have anyone spinning the wheel today, though.

DR. BULLIMORE: Thank you, Vanna.

DR. OWSLEY: When we use visual performance and those sorts of phrases
with patients, those are sort of scientific.

DR. WEISS: I think Dr. Grimmett is actually going to add nouns and verbs
and adjectives together.

DR. GRIMMETT: Mike Grimmett.

I think we have two concepts on the table, and I believe we have
actually consensus on them, as Dr. Bullimore suggested. Number 1, as Dr.
Owsley stated, there\'s no data to support higher functional
performance, and I put parenthesis, activities of daily living, such as
reading or driving, end parenthesis, or satisfaction rates in patients
with customized treatment. That\'s Issue Number 1.

Issue Number 2.

DR. WEISS: I think you\'d have to say customized versus conventional
treatment.

DR. GRIMMETT: Sure. Issue Number 2, Dr. Bradley stated, is that while
data can be provided, the psychophysical data can be provided that is
slightly better, such as low and high contrast visual acuity, low and
high contrast sensitivity measurements, the relation to satisfaction or
IADLs is actually unknown.

There\'s a theoretical benefit by all those visual functional
performance measures that were obtained. There is a theoretical benefit.
We all agree that we\'d like to see those better. We just don\'t know
for everybody.

DR. WEISS: Dr. Bradley, and then Dr. Maguire.

DR. BRADLEY: As a failed English language student in England, I\'m
always nervous at making concise statements, but does this work?
Wavefront-guided LASIK has demonstrated slightly superior optical
performance than conventional LASIK and minor improvements in visual
acuity and contrast sensitivity.

DR. WEISS: When you say optical performance, what do you mean? What is
optical performance?

DR. BRADLEY: Reduced monochromatic aberrations.

DR. WEISS: I would personally prefer to say that because optical
performance again makes me think I might see like an eagle.

DR. BRADLEY: Well, the reason I didn\'t say reduced monochromatic
aberrations is because as we saw this morning, even we needed a lecture
on what they were, and I think the patient would have no idea what they
are. So I was trying to think of a wording that would keep the flavor of
it for the patients and slightly superior optical quality, I think,
would be consistent with that data and minor improvements in visual
acuity and contrast sensitivity would also be consistent with that data.

DR. WEISS: Perhaps we could state that sentence. If you could restate
the sentence and then we could have a little discussion on the sentence
or if there\'s consensus on the sentence?

DR. BRADLEY: Wavefront-guided LASIK has demonstrated slightly superior
optical quality than conventional LASIK and minor improvements in visual
acuity and contrast sensitivity relative to conventional LASIK.

DR. WEISS: Any discussion? Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: This may really be better for the next section, but
in terms of the data that support the difference, I do have some
concerns about that cohort of 50 people, and I would feel much more
comfortable if the differences that have been shown were demonstrated in
data that were designed a bit more carefully. In other words, concurrent
randomization and blinding.

DR. WEISS: Actually, I think we\'re going to move on to the second
question fairly shortly. So we will put that in the second question, but
I personally have concerns on the use of that statement because I think
it\'s broad enough as to be, I can see that in one of the throwaways
very soon as to imply things that you don\'t mean by it.

Dr. Maguire?

DR. MAGUIRE: And that\'s why I think maybe a little something should be
added on to the end that says is rarely improved uncorrected vision to
20/10.

DR. WEISS: Dr. Owsley? Dr. Swanson?

DR. SWANSON: In terms of the sentence, we need to remember that 20
percent of people got worse in their low contrast sensitivity. So to
where the sentence is, it sounds like you\'re going to be better
afterwards, and we don\'t want the sentence to actually say that.

DR. WEISS: So you have concerns on the sentence. Dr. Maguire has
concerns.

DR. SWANSON: Yes. I like the sentence overall. I\'m trying to refine it.
I\'m not objecting to it.

DR. WEISS: Dr. Bullimore?

DR. PETTIT: I think relative to conventional LASIK needs to be in there.
That\'s all we\'re talking about and just as an aside, I was being a
little flip earlier, I would value Dr. Owsley\'s input on how best to
capture the activities of daily living sentence that she was advocating
there.

DR. OWSLEY: This is Cynthia Owsley.

I thought giving examples of reading and driving ‑‑ oh, that\'s what
they\'re talking about. Okay. Can I make a comment?

DR. WEISS: Yes, Dr. Owsley.

DR. OWSLEY: I don\'t want to change the subject. I just want to make
sure that this is discussed at one point. You asked a question as the
chairperson, what would you want to know if you were a patient and you
had to answer this question or question similar to this, and the
question that I think people like me talking as a consumer and other
people like I deal with who have myopia is am I going to be that rare
case that has the problem, and where in any of the patient information
‑‑ I\'m unfamiliar with the terminology. Is that in the labeling?

DR. WEISS: We can put that in the labeling.

DR. OWSLEY: Because some patients are going to be in the 20 percent who
lose one or more line of low contrast acuity. Some patients will not ‑‑
you know, maybe the higher myopes are not going to get the big benefit
from the reduced refractive error, and that, when you look through the
patient information packet, another issue is the dry eye. I have dry
eyes going in. A lot of women my age are interested in this procedure.
So where is that information presented? I just bring that up as a
general issue now.

DR. WEISS: It\'s not totally in there, but for example, I was going to
suggest that in the large dataset that we have, there\'s Table 35 that
has all the symptoms, whether it\'s slightly worse or severely worse.
Table 10 has the loss of best-corrected visual acuity, and there were
8.6 percent who lost one line, which is significant in my book, not just
the people who lost two lines, which was a very small percentage, and
Table 13 had the loss, the decreased vision and low contrast.

So depending on what the panel wants to do, some of those tables, all of
those tables, different tables or whatever can be put in that, but I
still want to try to finish off this particular question and try to put
it to rest so we can go on to the other questions.

Dr. Swanson?

DR. SWANSON: Yes, to finish the point I was making about, first of all,
we want to make it clear that that was an average. The other thing is in
terms of being super-vision, half of the people who went through this,
their uncorrected visual acuity afterwards was not as good as the best
spectacle-corrected visual acuity before. That\'s the number. We have 52
‑‑ it\'s 47.5, if you want to do it that way. Basically half of the
people ended up with uncorrected visual acuity after the operation that
was worse than the best spectacle-corrected had been, and if something
about that is in the sentence, then they understand we\'re saying it
might offer some improvements over conventional, but it\'s not saying
it\'s going to being super-vision because, as I said, half of the people
didn\'t get as good as spectacles could have done.

DR. WEISS: Mr. McCarley?

MR. McCARLEY: Yes, I\'ll try to represent all the laser industry maybe
with one point here.

I hope that with the stroke of a pen, you don\'t obsolete all current
products that don\'t have LADARVision, the new version, that corrects
aberrations. So I would just, Number 1, if there is a comparison being
drawn, I think it should be drawn against the control that they were
using, which is the conventional LADARVision, I think that\'s what it
was, rather than all conventional standard LASIK. That\'s what I\'m
trying to say.

I\'m not sure you can make a broad statement that says if you have this,
and again it\'s the medical-legal issues, what happens when a doctor
treats his patients with the current technology, not the upgraded
aberration instrument, and the patient\'s outcome doesn\'t come out like
they want to? Automatically, are they going to be sued because they\'re
not using the state of the art? I\'m just concerned about issues here
that with the stroke of a pen, you just wipe everyone in the market out.
I think it\'s a great technology.

The only question I would ask is if you had to have LASIK today, would
you pick something as advanced as this that may offer potential benefits
or what you already know is the standard? You know, for myself, I think
I would, if it costs the same, if obviously the safety and efficacy is
the same, why would you choose something less?

DR. WEISS: Well, I think it\'s an important point you raise, that in
that sentence, we can easily put conventional treatment with this laser
versus customized treatment with this laser. So that\'s a good point.

Dr. Grimmett?

DR. GRIMMETT: No comment.

DR. WEISS: I would appreciate perhaps if you read the few options that
we had for this particular issue and then maybe we can come up with some
final statement. We have, I think, Dr. Bullimore\'s version, Dr.
Bradley\'s version. Was there a Dr. Bullimore version?

DR. GRIMMETT: Mike Grimmett.

I didn\'t get Dr. Bullimore\'s version down on paper. Dr. Bradley stated
that wavefront-guided LASIK has demonstrated slightly superior optical
quality (reduced monochromatic aberrations) compared with conventional
LADARVision LASIK and minor improvements in visual acuity and contrast
sensitivity relative to conventional LADARVision LASIK.

We could actually just add a comma there and put Dr. Owsley\'s
statement, then put but there is no data to support higher functional
performance (activities of daily living, such as reading or driving) or
satisfaction rates in patients with wavefront-guided LASIK.

DR. OWSLEY: Instead of higher, how about better? Instead of higher, use
the word \"better.\"

DR. GRIMMETT: Better? Okay.

DR. WEISS: I have to say I don\'t know if anyone else is concerned with
the term, and if I\'m the only one concerned, we\'ll move on, of what
was the initial optical? What\'s the first phrase?

DR. GRIMMETT: Where I added ‑‑

DR. WEISS: Yes, because it\'s incorrect and that\'s not going to make
it.

DR. GRIMMETT: Slightly superior optical quality.

DR. WEISS: Okay.

DR. GRIMMETT: One option was to modify that, what you meant by that.

DR. WEISS: I\'m just concerned the quote\'s going to be that we\'re all
going to read that you have better optical quality with this laser and
that\'s not what the intent of the statement is and that I have a
concern about that.

DR. BULLIMORE: This is Dr. Bullimore.

That\'s what I think the data, the only thing that the data show
convincingly is the superior optical quality.

DR. MATOBA: This is Alice Matoba.

I agree, and actually I would have taken the word \"slightly\" out of
there. I think it\'s more than slightly improvement in optical quality.

DR. WEISS: Okay. So no one else has the same concern about that word?
Okay. That\'s fine.

DR. BANDEEN-ROCHE: Well, I do a little bit. As a non-ophthalmologist,
you know, I would interpret optical quality to mean that I\'m going to
see better.

DR. MATOBA: Compared to conventional?

DR. BANDEEN-ROCHE: Compared to conventional and so what we saw was
slight differences in average contrast sensitivity and certain measures
of visual acuity, plus the aberration measures which I think we\'ve said
we don\'t know how that affects optical quality as I can perceive it.

DR. MATOBA: But the optical quality refers to the aberration
measurements.

DR. WEISS: I think by putting it in parentheses, it will be easily open
to misinterpretation. I\'m going to defer to Glenda on this.

From a consumer standpoint, do you think it will be clearly understood
by a consumer that if we say optical quality ‑‑

DR. GRIMMETT: Reduced monochromatic aberrations.

DR. WEISS: ‑‑ is improved, what do you think they\'ll take away from it?

MS. SUCH: Blank look. No. Could you read the sentence again? I stepped
out for just one second, but read the sentence again.

DR. GRIMMETT: I\'ll just read the first section.

MS. SUCH: Yes.

DR. GRIMMETT: Wavefront-guided LASIK has demonstrated slightly superior
optical quality (reduced monochromatic aberrations) compared with
conventional LADARVision LASIK.

MS. SUCH: They\'re not going to get it. Optical, most people, I would
say, who are not in this field, when they see the word \"optical,\" I
think ‑‑ can we just say vision, you know? Can we have ‑‑

DR. WEISS: But it\'s not vision is the problem.

MS. SUCH: Yes, okay.

DR. WEISS: That is the problem.

MS. SUCH: So we\'re getting sort of stuck.

DR. MATOBA: Wait. Can we hear the whole thing?

DR. GRIMMETT: Yes. The last part I think qualifies it all, when I added
in Dr. Owsley\'s intent, I believe, by saying at the end of it, but
there\'s no data to support improved functional performance and then put
in the part about activities of daily living, such as reading or driving
or satisfaction rates in patients.

Dr. Matoba\'s pointing out that Dr. Bradley earlier had talked about
that data can be provided regarding the high and low contrast
sensitivity in the frame of contrast and vision. We can add that data
separately.

DR. MATOBA: It seems to me that there\'s significant improvement in the
optical aberrations, the higher-order aberrations. It\'s just the
contrast and the patient satisfaction we\'re not sure about. You could
clearly mention all of that and separate that out. I don\'t see why that
all could not go into the labeling.

DR. WEISS: You know, I\'m going to defer to Mr. Whipple at this point
just in the interest of time. I think you\'re getting the sentiment of
the panel.

MR. WHIPPLE: Exactly.

DR. WEISS: Which is that we don\'t know if patients are any happier. We
don\'t know if their symptoms are any less. We do know the contrast data
looks somewhat better. We don\'t know what it means. We do know the
aberration stuff looks better. We don\'t know what it means. Is there a
way for someone at the FDA to pen that in a clearer fashion in the label
to perhaps come up with the ‑‑

MR. WHIPPLE: Right. I think we can take this as guidance and develop it.

DR. WEISS: Okay.

MR. WHIPPLE: But I\'d also like to remind you, though, as you struggle
with the patient labeling, we also need some recommendations for the
physician part of the labeling as well.

DR. WEISS: Maybe we\'ll have one or two more comments on this question
and move on, and Dr. Bradley?

DR. BRADLEY: Yes, it\'s interesting we have struggled now for about half
an hour with this question, and in reality, for the patient, we have
already heard today from the sponsor and I presented some data, too,
that the magnitude of all of the aberrations amounts to maybe .2, .25
diopters equivalent, and these patients are having 4 or 5, whatever,
diopters of myopia corrected, and the accuracy of the correction of the
myopia, the spherical equivalent myopia, if that was off by .2 diopters,
that would bury any advantage produced by correcting the monochromatic
aberrations. So that big effect is still the correction of myopia.
That\'s the big effect on vision. That\'s going to be the biggest impact
for the patient, and if we\'re making statements here, although it\'s
important for us to make statements about the monochromatic aberrations
in terms of the patient information, it\'s very important that they
understand that this is not the big effect here. The big effect is the
correction of their myopia.

DR. WEISS: Then maybe you can actually add that as a statement. The
major beneficial effect of this laser is the treatment of myopia and you
could actually put that as a phrase because I agree. I mean, the
difficulty I think the panel is having is to convey a very, very ‑‑ the
new technology which has a minimal import versus the old technology
which has a maximal import.

DR. BRADLEY: That\'s correct, and I think, also, and I had it in my
presentation, the statement should be very clear that this technique
does not reduce aberrations or improve optical quality relative to preop
best-corrected conditions.

DR. WEISS: Okay. That\'s an important statement as well. So I appreciate
that, Dr. Bradley.

So we\'re going to move on, believe it or not, to Question Number 2.
Okay. \"Are additional data, analyses or criteria needed to evaluate the
relative effectiveness of Custom and conventional treatment with regard
to higher-order aberrations and visual function?\"

I think Dr. Bandeen-Roche, you were addressing this, and in the interest
of time, what I would ask the panel members to do is tell us what you
want, tell us what you want, maybe we can get it for you, maybe we
can\'t, but just tell us what you want.

DR. BANDEEN-ROCHE: This is Dr. Bandeen-Roche.

Very briefly, while I think that the data are very interesting in terms
of aberrations, I wouldn\'t bet my life on that difference standing up
because it seems to me that it\'s reasonable that there could be sources
of bias with respect to that cohort, including that they were early on
in the study, maybe surgeons got better as the study went along. I
don\'t know if that\'s reasonable or not. So ideally, I would like to
see some data that was concurrent and randomized and assessed in a
blinded fashion. You may tell me that\'s, you know, patently
unrealistic. It\'s not going to happen. Perhaps you could do some
matched analyses, you know, where you actually do some analyses that
match by approximately the same time in the course of the study, same
position, same pupil size, whatever, temperature, that sort of thing
that\'s important.

I guess the second thing that I would like you to do is to assess the
variability between sites. Certainly if there is substantial
variability, that\'s important in its own right, but it also means that
the assessments of variability of the statistics, things like P values
and confidence intervals, aren\'t valid and that that variability would
need to be accounted for in that case, and then finally, I think several
of the reviewers in their written reports brought up that there was a
real focus on average findings, and I think it would be more important
to provide distributions.

So for instance, for stability, I believe Dr. Bradley brought this up,
it\'s not just mean change that matters but the percentage that have
some various levels of change, you know, some more focus on reporting
distributions and not just means in the statistics.

DR. WEISS: Dr. Burns?

DR. BURNS: As we talk about statistical analysis in future studies,
we\'re going to face the fact that it would be nice to have a
well-designed fellow-eye study for things like contrast sensitivity but
that won\'t be useful for things like questionnaires about quality of
life or things like that because you don\'t really know how the two eyes
interact. So there will have to be some sort of case-control type of
design for that part of the study. So it\'s going to be a complicated
issue to document.

DR. WEISS: I\'ll go to you, Karen, and then we\'ll go to you, Leo.

DR. BANDEEN-ROCHE: Just a brief clarification. I didn\'t even mean
randomizing one eye to one treatment and one eye to the other but
randomizing patients within the same clinic.

DR. WEISS: Dr. Maguire?

DR. MAGUIRE: I\'d just like to say that I think we should require the
sponsor to have more people at the higher end of myopia in the level
that they\'re asking for in the -5 to -7 group. That is something
that\'s been said by at least four, maybe five, people on panel since
either written or spoken during this thing, and the rationale for that,
Number 1, the N is low. Number 2, as Dr. Bradley\'s pointed out, this is
a thing that does two things, it not only corrects higher-order
aberrations but it also uses the wavefront analysis to measure myopia,
and there\'s no clear data that it\'s just as accurate at measuring high
myopia as low myopia, and we need the numbers to prove that it\'s at
least equivalent to conventional LADARVision correction because we
don\'t know that because we\'re comparing a subjective measurement of
refraction to the other.

The third reason for doing it is, is because the initial cohort is much
bigger and it\'s reduced because it fell short when it was correcting
higher rather than lower degrees of astigmatism, and so it\'s reasonable
to hypothesize that it may fall short measuring higher degrees of myopia
and lead to scatter.

DR. WEISS: Well, at this point, I don\'t think we can get more patients
who are above -5 because my assumption is we got all the patients that
you had that were above -5. So the only way that I can see, and Mr.
Whipple can add anything to this, is that you have a postmarket study,
if you want it above those people, or you limit the approval to up to
that level. Any other way that we could do this?

MR. WHIPPLE: Well, I think what you\'re saying basically is you need
these additional analyses if they\'re going to make more specific claims
about the success of their device over what is being allowed, what
we\'re discussing here today. So that may have to come in as a
supplement, that may have to come in as additional information to make
other specific claims later on. What can you say about the data we have
here today?

DR. WEISS: Are you comfortable with the data we have here today, Leo, in
terms of saying that the range of approval would go up to -7?

DR. MAGUIRE: No.

DR. WEISS: So you would want to cut it off at -5?

DR. MAGUIRE: If I read Dr. Huang right, he isn\'t either, and I think
I\'d be interested to see what other people are not comfortable and for
the reasons we discussed.

DR. WEISS: So then, I\'ll go back, Mr. Whipple. If, let\'s say, Dr.
Maguire, Dr. Huang, were not comfortable in extending the approval to
-7, the only two ways that I see to go about it is to have it extended
with postmarket surveillance of that higher range of myopes or to limit
the indication up to -5, is that correct? Is there any other way to go
about it?

MR. WHIPPLE: Well, I don\'t think the postmarket issue, I think that\'s
more of an issue where you do have this clinical study in the higher
ranges with additional data coming in as a supplement later. You can as
an option take the indication and say that the data here only support to
a certain range and you can recommend that as you so choose.

DR. WEISS: Okay.

DR. HUANG: My written recommendation, and I did not think the range of
indications should be from -1 to -7. I think it should be higher than
that and should be -1 to -6 or -1 to -5.

DR. WEISS: Mr. Whipple, and then Mr. Bradley.

MR. WHIPPLE: I was just simply saying that that is something that is an
option for you to consider. So you may want to discuss that further here
to make sure everybody agrees.

DR. WEISS: Dr. Bradley?

DR. BRADLEY: Dr. Maguire raises an interesting point I had talked about
before. There are possible reasons for this technology whereby it would
not do a good job of measuring aberrations and indeed myopia in very
highly myopic eyes because of the dot quality in the Shack-Hartmann
aberrometer, and I wonder if you have a sphere correction built into
your device. I\'m talking to the sponsor now.

DR. WEISS: The sponsor could approach the panel just to answer the
question at the podium. If you can identify yourself first, please?

DR. PETTIT: Okay. I\'m George Pettit with Alcon.

I\'m sorry. Dr. Bradley, could you just restate the question one more
time?

DR. BRADLEY: The issue is with very high levels of myopia and the highly
curved nature of the exiting wavefront here, there\'s significant
curvature over the affected aperture of your lens and therefore the dot
quality in your final dot image is degraded and the potential is that
you cannot accurately measure the myopic aberrations because some
instruments put a variable collar correction for the myopia in because
of that very problem.

Does your instrument have that?

DR. PETTIT: We do not have that particular feature. We have some optical
features to get the largest dynamic range that we can using a static
optical design, and we have validation data demonstrating the accuracy
using test reference pictures of different myopic and various astigmatic
and comatic power and whatnot, and we\'ve supplied some of that to the
agency. We can, if it\'s important, we can supply specific information
demonstrating the accuracy of myopia up to the requested approval range,
but we have very high accuracy and we can demonstrate that data with the
measurement.

DR. BRADLEY: Yes, I think if you demonstrated that to the agency,
there\'s no reason, if it works for your model eyes in your calibration,
it should also work for this.

DR. PETTIT: That is the case.

DR. WEISS: Dr. Grimmett?

DR. GRIMMETT: Michael Grimmett.

Just a comment. It\'s known from prior PMAs and experience with all
these devices that the predictability and effectiveness falls off at
higher ranges. It\'s also typical that the higher ranges have less
patients in the subset. I\'m against limiting the approval because
there\'s no red flags that are being raised at this point that there\'s
anything inherently wrong with higher ranges.

I certainly understand the N is too low to make precise determinations,
but because this is an algorithm change and we know what conventional
LASIK does with a LADARVision unit, unless alarmed about the higher
scatter and the higher ranges simply because it\'s typical of what
happens with other devices.

Additionally, given the further information that was just presented that
they have accuracy data from model eye information, assuming that
that\'s valid and been reviewed by the FDA, I\'m not in favor of
limiting the range of approval.

DR. WEISS: So just to sort of see where we are with this particular
question, which has nothing to do with Question 2 by the way, but in any
way, 2A perhaps, I\'d like to just have a straw poll vote in terms of
those who would like to limit the approval to up to -5, if they could
raise their hands.

(Show of hands.)

DR. SWANSON: I\'ve got a question before I can answer that.

DR. WEISS: You can\'t do that. The Chair asked the question, you\'ve got
to answer. It\'s the prerogative of the Chair. You can ask your question
afterwards, though.

DR. SWANSON: I don\'t know what you mean.

DR. WEISS: So you have a yes, no or ‑‑

DR. SWANSON: I can\'t answer.

DR. WEISS: Can\'t answer. Okay. So we\'ve got three who would like to
limit it. Down here. And how many would say they do not want to limit
it?

(Show of hands.)

DR. WEISS: I\'ve got four who do not want to limit it, and then how many
are abstaining?

(Show of hands.)

DR. WEISS: We have three abstaining.

Dr. Swanson, ask your question.

DR. SWANSON: In terms of limit of the approval, I don\'t understand
exactly what that means. There\'s a list of precautions saying that it
hasn\'t been established beyond a certain amount.

DR. WEISS: Well, we would be saying that basically this is FDA-approved.
If the proposal is to vote for approval, it would be voting for approval
with the stipulation up to -5 is FDA approved and is not FDA approved
for anything beyond -5. That\'s what the question is. The concern has
been brought up by some members of the panel.

DR. SWANSON: Right. No, I understand that. I\'m just trying to look at
how it goes. So in other words, if a physician used it ‑‑

DR. WEISS: It\'s an off-label use.

DR. SWANSON: Then it would be off-label use.

DR. WEISS: Off-label.

DR. SWANSON: Right. Thank you.

DR. WEISS: So we\'re definitely sort of split on this.

Mr. McCarley?

MR. McCARLEY: Yes, just one comment for future applications, if in fact
this is approved. What justification do you have for cutting off at 5?
In other words, what\'s the distribution of the N? I mean, why 5? Why 5?

DR. WEISS: Dr. Maguire, Dr. Huang, either of you want to answer?

DR. HUANG: Basically, you know, there were 139 eyes in the sphere cohort
was reviewed and there\'s one patient in the -0 to -1 range. There are
four patients in the -6 to -7 range. So therefore, I think that N equal
to 1 doesn\'t mean anything and equal to 4 may mean something but it\'s
not sufficient. So therefore, my recommended indication rate was from -1
to -6, but if you\'re going to cut down the cohort from 139 to 5,
there\'s still enough ‑‑ I have done some preliminary calculation on my
own. I think 134 patients, most of the data still holds on.

DR. WEISS: I would actually ask the agency for their input on this
statistically. Does the agency have any concern concerning the small
numbers of patients with high corrections from a statistical basis as
far as having approval for these as the small number did very well but
there\'s concern on the panel?

Dr. Eydelman, thank you very much.

DR. EYDELMAN: Hi. Dr. Eydelman.

In the previous approvals for various LASIK devices, we have not
requested the sponsors to have statistically significant number of
patients in each dioptric range. It is well known that the higher the
myopia the harder it is to get large number of patients.

In the reviewing of this application, basically there were two
considerations taken in my recommendations of giving the full range for
the approval. Number 1 is that even though there was small number of
eyes in the higher range, we didn\'t see any significant safety problems
in that population, and second of all is that this, as was pointed out,
is a second generation of this device. So we\'re not really anticipating
any red flags, anything hidden, and then we have also looked at combined
myopic with astigmatism eyes for safety for that range, and you have
that cohort not in the efficacy but within the safety. You have a whole
bunch of patients ‑‑ I would have to look up the exact number ‑‑ where
the amerisee was between -6 and -7 and once again, there were no really
safety concerns.

If the panel has some reservations about possibility of equivalent
approval in optical qualities in this group, I believe that we can
definitely handle this in labeling, but otherwise, I would like to
understand what exactly the safety concerns are, if you\'re going to
vote on limiting the range.

DR. HUANG: Well, on these four patients, one of them is outside 20/40
range, and I think that was addressed by Dr. Hakim earlier today, you
know, that he specifically mentioned that patient eventually improved.
But one out of four patients has a problem. Even though it exceeded FDA
guidance, I still don\'t think that is sufficient to indicate this is
going to be safe in the larger population.

DR. WEISS: Thank you very much for those elucidating opinions.

I\'d like to have just another straw vote just for voting members of the
panel. After hearing this additional information, how many would feel
comfortable for voting for the full range up to -7?

(Show of hands.)

MS. THORNTON: Dr. Bullimore, Dr. Matoba, Dr. Grimmett, Dr. Owsley, Dr.
Swanson. Five.

DR. WEISS: Five. Thank you so much.

And how many would say do not feel comfortable voting for the full
range?

(Show of hands.)

MS. THORNTON: Dr. Maguire and Dr. Huang.

DR. WEISS: Okay, and then three of you are a maybe?

(Show of hands.)

DR. WEISS: We have a maybe from Dr. Bradley, maybe from Dr.
Bandeen-Roche. Is my math off? What does it add up to? That\'s right. Do
the maybes need any more information or can we move on?

Dr. Bradley, yes?

DR. BRADLEY: Well, I can just explain why maybe. On the graph that I\'m
looking at, I only have one eye between 6 and 7 and that eye had a
postop refractive error greater than 1 diopter. So that\'s why I was a
bit concerned about perhaps 6, but up to 6 seems fine.

DR. WEISS: We could perhaps address that in labeling. We could probably
address that in labeling that there were a small number of eyes above,
you know, XYZ. So if we address it in labeling, would you feel
comfortable then?

DR. BRADLEY: Yes.

DR. WEISS: Fine. Thank you.

Okay. Let\'s get back to Question 2. \"The additional clinical data
analysis or criteria needed to evaluate the relative effectiveness of
Custom and conventional treatment with regard to higher-order
aberrations and visual function.\"

I personally would like, when you have the data for the 19 conventional
versus the 19 customized, if you have symptoms as well as if you had any
satisfaction data, I think that would be helpful to any patient who\'s
trying to make a decision whether to have the customized versus the
conventional treatment.

Does anyone have any other suggestions? Otherwise we\'ll move on. Yes,
Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Yes, this one I forgot from before. In the symptom
data, I\'d like to see an analysis that is by first eye of patient. So
the current analysis just average symptoms over all eyes, but I don\'t
know whether there might be a bias because people who get the second eye
done might tend to be those who are more satisfied and didn\'t have a
problem with the first one.

I\'m sure the substantive members of the panel could address that.

DR. WEISS: Did you want to make a comment, Dr. Pettit?

DR. PETTIT: If it would be appropriate.

DR. WEISS: If you\'d like to, it will be appropriate.

DR. PETTIT: I hope it will be appropriate.

The patients were all treated at the same time. They received both eye
treatments in the same surgical session.

DR. WEISS: So they didn\'t have an opportunity to decide whether they
were satisfied or not. Okay. Thank you very much. That was appropriate.

Ms. Such?

MS. SUCH: Yes. One other piece that I actually would like is there\'s
been statements made by the sponsor that ‑‑ I\'m not sure if it was a
friend or one of the people that he worked on under the study had
expectations of getting down to 20/16 or was 20/16 and wanted to see
better.

I\'d like to have, if you could, information gathered from the people
who we\'re talking about, what their expectations were and whether or
not their expectations were met. If we put a qualifier on it, we would
get a sense of if those expectations were within normal human limits.

(Laughter.)

MS. SUCH: And find out what you\'re dealing with, because we may be able
to just rule them out or at least get a better sense and in your
brochure make statements that are indicating that, you know,
expectations were met and address people that want to see.

DR. WEISS: I think they have the satisfaction data here and if anything,
there\'ll be a bias against satisfaction if they\'re dealing with people
who are unreasonable and have high expectations. So actually the
satisfaction might have been higher than what was revealed if these are
demanding individuals.

Mr. McCarley, and then we\'re going to move on to Question Number 3.

MR. McCARLEY: Just very quickly from the consumer representative. Again
be careful about what you say in terms of general cautions you want to
add to LASIK procedures in general because it sounds to me like that\'s
a general LASIK procedure precaution that you wanted to be added to this
specific one.

DR. WEISS: I think she was just trying to commiserate with the sponsor
that some of the patients might have had higher than reasonable
expectations.

Question Number 3. \"What information about measurement, analysis, and
correction of higher-order aberrations is needed in the labeling to
inform physicians and patients about safety and effectiveness of
CustomCornea treatments?\"

I think we\'ve addressed some of this, but are there other things that
‑‑ Dr. Swanson?

DR. SWANSON: Well, looking at the thing, in various places, it talks
about delivering the correction, making the correction, improving, and
what we\'ve seen is it doesn\'t actually do that. It attempts to, but it
says it uses it to correct for the visual errors in the eye. Well, it
uses it to correct for some of them and then it induces others. So I
think part of the thing that could be stated in here, because if you
read it over, it gives the impression that it fixes everything that\'s
wrong, and what we\'ve learned is that it\'s more complex than that. So
I think in those places that there\'s reference to correct, there could
be some modification that made it look less like you\'re taking
something and making it perfect.

DR. WEISS: And actually, I should reiterate what was already mentioned,
I think, by the agency, is that, some of this is going to have to
address the physician booklet as well as the patient booklet so
physicians understand what this is about as well.

Dr. Grimmett?

DR. GRIMMETT: Yes. Mike Grimmett.

I think Dr. Bradley in his presentation made a statement for labeling
that would probably apply to this question. The information about the
correction of higher-order aberrations is that Dr. Bradley stated they
were promoted as a slight improvement over conventional LADARVision
LASIK, although the level of aberrations are higher than preop. I think
somehow that needs to be stated in the labeling somewhere.

DR. WEISS: Does anyone want to phrase that in any different way because
I would agree?

Dr. Bullimore, with verbs, adjectives and nouns, some adverbs, if you
want.

DR. BULLIMORE: In answer to this specific question, I don\'t think
anything technical needs to be in the patient labeling. I think that can
only confuse and obfuscate. In terms of the physician labeling, I think
it\'s adequately addressed at the moment through inclusion of the safety
and efficacy data. So I don\'t think we need to ask the sponsor to
include, for example, a tutorial on the wavefront measurement correction
and evaluation.

DR. WEISS: Dr. Bradley?

DR. BRADLEY: Yes, this brings us to my other points I was talking about
in my presentation about the correlation of analysis and whether or not
the sponsor has adequately demonstrated that the CustomCornea really is
a correction of the aberrations that existed in that eye, and I think
from my analysis, which is rather preliminary, I certainly was not
convinced that they had demonstrated correction of the inherent
aberrations within an eye, and I would leave it up to the sponsor and
the FDA to sort that out to see if they have adequately demonstrated
that because the issue is the effectiveness of CustomCornea. The
implication of CustomCornea is that you are correcting the aberrations
of the eye, and if you haven\'t demonstrated that, then one has to
question the effectiveness of CustomCornea and the end result, as we
know, is it\'s better than conventional LASIK, but is it really as
implied a correction for the aberrations of the eye? I think that needs
to be demonstrated before we put any statement into the label.

DR. WEISS: Would that not be addressed somewhat by Dr. Grimmett\'s
statement, is that, regardless of what you\'re treating, the end result
is the aberrations go up?

DR. BULLIMORE: This is Dr. Bullimore.

That statement does need to be in the labeling.

DR. WEISS: The aberrations ‑‑ which statement? The one that Dr. Grimmett
made or what Dr. Bradley\'s referring to?

DR. BULLIMORE: The one that Dr. Bradley had on his slide.

DR. GRIMMETT: I can read it.

DR. WEISS: Yes, if you could read that, Dr. Grimmett.

DR. GRIMMETT: Dr. Bradley stated wavefront-guided LASIK does not reduce
the level of higher-order aberrations of the preoperative eye, and he
also wrote there\'s no way wavefront-guided LASIK can correct
higher-order aberrations and render super-normal vision. That\'s the
second statement. Is that not correct?

DR. BRADLEY: Your memory is better than mine, but I can look at the
slide.

DR. GRIMMETT: No, I believe I transcribed it correctly.

DR. BULLIMORE: I agree. This is Dr. Bullimore. I agree with the
sentiments of both of those statements. Exactly how the second one is
worded, we could come back to, but the first one adequately ‑‑

DR. WEISS: Can you repeat the first one again?

DR. GRIMMETT: Sure. Wavefront-guided LASIK does not reduce the level of
higher-order aberrations of the preoperative eye.

DR. WEISS: Would that not be confusing to someone? Wouldn\'t that be
confusing?

DR. GRIMMETT: Michael Grimmett.

It may suggest somehow wording in that wasn\'t it that the higher-order
aberrations were 20 percent higher than the preop eye in the
wavefront-guided versus what, 80 percent was the number?

PARTICIPANT: Seventy-seven percent.

DR. WEISS: In here, is there any place saying that LASIK itself
increases aberrations and that customized corneal ablation increases
them less than conventional treatment?

DR. GRIMMETT: I think that\'s the idea.

DR. WEISS: So maybe we could put that wavefront-guided ablation ‑‑

DR. GRIMMETT: Conventional LADARVision LASIK increases higher-order
aberrations by that figure 77 percent while wavefront-guided LASIK
increases them by whatever, 20 percent, whatever the number is, or you
can say reduces them to a 20-percent level, if you want to use the word
\"reduces.\"

DR. BULLIMORE: I would avoid the term \"reducing.\"

DR. WEISS: I would say each of them increases it because basically
whether or not you\'re treating the preexistent or what\'s induced, the
bottom line is you still have more aberrations than you did when you
started off.

DR. GRIMMETT: Well, the intent is telling the traffic cop that you\'re
speeding less than the other speeders.

DR. BURNS: I think it\'s important. I think we can let staff sort of
wordsmith it because aberrations going up or down may not be that clear
to the lay public. So I think there\'s some wording still there.

DR. WEISS: Ms. Such?

DR. BURNS: But I agree with the sentiment.

MS. SUCH: On that note, I would suggest that perhaps we look at, if you
were going to say that for the average patient, you might say something
that while LASIK surgery does this 77 percent, this other only does it
dah, dah, dah or something in that order of while.

DR. WEISS: You might also have to have an opening statement, aberrations
may reduce visual quality or something, what aberrations mean.

MS. SUCH: Yes. I think by doing that, you don\'t have to say reduces or
anything else, you can just use, you know, something simple that says
that and while this surgery does it at this level, and the person will
draw their own reference from that without getting into trouble.

DR. WEISS: Okay. And that\'s something I think we would need to have
both in physicians as well as patient.

There are a couple of other items and this is probably not the place to
introduce it, but I\'ll introduce it anyway there. My prerogative,
right? There was only one African American patient treated. So I think
we would have to say that the safety and effectivity in African
Americans is, there\'s insufficient numbers of patients treated to
determine safety and efficacy in African Americans or if anyone can come
up with better wording than that.

DR. GRIMMETT: Michael Grimmett.

Wouldn\'t just including the demographic mix make the information clear?

DR. WEISS: Whatever anyone else wants to do.

DR. BURNS: I think it\'s worth calling out because there really isn\'t
very much in Caucasian stuff.

DR. WEISS: The other question that I have at this juncture for other ‑‑
yes, Dr. Swanson?

DR. SWANSON: You put me on hold.

DR. WEISS: I\'m sorry.

DR. SWANSON: On the last topic. That\'s fine.

DR. WEISS: I\'m sorry.

DR. SWANSON: You\'re doing a great job.

But the idea, wavefront aberrations are discussed in the patient
brochure because we were talking about how to modify that. There\'s a
whole paragraph that describes them.

DR. WEISS: Can you refer us to the page?

DR. SWANSON: This is page 7 of 24 of the patient information booklet,
the next-to-last paragraph on the right-hand side. It introduces the
idea. It states, \"These small errors called higher-order aberrations
may have an effect on vision in addition to any nearsightedness present
in the eye.\" The next sentence says, \"In CustomCornea LASIK, the
wavefront measurement is used by the LADARVision 4000 System to deliver
the correction you need to reshape the surface of your eye.\" That\'s
actually somewhat of a non-sequitur. It\'s mentioning the higher-order
aberrations and then it\'s as if it implies it\'s going to fix them and
that\'s the spot where what\'s needed to be inserted is after it\'s
introduced what they are, is this kind of surgery makes these things
worse and ours is not quite as bad as what it has been because the way
it\'s stated right now, it introduces the fact they\'re there and then
it implies that this method gets rid of them. So there has been a whole
effort to educate the person to tell them what they are and then
there\'s this thing where it ‑‑ you see page 7 of 24 in the patient
information booklet? So that\'s where this whole thing that we\'re
discussing, that\'s where it would go because they\'ve gone through,
they\'ve introduced what the thing ‑‑ what it is in the very last
sentence, before the last sentence.

DR. WEISS: Yes, we\'re in the next-to-the-last paragraph. So I think you
would feel, and I would agree with you, and we can get the opinions of
other members of the panel. There\'s a statement. The rest of it sounds
pretty good, but there is a statement saying, \"In CustomCornea LASIK,
the wavefront measurement is used by the LADARVision 4000 System to
deliver the correction you need to reshape the surface of your eye.\"

DR. SWANSON: Right.

DR. WEISS: So that\'s where you want that statement to get changed.

DR. SWANSON: Yes, right. That\'s the topic we were talking about.
You\'ve already introduced what it is and that\'s the point where they
need to know that this is not getting rid of those.

DR. WEISS: And do you want to just leave that line and then add Dr.
Grimmett\'s couple of lines where basically you will have less
aberration than you would have with the other treatment? Because it is
still going to be used to reshape your eye.

DR. SWANSON: Yes.

DR. WEISS: It\'s just not going to be 100 percent effective.

DR. SWANSON: I don\'t have a particular recommendation. I\'m sure that
they can do that. I just wanted to bring that up in our discussion of
that point, that that\'s where it would fit.

DR. WEISS: So the discussion of aberration for the patient booklet would
be on page 7. Patient information booklet on page 7.

Any other discussion on 3? Otherwise, we\'ll go on to 4 and 5.

DR. BANDEEN-ROCHE: Very briefly, this is Karen Bandeen-Roche.

First, going to the point about your vision will be better, whatever, I
know FDA will be careful about reporting that averages were thus and
such rather than, you know, individual outcomes were thus and such.

A question about the physician labeling. Should it include some
information about test/retest reliability?

DR. WEISS: I don\'t believe that we usually do that.

Mr. Whipple?

DR. BANDEEN-ROCHE: In terms of the measurement.

DR. WEISS: Any opinions on how? Dr. Bradley? Well, we usually use the
least burdensome and I think that\'s getting burdensome.

Mr. McCarley, and then we\'ll go on to 4.

MR. McCARLEY: Yes, just one question. Rick McCarley, industry rep.

Does the FDA typically require gender, age distribution, and race in the
labeling for the lasers? Is there a format that\'s already set up for
what they were talking about just a moment ago? Is that something new or
coming up?

DR. EYDELMAN: Dr. Eydelman.

We usually just include demographics distribution table in the labeling.

MR. McCARLEY: Including gender and race?

DR. EYDELMAN: Yes.

DR. WEISS: Fine. We\'ll move on to Question Number 4. \"What additional
stability criteria are needed for higher-order aberration treatments?\"
If there are any additional stability criteria needed.

I think things are fairly stable by three months, but between three and
six months, trifoil kept on decreasing, statistically significant, but
as I recall, that was the only one.

Dr. Bradley?

DR. BRADLEY: I think this is potentially an important point, but it\'s
one where unfortunately science is lagging behind here. We really know
very little of the variability, day-to-day variability, month-to-month,
year-to-year variability in these higher-order aberrations preop. So
trying to put in criteria for how much we want to allow the postop
aberrations to vary as we do for refractive error would be inappropriate
at this time.

DR. WEISS: So because we don\'t have the knowledge, you don\'t want to
add any specific criteria because we don\'t have anything to guide us,
basically.

Dr. Burns?

DR. BURNS: I agree with that on average. I think, as Dr. Huang pointed
out, there are individuals with high amounts preop of some of the
aberrations, like coma, and it might be worthwhile to pull those out as
a subgroup and look at the effect of treatment and stability just as we
do for sphere or for astigmatism now.

DR. WEISS: Dr. Grimmett?

DR. GRIMMETT: Michael Grimmett.

I\'m probably out of my league since I\'m a clinician, but the question
might be would it be reasonable to have some postmarket data tracking
changes in RMS values? That may be the intent of the question, maybe,
and would that be reasonable? I certainly understand Dr. Bradley\'s
sentiments that we don\'t have enough data to set guidelines as to what
might happen or what might be reasonable, but is it reasonable to
request data on tracking RMS values so that at least we know something
about what happens to higher-order aberrations?

DR. WEISS: I\'m going to defer to Dr. Huang and Dr. Bradley. It was my
recollection that the higher-order aberration change was stable at
around three months, except for trifoil, and if it was, then I would say
wonder why you would need to track it if the stability was ‑‑ or it
appeared stable, but ‑‑

DR. GRIMMETT: Michael Grimmett.

Due to lack of knowledge about anything about what happens to these,
I\'m just raising the point for discussion.

DR. WEISS: Dr. Huang or Dr. Bradley, what are your feelings on it? Dr.
Bradley probably expressed his already. Dr. Huang?

DR. HUANG: Andrew Huang.

I\'m in favor of Dr. Burns\'s suggestion, is that, because the
higher-order aberration, it\'s changing with age, so as the time goes
on, we have an increased higher-order aberrations. So we really don\'t
know, you know, that even though the trifoil is stable at three months,
what is going to happen on this treated eye, you know, at 12 months or
three years from the treatment?

DR. WEISS: I think it\'s important for the panel to distinguish what the
sponsor needs to do to establish safety and effectiveness of the device
that they\'re coming forward with versus what we would like to know as
clinicians and scientists. The latter should be those studies should be
done by us or our members of our community.

So does anyone on the panel or who on the panel feels that this is
necessary information to safety and efficacy of this device to have
postmarket studies? We need to be holding to the least burdensome proof
for the sponsor.

Dr. Burns?

DR. BURNS: Even though I suggested it, I don\'t think it\'s necessary
for safety and efficacy, but to justify additional claims or something
in the future, I think some of this information would be useful
postmarket to help evaluate them. I don\'t know if that\'s typically
done.

DR. WEISS: Sally Thornton points out something very relevant, is that,
if any future claims were made, then they would need to be justified by
further data. So the only claims that we\'re approving are the claims
that we\'re approving right now and, you know, you can say anything else
you want, but right now, we have to address what claims are being made.

Yes, Dr. Owsley?

DR. OWSLEY: Just a quick question. Is this something that would be
useful for the patient to know, that we don\'t know the long-term
effects of this?

DR. WEISS: Well, I\'ll leave that up to the panel.

DR. OWSLEY: I don\'t know. What is usually done on these devices for
labeling?

DR. WEISS: Well, this is first of a kind. This is first of a kind of
this particular device.

DR. OWSLEY: It\'s the first of a kind for this particular device, but we
don\'t have 50 years of wait a sec, you know, where we can evaluate
people when they\'re 70. So what\'s done usually? Is there any comment
to the patient as to what we know about this in 40 years when they\'re
old?

DR. WEISS: Would anyone want to put a statement in there saying
long-term, we don\'t have long-term ‑‑ Malvina?

DR. EYDELMAN: Dr. Eydelman again.

It\'s usual for us to put something in the labeling to the effect of no
long-term data is available to address X, Y, and Z and that\'s exactly
what we intended to do with this.

DR. WEISS: Fine. Excellent. Thank you.

Dr. ‑‑ Ms. Such?

MS. SUCH: I\'ve been promoted as well.

DR. WEISS: Yes, yes. I\'m handing them out.

MS. SUCH: I would also on the manufacturer\'s side, that when I was
reading this, I saw that the studies will be done in six months, my
first question, you know, obviously was why and why not longer, and some
people really just are not going to know that this hasn\'t been around
for awhile. So I would even suggest that you might put in there that,
you know, due to the short time of the existence of this, there\'s not
been long-term studies, you know, because a lot of people just won\'t
know how long this has been out and why you haven\'t done it as opposed
to worry that they haven\'t done it because you\'re afraid.

DR. WEISS: The curse of long-term follow-up?

Any other comments on this question? So basically, I think there\'s a
consensus that we\'ll put something in the booklet saying that long-term
data is not available but that no further studies will be required by
the sponsor.

Then we\'ll move on to Question Number 5. \"Should stability criteria be
more stringent for wavefront-based treatments than for conventional
treatments?\"

Dr. Bradley, Dr. Huang? Dr. Bradley?

DR. BRADLEY: Yes, I\'m guessing the origin of this question is that by
its very nature, this procedure is trying to correct for extremely small
subtle imperfections and if that is the goal of the procedure, then
presumably for that to be effective in the long run, stability needs to
be tighter or the eye has to be more stable for that effectivity to
remain. I think that\'s the origin of the question.

Should there be more stringent? I think in the end, still the most
important factor here is the correction of the spherical myopia and in
the end, that will be the primary determinant of visual quality and
patient satisfaction, and I think we already have standards for that
stability, and as we saw in the data and in the sponsor\'s presentation
and in mine, the stability is excellent for the spherical myopia
correction.

DR. WEISS: Dr. Huang, do you have anything to add to that?

DR. HUANG: No.

DR. WEISS: No one has anything to add to that.

So we, I think, have concluded the five questions put forward by the
FDA. I have a couple of things that I personally wanted to bring out for
the patient information book and also if anyone has any other concerns
that they want to introduce and these are fairly trivial.

The patient information book is White Tab Number 2 for those who have
the book. It indicates to the patient D2, that the vision becomes stable
within the first few weeks after surgery. To me, as I recall, the
stability line started at one month. So I\'d rather say your vision
becomes stable in approximately one month after surgery rather than
first few weeks where they might assume it might be Week 2 or something.
I don\'t know if anyone has looked at that, has any thoughts, agrees,
disagrees. Okay. And we have some nods of agreement. So we\'ll add that.

The other thing, the chart on page 9 on the top. It\'s Visual Acuity
with Glasses Best-Corrected after this procedure, but the chart actually
just says Visual Acuity and just a trivial thing that it should just say
best-corrected visual acuity, visual acuity with glasses in the body of
the chart because if you look at it quickly, it will be sort of
deceptive to the patient.

On page 11, there\'s a list of subjective symptoms and the list is the
significantly worse, and I think, I would personally like to expand the
table to the full Table 35, at least showing the worse and significantly
worse because the significantly worse may only be a couple of percent
where if you include the worse symptoms, you may have 23 percent, and I
think this is sort of alluding to what Mr. Link and the other people
were referring to in the public session, is that they don\'t really have
a full idea of what they\'re getting into.

So I personally would prefer if the subjective symptoms had not only the
significantly worse but those patients who also had worse symptoms.

Mr. ‑‑ Dr. Bradley?

DR. BRADLEY: I\'ve lost my degree.

(Laughter.)

MS. SUCH: I took it.

DR. BRADLEY: I\'m sure if I hang around long enough, I\'ll get another
one.

DR. WEISS: You will. Actually you might get two.

DR. BRADLEY: Okay. I guess I have pretty strong opinions about these
sorts of data reporting tools. As always, if you recall one side of any
distribution, you get a skewed view of the reality, and this has already
one side of the distribution, essentially the tail is significantly
worse, and I think if this table or tables like this should go in, I
would like to see both sides of the table.

DR. WEISS: Put the whole table. You got it.

DR. BRADLEY: So those who got better and those who got worse.

DR. WEISS: Table 35, it\'s yours.

I also would bring this out to the panel. Should we include for the
patient, maybe also for the docs as well, Table 10 talked about not just
two lines of best-corrected visual acuity loss but one line of
best-corrected visual acuity loss, and we could also have for Dr.
Bradley the gain in visual acuity to be fair because it was 8.6 percent
of patients who lost one line of best-corrected visual acuity. As a
patient, I think I would want to know that.

Ms. Such, would you want to know that or is just leaving two lines or
more enough?

MS. SUCH: No, I\'d want to know about the one line. I mean, if I go for
this surgery, I\'d want to know about any change.

DR. WEISS: Fine. I would suggest to include Table 10, and Table 13 had
change in low contrast best-corrected visual acuity, and you lose low
contrast best-corrected visual acuity and that seemed to be a complaint
from those people who came before us today, that they didn\'t know about
it, and if they want to know about it, I think it would make sense to
put the whole table in there to be fair, and does anyone have any
thoughts on that?

DR. BULLIMORE: Which table?

DR. WEISS: That\'s Table 13. It\'s Change in Low Contrast Best-Corrected
Visual Acuity.

Mr. McCarley?

MR. McCARLEY: You\'re going pretty quickly here, and I don\'t have the
benefit of seeing the tables that you\'re referring to.

PARTICIPANT: Which section are you in when you\'re talking about those
tables?

DR. WEISS: Table 10. Low Contrast Visual Acuity is pink Tab 6 and
actually it\'s pink Tab 6, actually Table 19, and for the change in
symptoms, it\'s pink Tab 6, it\'s Table 34, including those who are
better, from those who were significantly better to those who were
significantly worse.

DR. OWSLEY: Excuse me.

IF it\'s the change table, wouldn\'t it be Table 13 for low contrast
acuity?

DR. WEISS: No, I think they\'re labeled with more than one ‑‑ where is
Table 13? I think they have more than one number on them.

DR. BULLIMORE: Page 20.

DR. WEISS: Dr. Matoba?

DR. MATOBA: Now, this patient booklet ‑‑

DR. WEISS: Actually, Table 13. We\'ll go back to Table 13, Table 10.
Yes.

DR. MATOBA: I have just a general question.

This patient booklet, the original format was already approved for
conventional LASIK, is it not, and then they\'re just adding the
CustomCornea to it, and is it fair to make ‑‑ should it list more
problems for the CustomCornea while the patient booklet for the
conventional LASIK is not going to have all this stuff about contrast
sensitivity loss?

DR. WEISS: Let\'s bring that out to the panel. I don\'t know what\'s in
the conventional book.

DR. MATOBA: I mean, wouldn\'t it be more fair just to add things that
pertain to the CustomCornea?

DR. WEISS: Well, I would agree with you.

DR. MATOBA: It\'s already approved.

DR. WEISS: I would agree with you, we shouldn\'t make it more detailed
for symptoms than the original book. I don\'t know what the conventional
book looks like. So if the conventional book only has significantly
worse, then I think we\'re forced to just put significantly worse in
this, but that\'s something we can probably have to refer to FDA.

I\'m going to just continue with Mr. McCarley because I cut you off.

MR. McCARLEY: You answered one of my primary questions. One is, I heard
someone wanting to see every possible or every complication that
happened and the percentage and I don\'t think that\'s the normal
labeling that the FDA requires. I think there\'s percentages where it
drops into other ‑‑ and what the ramifications of that would be to other
products, and again I agree, this is simply a new indication for a
current device. Why would you want different labeling?

Now, the other way is just continuing to add more information in here,
just, you know, more information for the patient to try to digest. Loss
of one line as far as I know is not a clinically significant issue.
Correct me if I\'m wrong.

DR. WEISS: It may be more clinically significant than the aberrations
we\'re talking about.

MR. McCARLEY: I agree, but does it confuse the patient? Does the patient
look at one line of visual acuity as a significant clinical issue when
in fact it may not be?

DR. WEISS: Are you confused by one line in loss of visual acuity?

MS. SUCH: I wold perhaps give an example of what that could mean
acuity-wise.

DR. WEISS: I think we should probably maybe get the FDA involved again
at this point because we don\'t want to be more burdensome than the
usual approval. So if requiring the whole gamut is too much, we should
not.

DR. EYDELMAN: Even though the booklet has already established sections
for each one for the wavefront-guided LASIK, it will have a separate
section per se. So you can certainly specify certain points that you\'re
interested in conveying and then we\'ll try to work out the details to
make sure that it\'s consistent and not too much for the patient
booklet. You don\'t necessarily need to give us every single table.
We\'ll work it out.

DR. WEISS: Dr. Burns, and then Dr. Owsley.

DR. BURNS: Yes, Steve Burns.

I just wanted to say that because this is the first wavefront-guided, it
is sort of a new category, so I think some extra information is
potentially valuable to the patient.

DR. WEISS: I mean, where I\'m coming from is we had more than one person
talk about the severity of the dryness they have and the point that they
wish they knew and only 7.4 percent had significantly worse but 21.5
percent had worse. So you have 32 percent that had worse, and I think I
personally would want to know that as a patient without being too
burdensome, but I think that\'s important information. Dryness, glare,
halos, night driving difficulty, and fluctuation of vision, all of those
had approximately more than 20 percent of people in the worse or
significantly worse category which is not trivial.

Dr. Owsley?

DR. OWSLEY: Yes, I think the spirit of these suggestions that some of
the panel members are making is that what we heard today and we hear
about this all the time is that patients want more information. So the
spirit is not to be overburdensome in providing all this extra
information about a new product that has evidence that it\'s better in
some ways. It\'s to provide the patient with more information which I
think they deserve to know.

DR. WEISS: Dr. Bradley?

DR. BRADLEY: I\'m just wondering which table the Chair was viewing when
talking about some of the symptoms.

DR. WEISS: Table 34.

DR. BRADLEY: Which is what I\'m looking at, too, and again this is a
one-sided view of the table.

DR. WEISS: No, we\'re going to include the whole table.

DR. BRADLEY: But I\'m seeing 21 percent reported worse, but 17 percent
reported better.

DR. WEISS: Correct. But from the ‑‑

DR. BRADLEY: There\'s a differential of 4 percent. Again, it would be
nice to have ‑‑ and it\'s not really the sponsor\'s responsibility. It
would be nice to know, for example, if he just took a bunch of people,
got these symptoms, came back a month later, six months later, got the
symptoms again, how many of these would be identical, and in the end,
that\'s the dataset that we really need to know because in the end,
these data may be no different than taking two measurements on a group
of people who\'ve not had LASIK, and if that\'s the truth, then one
would draw the conclusion that LASIK has no effect whatsoever on these
symptoms, but without those data, we can\'t really say this.

So I\'m really nervous about making a lot of these data without the
full ‑‑

DR. WEISS: Dr. Owsley?

DR. OWSLEY: That\'s why you have to do the questionnaires pre and post
and that\'s such a very important piece of information for any future
studies in this area.

DR. WEISS: Glenda, and then Alice.

DR. MATOBA: Alice Matoba.

But my question is still what ‑‑

DR. WEISS: Glenda, and then Alice. Glenda, and then Alice.

MS. SUCH: I wanted to comment on the issue that\'s being brought up over
and over again and that is that what we\'re looking at and what we\'re
trying to figure out and what was already passed and so on and so forth,
and I guess part of what I need to respond to as the consumer advocate
is this is the document that\'s being presented in front of me as a
consumer advocate on this FDA panel and this is what I\'m looking to
give feedback on.

If this is what\'s being handed out, and I don\'t have a copy of
something that\'s being handed out with this, I\'m taking this as the
replacement, and the replacement needs to have feedback from us now on
what we\'re seeing now and where we are in time as far as what do
patients want now and what have we learned in the meantime, you know,
including anecdotal stories from people that have come and given
testimony or have written letters that we need to have that in hand and
the consumers have become much more demanding about what\'s going to
happen.

So in response to that, I think that expanding on some of the
information is only going to assist in providing this information and
benefiting the consumers, and if you\'re looking at aspects of this
where it talks about some of the adverse reactions, again, as I had
mentioned earlier answering a question that had nothing with it, and
that was talking about some of the terminology of some of the adverse
reactions, they talk about dryness. That doesn\'t sound like what I
heard today. What I heard today was somebody was talking about that
they\'ve got chronic dry eye. They\'ve got a lot of problems coming with
it. Saying that you have problems with driving at night sounds, while it
is a good example of an ADL problem, it is not necessarily indicative of
what\'s going on overall, you know, that you\'ve got a reduction in your
ability to see at night.

So those are the things that I think we are encouraging that we expand
upon, not things that are so far in left field that we\'re talking about
one case in eight million, but the fact that we\'re being more clear so
people are making more informed decisions and it benefits you in the
long run.

DR. WEISS: So perhaps without the panel having to make a final decision,
would it be something that the agency could pen in terms of inclusion
about more of the symptoms, loss of best-corrected visual acuity, and
loss of change of low contrast in visual acuity, or what you would need
from us, whether or not we want inclusion of the full table?

MR. WHIPPLE: No, I believe we could pen it, but what I want to explain
to you is that you really need to give us as much guidance as you can
about what you believe needs to be in this application\'s labeling and
don\'t necessarily let yourself be bound by all the precedents, although
some of the precedents are there. You have the right to look at this
application as a stand-alone application and decide what you think you
need to have in that particular labeling.

DR. WEISS: We don\'t have to make any final decisions now, but when we
come down to the final vote, it could be put forward as a motion and
those in favor will agree and those who are opposed will disagree and
conclusion can be drawn that way.

Mr. McCarley?

MR. McCARLEY: Yes, just very quickly. This is Rick McCarley.

One thing I would say is that if there are any recommendations I think
that the panel would make, in general terms, regarding LASIK, I think it
should be separated and then consideration should be taken by the FDA of
how you\'re going to get that out to the rest of the companies. This dry
eye issue, as far as I know, isn\'t inherent to this procedure that
you\'re discussing today for this application. So this is a new issue
that\'s industry-wide. I don\'t think this PMA application should be
burdened with having that as, you know, a portion of their labeling
while the other ones don\'t.

DR. WEISS: Dr. Bullimore?

DR. BULLIMORE: This is Dr. Bullimore.

I welcome the opportunity we have to set a precedent, and I would also
welcome the rest of the industry being asked to update their patient and
physician information to reflect the current climate. So I mean, if you
feel that the industry wants to come back to the FDA and update all of
the physician and patient booklets, I think the panel would be generally
supportive of that issue.

DR. WEISS: I can see them lining up.

(Laughter.)

DR. WEISS: Dr. Swanson?

DR. SWANSON: In terms of this patient booklet but also in the spirit of
changing it, under \"What Are The Benefits?,\" the table that we have
says what the best-uncorrected and corrected visual acuity are, but the
piece of information we got in the slides which isn\'t really in here
was comparison postop uncorrected with preop best spectacle-corrected
because what a person runs around thinking the vision is is what I can
see now, and the table we got showed that half of the people after LASIK
didn\'t have as good of vision without glasses as they had with glasses
before, and so a person sees an ad where they throw the glasses away or
something, it\'d be useful to communicate to them what\'s the likelihood
that you will be able to see just as well without glasses, and what we
saw in the slides today was about half the people were able to do that
and the other half were worse and that\'s not in the patient information
booklet, and I don\'t think it has been for other types of LASIK either.

DR. WEISS: Well, actually, I\'m trying to ‑‑ page 9 in the patient
information book has best-corrected visual acuity, and it has without
astigmatism 99 point ‑‑

DR. SWANSON: No, that\'s the postop best-corrected.

DR. WEISS: I see.

DR. SWANSON: If you compare postop uncorrected with preop
best-corrected.

DR. WEISS: Well, then in that case, you\'re sort of referring back to
the suggestion that I had that Table 10 be included because that talks
about ‑‑

DR. SWANSON: Is that Table 10?

DR. WEISS: ‑‑ best-corrected visual acuity. That\'s in the pink Insert
6. Perhaps too confusing, I don\'t know.

DR. SWANSON: Not loss of best-corrected.

DR. WEISS: It has change in best-corrected, best spectacle-correct
visual acuity for Custom spherical myopic LASIK eyes.

DR. SWANSON: Right. That\'s not what I\'m saying, though. Not change in
best-corrected.

DR. WEISS: I\'m not clear.

DR. SWANSON: Maybe I\'m not clear. What page is the table on?

DR. WEISS: It\'s Section 6, the pink section.

DR. SWANSON: It\'s 6, the pink section.

DR. WEISS: Pink section 6, and it\'s Table 10, and it talks about, my
assumption, preop best-corrected spectacle acuity versus one month,
three months, four months, and six months, and the decrease of one, two
or more lines, the increase of one, two or more lines.

DR. SWANSON: But that\'s best spectacle-corrected, both pre and post.

DR. WEISS: Correct.

DR. SWANSON: What I\'m saying is in the slides that we got, there was a
comparison. The postop uncorrected ‑‑

DR. WEISS: Oh, versus the preop?

DR. SWANSON: ‑‑ versus the preop best-corrected, what happens is half of
the people are not as good after the surgery as they were with their
glasses. The question of whether or not they\'re going to want to wear
glasses or something, but that\'s really not communicated to the person.
What are the benefits? The benefits are you have a 50-percent chance
that without glasses, you\'ll have as good acuity as you do now.

DR. WEISS: Dr. Bradley?

DR. BRADLEY: Yes, I think Dr. Swanson\'s point is a very good one, and I
recall from previous panel meetings that we have required the FDA and
the sponsor to include statements of the form of a certain percentage
likely, a certain percentage of patients will require spectacle
correction after the procedure to achieve their preop ‑‑

DR. WEISS: But here, I think the difficulty is that if you look at the
table in the patient information book, I think there\'s a surplus of
riches here because you\'ve got a 100 percent of nearsighted eyes ‑‑ I
see what you\'re saying ‑‑ uncorrected. Okay. Uncorrected, 20/20 or
better, with 80 percent.

DR. SWANSON: Yes. Maybe a table.

DR. WEISS: And that\'s in here. So the question is ‑‑ okay. It shows the
patient at six months, 91 percent are 20/25 or better and 80 percent are
20/20 or better. So would you like, in addition to the fact, pointing
out that only half of the people, 50 to 60 percent, were actually as
good as they were best-corrected? Do you think that\'s needed, in
addition to the fact of saying that 99 percent are 20/40 or better?

DR. SWANSON: Yes, because if a person has corrected to 20/15 and
they\'re walking around with glasses that way and you get them after
LASIK to 20/25, they won\'t be saying I got rid of my glasses because of
surgery.

DR. WEISS: Is there discussion on that on the panel? Do people want to
add that information?

Dr. Bradley?

DR. BRADLEY: Yes, it may be something that would be very important to
patients and they get the sense that LASIK is not as accurate as
spectacle or contact lens correction in the sense there is often
residual myopia and vision is not quite as good uncorrected as it is
pretreatment with a standard correction and really that\'s what patients
want. They want to throw away their glasses, as Bill was saying, and
therefore giving a sense of what ‑‑

DR. WEISS: Not quite yet, Dr. Swanson. After the meeting.

DR. BRADLEY: But I think to give patients a sense of how well they\'re
going to do after the procedure without glasses compared to how well
they\'re doing preprocedure with their glasses would be important
information, and in fact, I think it would be a very valuable marketing
tool really for the company providing the device in that they could say,
you know, 50 percent of you will see as well without glasses after as
you did with glasses before and say 85 will see within one line, you
know. I think this is tremendous news to the myope, and I think that\'s
an effective marketing tool. I think it could be a real positive.

DR. WEISS: So maybe we could just add a line that your uncorrected
visual acuity after this procedure may not be as good as your vision
with glasses.

DR. GRIMMETT: This is Mike Grimmett.

I\'d probably say 50 percent of patients see as well without glasses
postop as they did with glasses preop.

DR. BRADLEY: Yes, I\'d recommend putting the data in. Put another little
table in to show.

DR. GRIMMETT: That\'s fine.

DR. WEISS: Dr. Owsley?

DR. OWSLEY: Doesn\'t the sponsor provide this information in a
qualitative way on page 8 in the patient handbook, information booklet?

DR. WEISS: It\'s not comparing you to what you are with your glasses.
It\'s telling you what the level of visual acuity is, but let\'s say you
were 20/10 with your glasses.

DR. OWSLEY: Well, no. In the first paragraph under Section D, it says,
\"Although some people still needed glasses or contacts after surgery,\"
and I think the recommendation is we just need to quantify that.

DR. WEISS: So maybe just add that line there.

DR. OWSLEY: It would seem like it would go in that section.

DR. WEISS: Okay. Section D, LASIK Correction of Nearsightedness. Section
D, page 9. I don\'t think we have to use the line. I think the sentiment
is there.

Dr. Swanson?

DR. SWANSON: Yes, and I\'m sure that the FDA can handle that, but
someone who\'s 20/20 and could be 20/15 or 20/10 doesn\'t need glasses,
and so that sentence about who needs glasses is defined a little
differently. See, part of the issue is the patient expectation. The
patient\'s expecting I\'m going to come here as good or better than I
was with glasses, they\'ll be more disappointed than the patient that
understands I\'m likely to be 20/20, I may or may not get up to as good
as my glasses. Then they have a more reasonable expectation. They\'re
not thinking they\'re going to get super-vision, whereas this thing
about the percentage who need glasses, it depends how you define it.
Somebody who\'s 20/20 probably doesn\'t need glasses.

DR. WEISS: I think that\'s a very good point, Dr. Swanson.

Ms. Such?

MS. SUCH: Just a very, very non-technical way at the very beginning of
this patient information pamphlet where you have some description, very,
very lay terms, if you could just add a sentence that would say who
should get this. It could say something like ‑‑ I\'m sorry, not like. It
could say something as simple as if you would like to have your glasses,
you know, less strength to your glasses or perhaps not need glasses at
all, there\'s a procedure you could consider. That way, it is laid out
in the beginning that there\'s a chance, rather than taking it from the
other end that if this doesn\'t work, you will, but work from a positive
endpoint. If you\'d like to have a reduction in the strength of your
glasses or not need glasses at all, you should consider this surgery.

DR. WEISS: Any other additions?

Mr. McCarley?

MR. McCARLEY: Again, I\'d just like to reiterate, I think this sounds
like general labeling that would go to all companies, is that correct?

MR. WHIPPLE: All of this is good recommendations for updating
everybody\'s labeling, but we\'re still trying to focus on this, the
needs of this particular application.

MR. McCARLEY: Okay, and my second comment is, if there are any numbers
that are placed in there about, you know, what a clinical study has
shown as being the number of patients that achieved 20/40 or 20/20 or
20/10, I think it should be very ‑‑ you\'re almost going to have to
clarify that by saying what the objective was or using the subgroup
where you were trying to achieve emmetropia or something. I mean, there
are a lot of studies where the objective, for instance, is not
emmetropia, for instance, monovision or something like that.

DR. WEISS: I don\'t believe there are any monovisions that were included
in this.

MR. McCARLEY: I\'m not specifically talking about this study because
it\'s a general recommendation.

DR. WEISS: Well, actually, right now, we\'re just confining ourselves to
recommendations for this study. Whether the FDA chooses to broaden this
is their prerogative.

If there are no other comments, I\'d like to move on then to the FDA
Closing Comments for five minutes and then we\'ll move on to the
sponsor. Wait. I guess I don\'t want to move on. We have the Open
Hearing Public Session. Excuse me.

So are there any comments from the public? We have a comment from the
public. Mr. Link?

MR. LINK: Thank you.

Just three brief points.

MS. THORNTON: Could you identify yourself, please?

MR. LINK: I\'m Ron Link from Surgical Eyes.

Three brief points. Surgical Eyes recommends as a condition of approval
that clinical trials on postrefractive eyes be attached to this PMA.
Astigmatism above .5 is already not part of the PMA because of efficacy
concerns at higher levels of astigmatism. Given the large percentage of
patients in a holding pattern after previous refractive surgery with
conditions even more complex than simple cylinder, it is incumbent that
the efficacy of this wavefront device be monitored under controlled
conditions to prevent surgeries on patients who may not be helped and
are often limited by other factors, such as residual corneal thickness.

The second point. I\'m not really picking on the sponsor here. This is
something that was alluded to through the course of these proceedings,
that perhaps the

‑‑ not perhaps. That in fact the labeling and patient information
booklets across all laser platforms need to be updated. Referring
specifically to the PMA in front of us here, since the highest
percentage of complaints in postoperative dry eye, 32 percent as I
remember in the much worse to significantly worse category, it stands to
reason that these people had preexisting dry eye. It\'s like, you know,
an unexpected pregnancy. I mean, can you get more unexpectedly pregnant?
No. I mean, it seems to stand to reason that they had preexisting dry
eye.

Again, yet another point that this belongs in the professional
information and patient information booklets which would then in fact
also match the FDA\'s website which states as a preoperative risk, dry
eye, LASIK surgery tends to aggravate this condition.

Thirdly, quoting the sponsor, the Zernike coordinate system extends to
the edge of the pupil. Therefore, corneal maps of the Zernike-defined
aberrations change in pupil size. The FDA website warns under \"When Is
LASIK Not for Me? Other Risk Factors,\" \"Your doctor should screen you
for the following conditions or indicators of risk: large pupils.\"

Surgical Eyes recommends an indication that limits use to a 6.5mm pupil
to match the ablation zone of this device. We believe spherical
aberrations translated into patient language, night vision complaints,
would be lessened by such a limitation. We remain hopeful that after
further controlled study, that this device may in fact be appropriate
for postrefractive eyes.

Thank you.

DR. WEISS: Thank you, Mr. Link.

Now, I would ask for the FDA closing comments.

MR. WHIPPLE: I think the only thing I\'d like to say is that I think you
can see from this discussion that the labeling issues are really
challenging and very difficult, and I kind of think we knew that coming
in here. We wanted to let the discussion take its course without
interfering too much because we\'re going to need every bit of guidance
and every bit of direction that you can give us, and I think you\'ve
done that today. You\'ve given us some pretty good boundaries, and
you\'ve given us some what you can say and what you can\'t say
direction, and I think that will be very beneficial when we try to work
out labeling issues with the sponsor and it\'s going to be a long time
to try to address this with them. It\'s going to be as difficult as it
is here.

Thank you.

DR. WEISS: Thank you.

I actually just want to divert for one moment. Dr. Grimmett asked me
whether dry eyes was a contraindication or precaution, and I don\'t see
that. Without going through the rest of the data here, if I could just
ask the sponsor whether this was part of the entry criteria because
you\'ll be coming up, if you can come up for your closing comments in
any case, and if you, as part of those, can address that.

DR. PETTIT: With regard to the study, the dry eye issue, if the patients
had significant dry eye that could not be controlled with drops and what
have you, then they were excluded from the study. I don\'t think we have
a specific contraindication in the label to that effect at the present
time.

DR. WEISS: So would that be listed in the body of the study? Would I
find that in the body of the study, that the patients with significantly
dry eye were excluded?

DR. PETTIT: It\'s actually in the protocol, and we can find exactly
where that is.

DR. WEISS: So it\'s in the protocol, but would it be in the physician\'s
book? Because I don\'t see it in the physician\'s book.

DR. PETTIT: I don\'t know.

DR. WEISS: And I think Mr. Link\'s question would be then addressed to
why, if it was in the study, why would it not be in the physician\'s
book?

DR. PETTIT: It should be in the physician\'s book.

DR. WEISS: So just addressing myself to the panel and to Dr. Grimmett
who\'s scribing for me so kindly, maybe you can put that as an
additional.

Dr. Matoba?

DR. MATOBA: Alice Matoba.

But again, that applies generically to all LASIK, not to Custom
ablation, and we should separate out those things that we are
recommending specifically for Custom ablation and others that are going
to apply to all lasers and all LASIK.

DR. WEISS: But it is for this application. I think we run into a little
bit of a problem. The question is if you want to improve things, are you
prevented from improving things because you haven\'t improved them
before, and it would still apply to this PMA, although perhaps it should
have applied to other PMAs in the last couple of years. So we don\'t
want to be too burdensome. On the other hand, if we could make things
better for patients and doctors alike, we would like to.

So I\'m going to defer to Mr. Whipple as to whether we should withhold
from making improvements because it would be unfair to this manufacturer
sponsor or whether these improvements will actually improve the field
and not be too burdensome.

MR. WHIPPLE: I think you can make those recommendations for approval and
we\'ll deal with them as we go through the labeling with the sponsor.

DR. WEISS: And any of those who disagree with that on the panel,
obviously when that motion comes forward, you can disagree and vote it
down, if you so desire.

Dr. Burns? Sally, first.

MS. THORNTON: Are we continuing with the panel discussion or are we
doing ‑‑

DR. WEISS: No, actually, we\'re going to go the FDA response. Excuse me.

DR. PETTIT: No problem.

Just on behalf of the sponsor, I\'d like to thank you for your
thoughtful consideration of our application, and we really have nothing
else that we need to say at this point.

DR. WEISS: Well, in that case, what we\'re going to do is have the
voting options read at this point.

MS. THORNTON: These are the panel recommendation options for premarket
approval application.

\"The Medical Device Amendments to the Federal Food, Drug, and Cosmetic
Act, as amended by the Safe Medical Devices Act of 1990, allows the Food
and Drug Administration to obtain a recommendation from an outside
expert advisory panel on designated medical device premarket approval
applications or PMAs that are filed with the Agency.

\"The PMA must stand on its on own merits, and your recommendation must
be supported by safety and effectiveness data in the application, or by
applicable, publicly available information. SAFETY is defined in the Act
as reasonable assurance, based on valid scientific evidence, that the
probable benefits to health under conditions of intended use outweigh
any probable risks. EFFECTIVENESS is defined as reasonable assurance
that in a significant portion of the population, the use of the device
for its intended uses and conditions of use when labeled will provide
clinically significant results.

\"Your recommendation options for the vote are as follows:

\"APPROVAL, if there are no conditions attached.

\"APPROVABLE with conditions. The Panel may recommend that the PMA be
found approvable subject to specified conditions, such as physician or
patient education, labeling changes, or further analysis of existing
data. Prior to voting, all of the conditions should be discussed by the
panel.

\"The third option is NOT APPROVABLE. The Panel may recommend that the
PMA is not approvable if: the data DO NOT provide reasonable assurance
that the device is safe, OR if a reasonable assurance HAS NOT been given
that the device is effective, under the conditions of use prescribed,
recommended, or suggested in the proposed labeling.

\"Following the voting, the Chair will ask each panel member to present
a brief statement outlining the reasons for their vote.\"

Thank you, Dr. Weiss.

DR. WEISS: Thank you, Sally.

I would like to ask for a motion to be made from the floor concerning
this PMA.

Dr. Bullimore?

DR. BULLIMORE: Dr. Bullimore.

I move that the PMA is approvable with conditions.

DR. WEISS: Do I have a second?

DR. SWANSON: Second.

DR. GRIMMETT: Second.

DR. WEISS: Dr. Swanson and Dr. Grimmett second.

A motion has been made and seconded that this is approvable with
conditions. Then I would then ask for a motion to be made to introduce
each condition. We will second those motions and then vote on those
individual motions before we vote on the initial PMA.

I think Dr. Grimmett will list one by one the motions that have already
been introduced and perhaps introduce them and then if anyone wants to
second them and then we can vote on those individually.

Dr. Grimmett?

DR. GRIMMETT: Dr. Grimmett.

Just for clarification, I\'m making changes just for labeling, is that
correct?

DR. WEISS: And the other thing I think that we will need to add as to
whether these are labeling for physician booklets or patient booklets or
both. Sorry about that. You didn\'t know it was dangerous to sit next to
me.

DR. GRIMMETT: Yikes.

Labeling Condition 1, I\'m going to split it into three parts. There\'s
three different sentences. 1A, a comment by Dr. Bradley.
Wavefront-guided LASIK has demonstrated a slightly superior optical
quality (reduced monochromatic aberrations) compared with conventional
LADARVision LASIK and minor improvements in the visual acuity and
contrast sensitivity relative to conventional LADARVision LASIK.

DR. WEISS: Does anyone second that motion? Dr. Bradley seconds that
motion.

Can we have a vote on that motion? All of those in favor, please raise
your hands.

(Show of hands.)

DR. WEISS: Nine in favor.

All those opposed?

(No response.)

DR. WEISS: That\'s unanimous. Okay. Fine. That motion passes.

DR. GRIMMETT: Okay. 1B, related, forwarded by Dr. Bradley. The accuracy
of the correction for myopia is still the primary determination of
uncorrected image quality and vision. That\'s the corollary to the first
one we just approved.

Dr. Bradley\'s intent, just to describe, Dr. Bradley\'s intent during
the discussion was to make sure that the patient knows that the
spherical defocus is still the primary component rather than the
aberration statements we just made regarding superior optical quality.

Let me read the statement again. 1B, the accuracy of the correction for
myopia is still the primary determination of uncorrected image quality
and vision.

DR. MATOBA: Second.

DR. WEISS: We have a second from Dr. Matoba.

Can we have a vote? All those in favor, raise your hands.

(Show of hands.)

DR. WEISS: Nine. It\'s unanimous. The motion passes.

The first two motions, are these for the physician book, for the patient
book, for both? So we stay on track, maybe we could just repeat the
first one, determine retrospectively if it\'s for the patient or the
physician or both, and then from now on, then do it prospectively.

DR. GRIMMETT: These were initially discussed for the patient information
booklet.

DR. BRADLEY: This is Bradley.

I think they should be in both because as we discovered today, amongst
the physicians, there\'s still some confusion about the relative role of
aberrations in myopia.

DR. GRIMMETT: This is Dr. Grimmett.

I agree with Dr. Bradley that it should be in both. I submit that most
of the issues that we raised are actually probably going to be relevant
for both.

DR. WEISS: So the first two will be in both, and we will assume that all
of them are for both physician and the patient book, unless mentioned
otherwise.

Motion Number 3.

DR. GRIMMETT: 1C, related by Dr. Owsley. There are no data to support
improved functional performance (activities of daily living, such as
reading or driving) or satisfaction rates in patients with
wavefront-guided LASIK.

DR. WEISS: Do I have a second?

PARTICIPANT: Second.

DR. WEISS: We have some seconds. Can we have ‑‑ we can\'t discuss it.
Well, actually, yes, we can discuss it at this point. So yes.

DR. BRADLEY: If I recall, there was a question of the sponsor to provide
those data.

DR. WEISS: We can put this in there as is and then request that the
sponsor provide the data and then the FDA can change that statement on
receipt of the data. If it\'s contrary to that statement, we can make
that request.

Dr. Swanson?

DR. SWANSON: I may not have heard that. It\'s supposed to be relative to
conventional LADAR. Does it say that in there?

DR. GRIMMETT: I can add that.

DR. SWANSON: Because otherwise, it sounds like there\'s no benefit. It
hasn\'t been shown. There\'s got to be some benefit of getting to zero.

DR. WEISS: So maybe the statement ‑‑

DR. OWSLEY: It\'s true for all of them.

DR. WEISS: When you recount it, maybe you can reread it.

DR. GRIMMETT: Yes. It\'s true that it\'s compared to conventional
LADARVision LASIK for all 1A, 1B, and 1C.

DR. WEISS: Well, maybe we can just, in ease for Dr. Grimmett, when we
say conventional laser, maybe we can have the FDA understand for all of
the time we say conventional laser, we mean conventional LADARVision.

DR. GRIMMETT: Correct.

DR. WEISS: So that gets added, if it\'s not stated that way up front.

DR. GRIMMETT: Right. So just to reread, to summarize 1C, there are no
data that support improved functional performance (activities of daily
living, such as reading or driving) or satisfaction rates.

MS. THORNTON: Mike.

DR. WEISS: Speak into the mike.

DR. GRIMMETT: In patients with wavefront-guided LASIK compared to
conventional LADARVision LASIK.

DR. WEISS: Second, do I have?

DR. HUANG: Second.

DR. WEISS: We have Dr. Huang seconds.

Can we have a vote? All those in favor, raise your hands.

(Show of hands.)

DR. WEISS: All those opposed?

(No response.)

DR. WEISS: So it\'s unanimous.

DR. GRIMMETT: Michael Grimmett, again.

Labeling Recommendation, related by Dr. Bradley. Add a statement
regarding that there is a small number of eyes above 6 diopters.

DR. WEISS: Is there a way to rephrase that?

DR. GRIMMETT: Dr. Bradley?

DR. WEISS: Dr. Bradley?

DR. BRADLEY: The small number was one the way I saw it.

DR. GRIMMETT: There you go.

DR. BRADLEY: But I saw the sponsor checking that. Obviously they know
the exact numbers, but I think if the answer really is one, then we
should say one.

DR. WEISS: Only one eye was treated above.

DR. BRADLEY: Between 6 and 7, I think there was one. There was one above
7, I believe.

DR. WEISS: Well, you know what? I\'m sure the FDA can look it up for us
with the help of the sponsor. So we don\'t have to determine the number
now. Whatever that exact number was can be put into that phrase. So X
number of eyes were treated.

DR. GRIMMETT: Above.

DR. WEISS: Above -6.

DR. GRIMMETT: Six, with the intent that the strength of the data tapers
off for higher myopic ranges. That\'s the intent for labeling
recommendation.

DR. WEISS: But the phrase is just to list the number of eyes that were
treated above -6.

Dr. Matoba?

DR. MATOBA: I think Dr. Eydelman stated that the FDA has a standard
statement about the fact that there may be fewer numbers for the higher
ranges.

DR. WEISS: Mr. Whipple?

DR. MATOBA: So I\'m not sure it\'s necessary to do that.

MR. WHIPPLE: We do have statements like that, and we take what Dr.
Grimmett is saying as guidance, and we\'ll pretty much use the same
language we\'ve always used.

DR. WEISS: So can that be restated? If you can restate that so we can
get a second so we can vote on it?

DR. GRIMMETT: Statement. Michael Grimmett.

In the study, there were X number of eyes above 6 diopters spherical
refractive error.

DR. WEISS: Do I have a second? Dr. Bradley seconds. Vote? Those in
favor, raise your hands.

(Show of hands.)

DR. WEISS: We have seven in favor and four against.

MS. THORNTON: Dr. Matoba and Dr. Huang are against.

DR. WEISS: Two against. Seven in favor, two against. I think, Dr.
Bradley, if you want to make an amendment to that, you could make an
amendment at this point.

DR. BRADLEY: It\'s a very short amendment.

DR. WEISS: A shorter or long one can be made. Well, not too long but an
amendment can be made.

DR. BRADLEY: The statement that we had voted on is that there were X
number of dah, dah, dah. I think for the patient, it should be perhaps
stated there are only X number, indicating the point of giving them that
number is that it\'s a very small number. The physician will understand
this but the patient might not.

DR. WEISS: So as I understand, you would like to add the word \"only\"
to that?

DR. BRADLEY: Correct.

DR. WEISS: For the patient booklet specifically or for both booklets?

DR. BRADLEY: Specifically the patient.

DR. WEISS: Specifically the patient booklet, add the word \"only.\" Is
there a second? Second. Can we have a vote? All in favor?

(Show of hands.)

MS. THORNTON: Eight.

DR. WEISS: Eight in favor. Can we have against?

(Show of hands.)

MS. THORNTON: Dr. Matoba is against.

DR. WEISS: One against. Motion passes.

DR. GRIMMETT: Dr. Grimmett again.

This is a consensus statement. Conventional LADARVision LASIK increases
higher-order aberrations approximately 77 percent, whatever the correct
figure is, 77 percent over preoperative levels while wavefront-guided
LASIK increases higher-order aberrations approximately 20 percent over
preop levels. I would caution those numbers need to be verified by the
data.

DR. WEISS: Do I have a second? Dr. Bradley, Dr. Huang seconds. We will
vote. All in favor?

(Show of hands.)

DR. WEISS: Eight for. Can we have those against?

(No response.)

DR. WEISS: And then we have those abstaining?

(Show of hands.)

DR. WEISS: One abstention.

MS. THORNTON: Eight for and one abstention. Dr. Matoba abstains.

DR. WEISS: The motion passes.

DR. GRIMMETT: Dr. Grimmett.

Statement forwarded by Dr. Huang in his presentation. There are no
retreatment data available.

DR. WEISS: Do I have a second?

DR. GRIMMETT: I second.

DR. WEISS: I don\'t think you can second yourself. Dr. Owsley seconds.
Can we have a vote? All in favor?

(Show of hands.)

MS. THORNTON: It\'s unanimous.

DR. WEISS: It\'s unanimous. It passes.

DR. GRIMMETT: Dr. Grimmett again.

Forwarded by Dr. Weiss. Include a statement that the population is
primarily Caucasian, Part A, and Part B was include the demographic
data, which I think Dr. Eydelman stated is customary in applications.

DR. WEISS: Do we have a second? Dr. Bandeen-Roche seconds. Dr.
Bandeen-Roche has a comment.

DR. BANDEEN-ROCHE: A possible amendment.

DR. WEISS: Actually, yes, you can have a comment now.

DR. BANDEEN-ROCHE: Yes, a possible amendment would be that ‑‑

DR. WEISS: You don\'t have to amend now. You can ask the maker of the
motion if he wants to change it.

DR. WEISS: Maker of the motion, may it be changed to include individuals
65 and older? It seems to me if we\'re going to mention African
Americans, that older people are equally relevant.

DR. WEISS: Were there any people 65 or older?

DR. BANDEEN-ROCHE: There were not.

DR. GRIMMETT: So you would like to, just for clarification, add a thing
of the population is primarily Caucasian and younger than 65 years of
age?

DR. WEISS: Do I hear a second? Dr. Bandeen-Roche seconds. We can vote on
this revised motion.

Yes?

DR. BRADLEY: Again, I\'m not recalling the age distribution, but I
don\'t ‑‑

PARTICIPANT: Thirty-five.

DR. BRADLEY: Thirty-eight. Was there anybody over 55?

DR. BANDEEN-ROCHE: To 64, I believe.

DR. BRADLEY: Okay.

DR. WEISS: What we can do for clarification, I\'m sure the agency can
look at the highest age and say that there was no one above that highest
age, whatever it was. So that could be altered, but in any case, the
revised motion would include both age and race.

So we did have a second of that motion. We will have a vote. All in
favor, raise your hands.

(Show of hands.)

DR. WEISS: It\'s unanimous. It passes.

Yes, Dr. Grimmett?

DR. GRIMMETT: Dr. Grimmett again.

I have six labeling recommendations forwarded by Dr. Weiss. Number 1.
She pointed out in the patient information booklet a D2 which stated
that a statement that vision was stable two weeks after surgery should
be changed to reflect the actual data which was put forth as one month
after surgery.

DR. WEISS: Do we have a second? Second by Dr. Owsley and Dr. Matoba. Do
we have a vote? All in favor, raise your hands.

(Show of hands.)

DR. WEISS: We have nine. It\'s unanimous. It passes.

DR. GRIMMETT: Number 2 from Dr. Weiss. There was a chart ‑‑

MS. THORNTON: Excuse me. Is this 6A, 6B? Are we doing 6, 7, 8?

DR. GRIMMETT: Sure. Well, they\'re all separate issues. They\'re not
related.

MS. THORNTON: Thank you.

DR. GRIMMETT: Sure. I\'ve lost count. Dr. Grimmett again.

There was a chart on page 9 at the top that listed a statement on visual
acuity. Dr. Weiss would like it clarified to say that best-corrected
visual acuity, implying that it was visual acuity with glasses, for
clarification.

DR. WEISS: Do we have a second? Dr. Bradley seconds. Vote? All in favor?

(Show of hands.)

DR. WEISS: We have nine. It\'s unanimous.

DR. GRIMMETT: Dr. Grimmett again.

Include full Table 35 which included, I believe, all the symptom data
for the intent of including both the worse and significantly worse
categories but for balance including the whole table. So symptom data in
the labeling.

DR. WEISS: Do I have a second? Dr. Bandeen-Roche. Can we have a vote?
All in favor, raise your hands.

(Show of hands.)

DR. WEISS: Unanimous. That passes.

DR. GRIMMETT: Dr. Grimmett again.

A recommendation to add the entire Table 10 regarding the gain versus
loss of best-corrected visual acuity.

DR. WEISS: Do I have a second? Dr. Bullimore seconds. All in favor,
raise your hands.

(Show of hands.)

MS. THORNTON: Eight for.

DR. WEISS: Eight for, one against. Motion passes.

MS. THORNTON: Was that an against or an abstention? Okay. Dr. Huang is
against.

DR. GRIMMETT: There\'s a recommendation to add Table 13 regarding
information on low contrast best-corrected visual acuity. I would just
make a suggestion here. I\'m not sure if it would differ to panel
members to add that differently to the patient versus the physician
booklet.

DR. WEISS: How would you like to ‑‑

DR. GRIMMETT: Personally, I think it would mean more to physicians in
the physician book, but I don\'t know that patients would understand too
much information on contrast stuff.

DR. MAGUIRE: I second that.

DR. GRIMMETT: We can try it both ways.

DR. MAGUIRE: I second that for inclusion only in the physician booklet.

DR. WEISS: Okay. So I see consensus for that.

DR. GRIMMETT: We can vote both ways, if necessary, but let\'s start out
with that information on low contrast visual acuity in the physician
information booklet.

DR. WEISS: I see a second. We\'ll have a vote. All in favor, raise your
hands.

(Show of hands.)

DR. GRIMMETT: One clarification. We\'re making sure the table I quoted
was correct.

DR. WEISS: What table was it?

MS. THORNTON: Table 13?

DR. WEISS: 13.

PARTICIPANT: Can we just get a chance to look at it?

DR. GRIMMETT: Let\'s have everybody look at Table 13, Tab 8.

DR. WEISS: Has everyone found Table 13?

DR. BULLIMORE: Yes, but I thought we wanted ‑‑

DR. WEISS: I think Table 13 was under the pink Index 6, was that not?

PARTICIPANT: It\'s under Tab 6.

DR. WEISS: Tab 6? Well, I have a Tab 6 and a Table 13 on Section 6, page
20 out of 56, which has Change in Low Contrast Best Spectacle-Corrected
Visual Acuity.

DR. BULLIMORE: This is Mark Bullimore.

The one we discussed before was Tab 6, Table 13, on page 20.

DR. WEISS: Yes, which is what I just mentioned. Is there another table
that is identical? Tab 8, Table 13. Here\'s my Tab 6, Table 13. There\'s
your Tab A, if it\'s the same.

DR. BULLIMORE: No. No. Mark Bullimore.

Table 13 on Tab 6 is the Change in Low Contrast Visual Acuity. They\'re
different cohorts, basically.

PARTICIPANT: They\'re both Table 13 but different cohorts.

DR. BULLIMORE: Different cohorts. Tab 6 was the Efficacy Eyes Tab. Tab 8
was the Safety Eyes.

DR. WEISS: So which is the one we would want for inclusion? Tab 6, Table
13. So Tab 6, Table 13, the motion has been read by Dr. Grimmett and has
been seconded for inclusion of this table in the physician\'s booklet.

If we\'re all clear, we ‑‑ Dr. Bradley?

DR. BRADLEY: Just to iterate the point I made earlier with these tables,
if we knew in a non-LASIK population, if we took these datasets twice,
six months apart or three months apart, and found the same basic
distribution, these tables could be removed and a simple statement that
there is no evidence that low contrast acuity changes.

DR. WEISS: We can ask, if you\'d like, the sponsor.

DR. BRADLEY: Well, that was a comment to the FDA in future studies to
try and collect some control data of this type over time and that might
eliminate this complication that we have because it\'s quite difficult
to interpret a table like this.

MR. WHIPPLE: Well, I believe the sponsor can do those kind of studies
and submit, you know, additional data thus and have it removed at any
time passed the approval.

DR. WEISS: The other thing that could be done is instead of including
the table, it can be indicated there is a loss of low contrast best
spectacle-corrected visual acuity.

DR. BULLIMORE: Madam Chairman, I believe there\'s a motion on the table.
Call for the question.

DR. WEISS: Well, I think it hasn\'t been voted on and hasn\'t been
restated by me. So I think it still can get changed, if anyone wants to
change it, before I restate it.

DR. BULLIMORE: Okay. I\'m just trying to move things along.

DR. WEISS: It\'s gone beyond that. It\'s too late. But it doesn\'t sound
like anyone wants to change that. So if no one wants to change that, and
we have a second, we can go ahead with a vote. I\'ll restate it and
I\'ll ask for the vote and all of those in favor of that, including this
table in the physician\'s booklet, raise their hands.

(Show of hands.)

DR. WEISS: So it unanimously passes.

Any other motions?

DR. GRIMMETT: Dr. Grimmett.

Dr. Swanson wanted a statement regarding data that 50 percent of
patients see as well without glasses postoperatively as compared to
their best-corrected visual acuity preop and/or we can include a table
of information regarding that patients want to know what their
uncorrected visual acuity will be postop as compared to what their best
vision was preop with glasses.

DR. WEISS: Do you want to have that motion to include the table?

DR. GRIMMETT: I\'d have to have a specific to show me the table. I need
to see the table. Does someone know what that is?

PARTICIPANT: It\'s in a slide.

PARTICIPANT: Page 21.

DR. GRIMMETT: We\'re being directed to page 21 of the slides.

DR. WEISS: Here it is. The table name is on page 21, bottom slide, Slide
Number 139 from the sponsor, \"Postop Uncorrected Visual Acuity Versus
Preop Best Spectacle-Corrected Visual Acuity\" which is at one month, 59
percent have it equal, three months 55.4 percent, at six months 52.5
percent.

So the motion as it stands is to include the table?

DR. GRIMMETT: I\'d include the table.

DR. WEISS: Okay. So if you could restate the motion and then we\'ll see
if we have a second, then we can vote.

DR. GRIMMETT: Include a table as on page 21 of the sponsor\'s slide
presentation entitled \"Postop Uncorrected Visual Acuity Versus Preop
Best-Corrected Visual Acuity.\"

DR. WEISS: Okay. Do we have a second?

DR. SWANSON: Second.

DR. WEISS: Dr. Swanson seconds. Can we have a vote? All in favor?

(Show of hands.)

MS. THORNTON: Can you raise your hands a little higher, please? Eight
for.

DR. WEISS: Can we have those against?

(Show of hands.)

MS. THORNTON: Dr. Bullimore is against.

DR. BULLIMORE: Against.

DR. WEISS: Against. One against, eight for. The motion passes.

Any other motions?

DR. GRIMMETT: Yes, one more labeling issue. One more labeling issue and
then I have two more issues for requesting data from the sponsor, and
then Dr. Bradley has a few labeling issues.

The one more labeling issue on my list from Dr. Weiss concerns dry eye
patients and exclusion criteria in physician labeling to match the
protocol criteria. Make a statement relative to that issue.

DR. WEISS: And if it was going to be added to the physician booklet, I
would add it to the patient booklet as well just to map exactly what was
in the exclusion criteria of the study itself.

Do we have a second? Dr. Owsley seconds. Do we have a vote? All in
favor?

(Show of hands.)

DR. WEISS: It unanimously passes.

DR. GRIMMETT: Now, two requests. Is this request for data a separate
labeling issue?

MS. THORNTON: Let\'s put all the labeling together.

DR. GRIMMETT: Labelings together.

DR. WEISS: We\'ll do labeling and Dr. Bradley, I guess, will continue
and then if we have a request for information, does that get voted on?
It will get voted on at the end probably.

Dr. Bradley?

DR. BRADLEY: At several times today, there was a request that the
patient information and certainly the physician information include the
contraindications of dry eye and large nighttime pupils. I wondered if
that could be a motion.

DR. BULLIMORE: I\'d make a motion, if you like.

DR. BRADLEY: Please do.

DR. BULLIMORE: This is Dr. Bullimore.

Postoperative status ‑‑ let me start again. You try it. I want to
capture the spirit of something along the lines of poor patient
satisfaction may be associated with dry eye or large pupils and care
should be taken to screen patients prior to the procedure for these
predisposing factors.

DR. BRADLEY: I think screen and educate patients.

DR. BULLIMORE: I don\'t like the word \"screen.\"

DR. OWSLEY: It should be preoperative dry eye and large pupils.

DR. WEISS: That was Cynthia. Dr. Grimmett just brought up a point. Does
that specifically follow from the data in this study?

DR. BULLIMORE: I don\'t care.

DR. WEISS: Okay. Be that way.

Any discussion on that particular point?

DR. BRADLEY: Yes. I don\'t think it\'s an issue necessarily for the data
in the study, but the issue has been raised today and I think everybody
seems to agree that, sure, perhaps you shouldn\'t do this procedure on
somebody with dry eye. It\'s just going to get worse, and there are
these sort of ill-defined but widely held concerns that patients with
large pupils may have some problems, and as I think somebody pointed out
earlier today, this information is not adequately communicated to the
patient. So the intent that I had with this suggestion is that the
patient be alerted to these problems and also make sure the physician is
alerted and perhaps the patient and the physician can discuss this.

DR. WEISS: But when you say large pupils, would you want to be more
specific? Larger than the ablation zone or do you want to keep it at
that? Keep it broad?

DR. BULLIMORE: I\'d keep it broad.

DR. WEISS: So can you restate that and then maybe we can have a second?
Can you just restate what your ‑‑

DR. BULLIMORE: What did I say originally, Michael?

DR. GRIMMETT: I wasn\'t transcribing.

DR. BRADLEY: The preexisting dry eye condition and large nighttime
pupils ‑‑

PARTICIPANT: And/or.

DR. BRADLEY: And/or large nighttime pupils may decrease your
satisfaction with the LASIK procedure and you should discuss this issue
with your physician.

DR. BULLIMORE: I second.

DR. WEISS: Second. Can we have a vote? All those in favor, please raise
your hands.

(Show of hands.)

DR. WEISS: Nine in favor. It\'s unanimous. That passes.

Dr. Bradley, did you have another motion?

DR. BRADLEY: No, that was it.

DR. WEISS: That was the end of Dr. Bradley\'s motions.

Dr. Bullimore?

DR. BULLIMORE: This may not fly, but I\'d like also in the patient
information booklet to refer the patient to the FDA\'s LASIK website.

DR. WEISS: Do I have a second for that? I have a second. Mr. Whipple
seconds. But I have Dr. Swanson second officially, I guess. Can we have
a vote? All in favor, please raise your hands.

(Show of hands.)

MS. THORNTON: I have five/four.

DR. WEISS: We have five in favor. Can I have all of those against?

(Show of hands.)

DR. WEISS: We have three against. All those abstaining?

DR. BRADLEY: I didn\'t hear what Mark said.

DR. BULLIMORE: It\'s not the first time.

DR. WEISS: The motion will be restated.

DR. BULLIMORE: The motion was that the patient labeling refer the
patient to the FDA\'s LASIK website.

DR. WEISS: So Dr. Bullimore wants to refer patients to the FDA website
in the patient labeling.

DR. OWSLEY: Can I make a comment?

DR. WEISS: No, you can make a comment.

DR. OWSLEY: Well, the language maybe. It\'s not a bad concept, but to
refer them, I mean, they should be talking to the physicians about their
care. So perhaps if they want more information, they could check out the
FDA website.

DR. BULLIMORE: I accept that friendly amendment. This is Dr. Bullimore
again. I accept Dr. Owsley\'s friendly amendment.

DR. WEISS: So for more information, you can refer to the FDA website.

DR. BULLIMORE: Consult.

DR. WEISS: You can consult the FDA website.

DR. BULLIMORE: Consult the FDA website.

DR. WEISS: Do we have a second?

DR. SWANSON: Second.

DR. WEISS: Second by Dr. Swanson. Do we have a vote? All in favor?

(Show of hands.)

MS. THORNTON: Five.

DR. WEISS: Five.

DR. BULLIMORE: Six.

DR. WEISS: Six in favor. Those against?

(Show of hands.)

DR. WEISS: Three against. The motion passes.

If there are no other motions, then Dr. Grimmett will proceed with
requests for information. We\'ll vote on that.

DR. GRIMMETT: Dr. Grimmett.

There\'s a request for the manufacturer to submit the data for the 19
conventional versus wavefront-guided eyes regarding symptom and
satisfaction data.

DR. WEISS: Do I have a second to that?

DR. GRIMMETT: That should be put in the labeling, if indeed it\'s
available.

DR. WEISS: Do I have a second for that? Was that a weak second?

DR. BULLIMORE: I was waving to Dr. Bradley.

DR. WEISS: You\'ll second. Thank you, Dr. Bradley. You were pointing to
Dr. Bradley? Okay. Dr. Bradley seconds. Can I have a vote? All in favor?

(Show of hands.)

MS. THORNTON: Five in favor.

DR. WEISS: Five in favor. All those against?

(Show of hands.)

MS. THORNTON: Dr. Huang is against.

DR. BULLIMORE: Maguire.

MS. THORNTON: Dr. Maguire.

DR. WEISS: Two against, and those abstaining? Dr. Bandeen.

MS. THORNTON: Dr. Swanson abstains.

DR. WEISS: And Dr. Bandeen-Roche abstains.

MS. THORNTON: And Dr. Bandeen-Roche.

DR. WEISS: So the motion passes.

If there are no further motions, Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: We discussed a number of analyses that the sponsor
should submit or FDA should look at. Is that something we should vote
on?

DR. WEISS: If there is further information that you want, yes, it could
be put forward as a motion, but you need to specify whether it\'s data
that is already obtained and they just need to crunch the numbers and
give it to FDA or you\'re talking about anything postmarket.

DR. BANDEEN-ROCHE: Well, then I do move that a matched analysis be done
with respect to comparing the conventional and the Custom eyes and that
the site-to-site variability be examined. The FDA statisticians, I
think, will be able to interpret that data appropriately and the
ramifications are biased in the first instance and not correctly stating
the strength of evidence in terms of P values and confidence intervals
in the latter case.

DR. WEISS: Do I have a second for that? Dr. Owsley and Dr. Bradley
second that.

DR. GRIMMETT: Dr. Grimmett here.

Can you define how much data? Define again what you\'re asking for.

DR. BANDEEN-ROCHE: So the first thing I\'m asking for is a matched pair
analysis of conventional and Custom eyes, and so that would presumably
be as many to one matches as can be obtained within reasonable matching
specifications that I\'m not capable of stating but I\'ve heard pupil
size.

DR. WEISS: The problem is we only have 19 eyes.

DR. BANDEEN-ROCHE: No, no, no, no. This is not within ‑‑

DR. WEISS: Oh, I see. Not within the ‑‑

DR. BANDEEN-ROCHE: ‑‑ the provider by timing. I mean, we discussed this
earlier in the transcript.

DR. WEISS: Dr. Matoba?

DR. MATOBA: But the most number of pairs they can give you is 50, right,
because 50 were conventionally treated?

DR. BANDEEN-ROCHE: There could be multi-to-one match, and so, you know,
if there are more than one patient that appropriately matched to a given
conventional, that could be done.

PARTICIPANT: Question?

DR. WEISS: Mr. McCarley, and then Dr. Bradley.

MR. McCARLEY: Yes. I mean, when the data is submitted to the FDA, then
what? That\'s my question. If it doesn\'t meet something, then it comes
back to the panel or ‑‑ I mean, the recommendation is for approval, I
think.

DR. BANDEEN-ROCHE: Well, it\'s approvable with conditions, and so if you
observed that analysis and saw that in fact the difference between
Custom and conventional eyes with respect to aberrations was
substantially reduced, then that would suggest that there was bias in
the cohorts at work and that you might not want to strongly state there
is evidence that this procedure improves, if superior with respect to
aberrations. I don\'t expect that that will be the outcome.

DR. WEISS: Dr. Matoba?

DR. MATOBA: I\'m not sure if this information would change our
assessment of safety or efficacy.

DR. SWANSON: But it would change ‑‑

DR. WEISS: Dr. Swanson?

DR. SWANSON: Sorry. It would change one of our motions. We voted to put
a statement in there that it was better in terms of the optical quality
was better, and I think if this reanalysis showed it wasn\'t, we
withdraw that sentence we wanted to add. So I think that\'s why it\'s
relevant, because we\'ve said we want to add a statement and if the
analysis came out differently, we wouldn\'t want to add that statement.

DR. BANDEEN-ROCHE: That\'s right.

DR. WEISS: Dr. Bradley, and then Dr. Bullimore, and then we can go back.
Dr. Bradley?

DR. BRADLEY: I think it\'s typical when you do a matched design like
this, it\'s a means of extracting other sources of data from your
effect, and it usually results in a more significant result. So that\'s
a likely outcome, but it may not.

DR. BANDEEN-ROCHE: Right. I agree with that statement.

DR. WEISS: Dr. Matoba?

DR. MATOBA: Is it possible to get input from the statisticians at the
FDA as to if this is a significant issue, why it was not dealt with
before?

DR. WEISS: Dr. Eydelman or anyone else from the agency, do you have a
comment? Mr. Whipple?

MR. WHIPPLE: I think you should just make your recommendation. You know,
discuss it and make your recommendation, and we\'ll deal with it.

DR. WEISS: Okay. I think it might be helpful, Dr. Bandeen-Roche, if
perhaps you put each of those into a separate motion that we can vote on
rather than lumping them. So if you could just put into the motion the
first thing you had and we can second it and have a vote and then
continue on on those couple of things that you\'d like.

DR. BANDEEN-ROCHE: So the first motion would be for sponsor to submit a
matched analysis comparing aberrations in conventional and Custom eyes.

DR. WEISS: Do we have a second? Dr. Owsley and Dr. Bradley second.

Dr. Bullimore?

DR. BULLIMORE: Dr. Bullimore.

Friendly amendment. These patients can be matched for refractive error,
preoperative aberrations, or both.

DR. WEISS: Do you accept that, Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Absolutely.

DR. WEISS: If there are no other discussion about this, we\'ll have a
vote. All those in favor, raise your hands.

(Show of hands.)

DR. WEISS: Nine. It\'s unanimous. That passes.

Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: And the second motion is for there to be a
presentation of site-to-site variability in the aberration outcomes, the
reason being that there was no accounting for correlation within sites.
If there\'s substantial site-to-site variability, then confidence
intervals, P values, et cetera, are totally invalid as reported.

DR. WEISS: Do I have a second for this? Dr. Bradley. We\'ll have a vote.
All in favor, please raise your hands.

(Show of hands.)

MS. THORNTON: Three on this side. Seven and four.

DR. WEISS: Seven in favor. Can we have those against raise your hands?

(Show of hands.)

DR. WEISS: Dr. Bullimore is against.

MS. THORNTON: Dr. Huang is against.

DR. WEISS: Dr. Huang is against. Two against. The motion passes.

Dr. Bandeen-Roche, that\'s the end of the motions.

Does anyone else have any other motions?

DR. BRADLEY: Jayne?

DR. WEISS: Dr. Bradley?

DR. BRADLEY: As I raised in the correlational analysis in my
presentation, I\'m not convinced that the sponsor has demonstrated that
they are able to correct inherent aberrations, monochromatic aberrations
of the eye, and although often implied in the text of the patient and
physician information, it is certainly there the indication that they
are able to make these corrections, and I do believe that the sponsor is
required to demonstrate that they have corrected the inherent
aberrations of each individual eye, and I believe it\'s possible to do
with the correlational analysis, and I would defer to the statistician
on whether that is possible, but I think in order to make those sorts of
claims, you have to demonstrate that you\'ve done it.

DR. WEISS: Would you be able to comment as far as any other data that
would be able to support this? Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: My answer would be that it should be possible. I have
to admit that my mind was elsewhere during half of the comment, but I am
confident that a careful analysis can be designed. I would not be
confident in being able to state the best analysis in two minutes off
the cuff. I think it\'s something that should be considered quite
carefully.

DR. WEISS: Would there be anyone from the agency who would be able to
help with this as far as any other data that would satisfy this
question?

DR. BRADLEY: Let\'s clarify.

This is not an optics question really. It\'s a statistics question and
maybe a motion could be for the FDA to, with sponsor, to examine the
validity of the claim that the CustomCornea procedure is able to correct
the higher-order monochromatic aberrations of the eye.

MR. WHIPPLE: As I see this, you\'re in the middle of making your
recommendations, and I\'m afraid if we bring some more people into this
right now for your ‑‑

DR. WEISS: It would confuse things.

MR. WHIPPLE: Right. And so I would just rather you just make your
recommendations and if it\'s stated as you said, that would be an
appropriate recommendation for us to look at.

DR. WEISS: If you want to make that recommendation, we can put it
forward as a motion.

DR. BRADLEY: That would be my motion.

DR. WEISS: Do you want to restate that motion so someone can scribe it,
namely my loyal colleague to the left?

DR. BRADLEY: The motion is that the FDA and sponsor establish the
statistical validity of the claim that the sponsor has been able to
correct higher-order monochromatic aberrations of individual eyes with
the wavefront-guided LADAR System before any such claim can be included
in labeling.

DR. WEISS: Does anyone second that motion?

DR. HUANG: Second.

DR. WEISS: Second, Dr. Huang.

Dr. Bullimore has a comment.

DR. BULLIMORE: This is Dr. Bullimore.

I speak against the motion on the grounds that I find it all too
nebulous for this state of the procedure, and (B) I don\'t think we\'ve
included in the claims that it does in any way correct.

DR. BRADLEY: Just for clarification.

We have not included it but the sponsor has.

DR. WEISS: You can make a motion, if you want, to not have it in the
labeling. That\'s another way of going about it.

DR. BRADLEY: No, I don\'t think that would be appropriate because I
think there is a possibility in the data that they have done this, and I
think if that\'s correct, then it makes sense for them to put it in the
labeling.

DR. WEISS: So you want the data.

Dr. Swanson?

DR. SWANSON: I think we addressed that actually in one of the earlier
motions.

DR. BULLIMORE: Yes.

DR. SWANSON: Because we added the statement that it increases the
monochromatic aberrations of the eye in the patient information
brochure.

DR. WEISS: We added that it increases at less than conventional
treatment.

DR. SWANSON: Right.

DR. WEISS: So would that be satisfactory? Dr. Grimmett can read it back
to us. He\'ll read it back and then we\'ll see, Dr. Bradley, if that is
satisfactory to you or do you need more data.

DR. GRIMMETT: This is Dr. Grimmett.

The prior motion that we voted on and was accepted was that conventional
LADARVision LASIK increases higher-order aberrations approximately 77
percent over preoperative levels while wavefront-guided LASIK increases
higher-order aberrations approximately 20 percent over preoperative
levels.

DR. WEISS: Is that satisfactory to you as it reads?

DR. BRADLEY: Sure.

DR. WEISS: Sure. Hey, who says we don\'t compromise here? So is that
motion withdrawn?

DR. BRADLEY: Yes.

DR. WEISS: Yes. I think we\'ve hit the high points here and so I
personally would like to start wrapping this up, so to speak.

Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: I withdraw my comment.

DR. WEISS: Thank you so much.

(Laughter.)

DR. WEISS: So if there are no other comments, we will vote on PMA
P70043/SO10 with the conditions as stated, and I will point out that
this is for correction of myopia up to -7 as listed at the present time,
unless anyone wants to vote on any condition before we vote on all the
conditions and the main motion.

(No response.)

DR. WEISS: Hearing no other conditions, then we will vote on the main
motion with all the conditions attached. All of those in favor of this
PMA, would you please raise your hands? In favor of the main motion with
all the conditions that have been listed and voted on.

(Show of hands.)

MS. THORNTON: It\'s unanimous.

DR. WEISS: We have nine in favor. It\'s unanimous. The main motion and
the side motions pass.

I will now poll the panel as far as the reasons they voted the way they
did. We can start with Dr. Swanson.

MS. THORNTON: Would you state your vote and why you voted that way?

DR. SWANSON: I voted yes, and it\'s because basically as the panel, we
reviewed everything carefully and not always unanimous. We pretty much
worked to consensus even though it took us more time than we thought.

DR. WEISS: Well put.

Dr. Owsley?

DR. OWSLEY: This is Cynthia Owsley, and I voted yes, because there was a
lot of consensus and my own opinion was consensus for all the evidence,
including the conditions.

DR. WEISS: Thank you.

Dr. Maguire?

DR. MAGUIRE: Leo Maguire, voting yes, basically because there\'s not
much clinically significant difference between this PMA and earlier
approved PMAs.

DR. WEISS: Thank you.

Dr. Huang?

DR. HUANG: Andrew Huang.

I voted yes, because I think the data itself show enough on safety and
the efficacy, even though I have a personal reservation about the
expanded indication.

DR. WEISS: Thank you.

Dr. Bradley?

DR. BRADLEY: I voted approvable with conditions, because I believe the
sponsor has effectively demonstrated efficacy and safety well within the
FDA Guidance Document standards, and I believe with our conditions that
the value of this procedure to the patient can be effectively
communicated.

DR. WEISS: Dr. Grimmett?

DR. GRIMMETT: Dr. Grimmett.

I voted approvable with conditions, because I believe the sponsor has
effectively demonstrated reasonable safety and efficacy, and the
labeling concerns as previously listed will address to the patient the
specific issues with wavefront-guided ablations.

DR. WEISS: Dr. Matoba?

DR. MATOBA: Alice Matoba.

I voted approvable with conditions for the reasons that Dr. Grimmett
stated, but I hope that the FDA in considering our labeling suggestions
will take into consideration those suggestions that pertain specifically
to Custom laser ablation versus those suggestions that are generic to
all LASIK and consider how to enforce them in a way that will be fair to
the sponsor, so they\'re not singled out to have more stringent labeling
criteria than the other laser companies.

DR. WEISS: Thank you.

Dr. Bullimore?

DR. BULLIMORE: Mark Bullimore.

I voted yes, approvable with conditions, on the grounds that the sponsor
brought a very nice and thoroughly prepared PMA with some very
high-quality data, and I would commend them on that. I\'d also commend
them on their trying to advance the technology in this area.

I would like to express some caution and concern that the technology is
perhaps not ripe for everybody yet and in postrefractive surgery eyes
and in eyes that fall outside of the approvable range, I would hope that
caution would be exercised in off-label use of these devices or this
device until more data are available in the public domain.

DR. WEISS: Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: I voted approvable with conditions, because I thought
there was reasonable assurance of safety and efficacy within FDA
standards.

DR. WEISS: I\'d like to thank the members of the panel for their
opinions and their vote. We\'re going to now have comments from the
consumer and the industry representatives.

Ms. Such?

MS. SUCH: Yes, I wanted to thank the sponsors for a very
well-put-together submission as well as an excellent presentation today.
I also wanted to thank the FDA panel for their presentation on the
findings of the study as well as the panel themselves that had put forth
a lot of good points and a lot of excellent issues.

I would like to thank this panel as well as the FDA and the sponsors for
looking at the modifications to the labeling as a move towards
improvement rather than burden and to take this as a positive step as we
learn more information.

Thank you.

DR. WEISS: Thank you.

Mr. McCarley?

MR. McCARLEY: I\'d like to reiterate that I\'d request the FDA to
consider requiring all refractive laser manufacturers to revise their
labeling to include any general labeling restrictions or requirements so
as not to disadvantage the current sponsor.

DR. WEISS: Thank you.

I\'d like to thank the FDA for their insightful comments and review and
I\'d like to thank the sponsor for doing the study the way a study
should be done and that\'s really the highest compliment that I can give
you.

I think we will now adjourn this open meeting for 15 minutes and then we
will begin the closed meeting for the FDA and the panel. So I\'ll see
you back here in 15 minutes.

(Whereupon, at 4:37 p.m., the meeting was recessed, to reconvene in
closed session at 4:52 p.m.)