PARTICIPANTS

James P. McCulley, MD, Chair

Mark A. Bullimore, MCOptom, PhD

Eve J. Higginbotham, MD

Marian S. Macsai, MD

Joel Sugar, MD

Jose S. Pulido, MD

Janice M. Jurkus, OD

Woodford S. Van Meter, MD

Alice Y. Matoba, MD

Frederick Ferris, MD

Ming X. Wang, MD, PhD

Mark J. Mannis, MD, FACS

Lynn Morris

Marcia S. Yaross, PhD

FDA PARTICIPANTS

Sara M. Thornton, Executive Secretary

A. Ralph Rosenthal, MD

Morris Waxler, PhD

CONTENTS

[PAGE]{.underline}

OPEN SESSION

Call to order - James P. McCulley, MD, Chair 1

Introductory Remarks - Sara M. Thornton, Exec. Sec. 1

Conflict of Interest Statement 4

Appointment to Temporary Voting Status 5

OPEN PUBLIC HEARING 6

Karl G. Stonecipher, MD 7

Peter N. Arrowsmith, MD 13

Keith Liang, MD 17

OPEN COMMITTEE DISCUSSION - James P. McCulley,MD, Chair 28

PMA P990010

SPONSOR PRESENTATION

J. Charles Casebeer, MD 32

Guy M. Kezirian, MD 35

FDA PRESENTATION

Morris Waxler, PhD, Chief, Diagnostic and Surgical

Devices Branch 57

Jan C. Callaway, PMA Team Leader 57

Clinical Review: Bernard P. Lepri, OD, MS, M.Ed 58

COMMITTEE DELIBERATIONS

Primary Panel Reviewers: Mark J. Mannis, MD 74

Mark A. Bullimore, MCOptom,PhD 78

PANEL DISCUSSION 83

30-MINUTE OPEN PUBLIC HEARING SESSION 162

FDA CLOSING COMMENTS 165

SPONSOR CLOSING COMMENTS 165

Voting Options Read 168

PANEL RECOMMENDATION TAKEN BY VOTE 169

POLLING OF PANEL VOTES 183

CONCLUDING REMARKS 186

CONTENTS (CONT\'D)

OPEN COMMITTEE DISCUSSON PERIOD (Continued)

PMA980051

SPONSOR PRESENTATION

Douglas D. Koch, M.D. 187

R. Doyle Stulting, M.D., Ph.D.

Till Anschuetz

FDA PRESENTATION

Morris Waxler, Ph.D., chief, Diagnostic and 232

Surgical Devices Branch

Everette T. Beers, Ph.D., PMA Leader

CLINICAL REVIEW

Malvina B. Eydelman, M.D. 233

COMMITTEE DELIVERATIONS

Primary Panel Reviewers:

Marian S. Macsai, M.D. 250

Michael R. Grimmett, M.D. 258

Open Public Hearing Session 289

FDA Closing Comments 291

Sponsor Closing Comments 291

[P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
[E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
[N]{.underline} [G]{.underline} [S]{.underline} 8:13 AM

DR. MC CULLEY: I will call the meeting to order. I would like to turn
the floor to Ms. Thornton.

MS. THORNTON: Good morning, and I would like to welcome all the
attendees. Before we begin with today\'s agenda, I have a few short
announcements to make. I would like to remind everyone that you are
requested to sign in on the attendance sheets in the registration area
just outside the meeting room.

You may pick up an agenda and information about today\'s meeting, as
well as tomorrow\'s meeting and how to obtain summary minutes or Panel
transcripts. You should make a note that there is a Panel meeting
tentatively scheduled for September 23, 1999.

Information will be on our web site as soon as it can be put up.
Messages for Panel members and FDA participants, information or special
needs should be directed through Ms. Amory Williams or Ms. Theresa Lewis
who are available at the registration table.

For those of you with cell phones and pagers we ask that you turn them
off or put them in the vibration mode. Lastly, will, not exactly lastly,
will all meeting participants please speak into the microphone and give
your name clearly so that the transcriber will have an accurate
recording of your comments.

For those of you who will be making presentations at the presentation
table, this includes FDA staff, there are name tents on the tables. You
cannot see them, but pick out whatever name you like and put it up when
you prepare to make your presentation.

There will be possibly if time allows some network news filming during
the open public hearing portion of the meeting and possibly a little bit
further into the meeting. I just wanted you to be aware of that, and
now, I would like to extend a special welcome to the Panel and to
express FDA\'s appreciation to them for the time they have taken from
their busy schedules to prepare for this meeting. This has been a pretty
hefty load of documents for everyone to go through, and they have all
done very well, I am sure, and I really want to thank them for the
effort that they put forth to prepare for us today.

I would like to have the Panel now introduce themselves for the record,
beginning with Dr. Marcia Yaross.

DR. YAROSS: Marcia Yaross. I am director of regulatory affairs at
Allergan in Irvine, California and industry representative to the Panel.

MS. MORRIS: I am Lynn Morris, California State Department of Consumer
Affairs, Deputy Director.

DR. FERRIS: I am Frederick Ferris, Director, Division of Biometry and
Epidemiology, National Eye Institute.

DR. VAN METER: Woody Van Meter, private practice in cornea and external
disease in Lexington, Kentucky.

DR. MACSAI: Marian Macsai, professor of ophthalmology, West Virginia
University School of Medicine.

DR. JURKUS: Jan Jurkus, professor of optometry, Illinois College of
Optometry.

DR. HIGGINBOTHAM: Eve Higginbotham, professor and chair, Department of
Ophthalmology, University of Maryland, School of Medicine.

DR. PULIDO: Jose Pulido, professor and head, Department of
Ophthalmology, University of Illinois.

DR. MC CULLEY: Jim McCulley, professor and chairman, University of
Texas, Southwestern Medical School.

DR. SUGAR: Joel Sugar, professor of ophthalmology, University of
Illinois, Chicago.

DR. BULLIMORE: Mark Bullimore, associate professor, Ohio State
University, College of Optometry.

DR. MATOBA: Alice Matoba, associate professor of ophthalmology, Baylor
College of Medicine.

DR. MANNIS: Mark Mannis, professor of ophthalmology, University of
California, Davis.

DR. WANG: Ming Wang, Director of Refractive Surgery, Vanderbilt
University.

DR. ROSENTHAL: Ralph Rosenthal, Division Director, Division of
Ophthalmic Devices.

MS. THORNTON: Thank you, everyone. I would like to now read the conflict
of interest statement for the Ophthalmic Devices Panel meeting for July
22. The following announcement addresses conflict of interest issues
associated with this meeting and is made a part of the record to
preclude even the appearance of an impropriety.

To determine if any conflict existed the agency reviewed the submitted
agenda and all financial interests reported by the committee
participants. The conflict of interest statute prohibits 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.

A waiver has been granted for Dr. Ming Wang for his interest in a firm
that could potentially be affected by the Panel\'s deliberations. Copies
of this waiver 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 certain matters
regarding Drs. Mark Bullimore, Frederick Ferris, Janice Jurkus, Marian
Macsai, Mark Mannis and Ming Wang. These individuals reported past
and/or current interest in firms at issue but in matters not related to
today\'s agenda.

Therefore the agency has determined that they may fully participate
today. The agency, also, considered Dr. Michael Grimmet and Dr. Mark
Mannis\' reported involvement related to vision correction. In the
absence of any financial interests the agency has determined that they
may participate fully in today\'s deliberations.

In the event that the discussions involve any other product 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 interests 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.

Thank you, and I would like to now read the appointment to temporary
voting status for today\'s meeting. Pursuant to the authority granted
under the Medical Devices Advisory Committee charter dated October 27,
1990, as amended April 20, 1995 and October 10, 1997, I appoint the
following individuals as voting members of the Ophthalmic Devices Panel
for the duration of this meeting on July 22, 1999, Drs. Frederick
Ferris, Mark Mannis, Woodford Van Meter, Alice Matoba, Ming Wang.

I, also, appoint Dr. Michael Grimmett as a voting member of the Panel
for the discussion of the homium(?) laser for the correction of
hyperopia. For the record these persons are special government employees
and are consultants to this Panel or consultants or voting members of
another Panel 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. This appointment order
was signed by Dr. David W. Feigel Jr., Director of the Center for
Devices and Radiological Health, July 21, 1999.

Thank you, Dr. McCulley.

DR. MC CULLEY: We will now begin the open public hearing. This is a
30-minute session. There have been three individuals who have stated
prior to the meeting that they wished to speak and have been allotted
time. Time allowing in this 30-minute session, others will be recognized
to speak. I am not allowing, I will make note for you that there will be
another 30-minute session for open public hearing near the end of the
Panel\'s deliberations. So, the clock will be running.

Each of the individuals who has been allotted time has been allotted 10
minutes maximum.

Dr. Stonecipher?

Please identify yourself and any interests, financial interests, ties
that you might have?

DR. STONECIPHER: Good morning. I am Dr. Carl Stonecipher. I feel very
honored to have this opportunity to speak before this Panel with regard
to data for laser in situ keratomileusis. It has been a pleasure to work
with this group of individuals over the past 3 years and finally see
these endeavors come to fruition. I have no vested interest in either
the company\'s laser technologies that we are looking at nor other
industry-related conflicts that I think would interfere with my
presentation to this Panel.

I do serve as a clinical adviser to Laser Vision Center\'s, but I am not
currently paid consulting fees from them other than travel reimbursement
to and from meetings regarding those consultations.

I have been associated with refractive surgery since its inception in
the US with the National Eye Institute\'s initial radial keratotomy
trials. As a medical student, I helped collect data for these trials for
one of the investigators. I have had the opportunity to work with the
Excimer laser starting with bench-top models back in the late eighties.
I was first exposed to the VISX and Summit lasers in clinical trials in
the late eighties as well. I have participated in a peripheral role in
data collection for these trials, as well as watched these lasers come
to approval in 1995.

I started my research career as a student at Southern Methodist
University. My first exposure to FDA-oriented trials was as a medical
student. Through my fellowship and my residency, we continued many of
these trials, as well as their data collection and clinical monitoring.

The number of FDA trials that I participated in as a primary
investigator, associate investigator or peripheral data collector is
many. These trials have included pharmaceuticals, techniques, technology
and at present laser vision correction. Today at my center we are
actively involved in seven different FDA trials. It is with this
background that I come to you today to try to present one person\'s
opinion with regard to this data collection set.

I have submitted data, both for the Summit and VISX laser arms in this
trial. I have participated in this trial since its inception when
roughly 20 surgeons came together and decided that we needed to validate
laser assisted in situ keratomileusis. We felt that our techniques and
technologies were evolving toward LASIK and the laser manufacturers had
no incentive to go and try to get approval for these techniques and
technologies. With the brainstorming of several individuals these trials
were put together. I applaud their efforts because they have not been
easy.

With our support, both physically and financially the data is now being
reviewed after 3 years. Some have chosen to criticize the feasibility of
a surgeon-funded study. As a participant in many FDA trials, I can
assure you that the rigors that I went through with this trial were
equal to that of any other FDA trial. These included site visits as well
as clinical monitoring and clinical monitoring of the data collection
sets.

Although we did not have the economics to promote the fanfare of
meetings and publications of our early work, the participants paid to
hold regular meetings to present the clinical data in controlled forums.
This allowed us to monitor the data and monitor our progress as a group
and as individuals.

An FDA approval of LASIK will improve my delivery of medical care. At
present I cannot discuss LASIK with the laser manufacturers. That
creates a problem with application of the technology and techniques
using the laser that has been approved for photorefractive keratectomy
but is used by the majority of the ophthalmic community for
laser-assisted in situ keratomileusis. The development of LASIK
nomograms are definitely surgeon dependent; however, as with PRK we see
that those laser nomograms can be improved when the laser companies and
the surgeon are in direct communication. The inability to freely
exchange ideas did not originate with the surgeons and the
manufacturers. It extends from the restraints imposed by limited
approval. Today we have manufacturers making lasers for photorefractive
keratectomy that are in fact used for laser-assisted in situ
keratomileusis. They should be able to make lasers that are specific for
laser-assisted in situ keratomileusis. The difference may not be major
but there will be some differences in the computer software programs for
the use of these lasers with regard to specific patients and patient
treatments.

Although clinical trials have never been a problem to me, they are
foreign to many individuals in the general ophthalmic community. I think
using a device as an off label is the choice of the surgeon, but it
would be better if we had the process approved so that discussions among
the laser manufacturers and surgeons could take place.

At present my patient population is confused as to what we are really
doing. Why are we performing LASIK when the FDA has labeled the lasers
for PRK? I do not think that sends a good message to the general
population. The informed patient is a better candidate. At present when
I advertise laser-assisted in situ keratomileusis I do it as a clinical
treatment trial. There is always an asterisk that labels the FDA
protocols we are going through. I know it is a better procedure. I have
done both PRK and LASIK, but PRK has the official standing of FDA
labeling. It would be much better to send a consistent message to the
patient population as a whole.

I understand that there are no good guys and no bad guys in this
equation. As I understand it this is the first collaborative LASIK trial
to come before this Panel. My point is not to lay blame but to encourage
a remedy for the current situation. As a profession we simply must bring
the labeling in line with the actual use of the lasers.

There will always be new technology, and there will always be FDA
treatment trials for new technology. Through the efforts of the CRS
LASIK study, laser-assisted in situ keratomileusis now has a proven
track record. Yes, there is room for LASIK to improve. Much of the data
in the CRS database were early cases done by pioneers in the field while
trying to iron out nomograms and techniques. Yet, the data is good.
LASIK is a proven procedure.

I see a bright future for physician sponsored studies. When industry and
physicians can work hand in hand, it makes it much easier for those
involved as well as it produces better outcomes for patients. Our
profession has a history of constantly striving for better techniques
and technology. I think that industry cannot always afford to burden the
load of clinical studies and the approval process. I applaud those
individuals including myself, for contributing the effort and money to
bring this study to this point. I challenge the critics to look at the
data in the clinical setting and the clinical monitoring in a true
light.

The CRS LASIK study has been conducted as a true clinical treatment
trial. I consider the protocols and follow-up equal to any other FDA
study that I run presently. I treat patients in this study no
differently than any of my other trials and rely on the clinical
monitoring in the same fashion as any of my other industry-related FDA
trials. There may not be as many bells and whistles in this study, but
it has been efficiently run. I applaud those individuals who have put
this together and who have persevered through the trials and
tribulations associated with the start-up process like this one.

I want to thank the Panel for giving me the opportunity to make these
comments. I intend to be here all day if you have any additional
questions.

Thank you.

DR. MC CULLEY: Thank you.

Do any of the members of the Panel have a question for Dr. Stonecipher?

Seeing none, Dr. Arrowsmith?

Thank you, Dr. Stonecipher.

DR. ARROWSMITH: Good morning. My name is Dr. Peter Arrowsmith.

DR. MC CULLEY: Please state any conflicts or support or anything or lack
thereof?

DR. ARROWSMITH: I have no conflicts of interest and no financial
interests in any of the companies involved or products involved with
LASIK. I am a board-certified ophthalmologist, licensed and practicing
in Nashville, Tennessee, for 22 years. I am an active member of the
American Academy of Ophthalmology, the American Society of Cataract and
Refractive Surgery and the International Society of Refractive Surgery,
as well as my own state and local societies.

I wish to speak to you this morning as an experienced refractive surgeon
who has, also conducted research in this field for approximately 2
decades, first on my own and then with a group of four researchers with
two very experiences academic researchers and now with the CRS study
group. I wish to share my opinion with you of the CRS study.

Since 1980, my practice has predominantly focused on refractive surgery.
I have performed a wide variety of procedures including approximately
5000 RKs, 00 Barraquer Cryolathe Keratomileusis procedures, the
forerunner of RK, ALK, PRK and now over 2000 LASIK procedures. I, also
perform intracorneal ring implantation and Artisan myopic lens
implantation. I have authored and published a number of scientific
reports, reporting results of my prospective studies of RK including
5-year results and a mathematical prediction model for that surgery.

I have been invited to present my work at the National Eye Institute and
have been awarded grant approval for two prospective refractive surgery
studies. I have, also been a consultant to the FDA PERK study for RK. My
practice is now devoted exclusively to refractive surgery and related
research. I care a great deal about refractive surgery and the care and
results provided for patients of my own and this country\'s increasing
number of refractive surgeons and their patients.

When I began performing LASIK approximately 3 years ago, after a number
of PRK procedures I quite naturally wanted to follow my results with the
primary goal of constant monitoring of results, improvement of my
technique and improvement in predictability of this procedure which was
as I found so much better than its grandfather Cryolathe keratomileusis
a decade earlier. I began this study on my own but soon became aware
that the CRS study group was undertaking such a study, and I might be
able to participate in this. Upon investigating the CRS study, including
its protocol, its training requirements, not only for the surgeon, but,
also for the office staff, to ensure reliable data collection and
reporting the scale of the study and its scope and importantly its key
directors, Dr. Charles Casebeer and Dr. Guy Kezirian I became convinced
that this was a study that I wanted to be a part of.

I felt that in this study I could make use of a well-organized and
scientifically sound protocol. I could then receive help from the
directors and their staff in monitoring the data entered by my office in
terms of quality and completeness, obviously crucial to being able to
retrieve any useful information upon analysis. I could, also, receive
assistance with the analysis from qualified and experienced researchers
who understand ophthalmic data and I could participate in the sharing of
results, experience and brainstorming with like-minded colleagues at
frequent meetings of study participants, and I must note that at these
meetings they, also, served to promote the scientific purpose of the
study and continually encouraged completeness and best possible
follow-up and to answer questions and provide guidance on issues of
study administration within our individual studies and practices.

I am pleased to say that my expectations for the CRS study most
definitely have been surpassed. Participation in such studies is not
without a price. I devote resources to help support the CRS study. This
includes fees paid directly to the study and the cost of extra staff and
their man hours required in the practical administration of the study in
my practice.

The CRS study has demonstrated that LASIK performed as prescribed upon
eyes of qualified patients using the VISX Star and Summit Apex laser
with the Chiron Automated Shaper or the Chiron Hansatome is a safe and
effective refractive procedure. This conclusion is clear based on the
CRS data study quality and on the findings of the study which meet or
surpass the FDA\'s specific criteria for unaided visual acuity, change
in best-corrected acuity, refractive results and adverse effects.

I am still an investigator in three CRS FDA studies for hyperopia and
its subgroups. In addition, I am a Phase II investigator in the
manufacturer\'s FDA study of the Ophtec Artisan lens for correction of
myopia. So, I will be continuing to learn from all of this work. I am
pleased and proud to be a part of this CRS study. I made the right
decision to participate in this scientific study group and its very
worthwhile efforts towards studying and elucidating the results of a
treatment modality which is used by the vast majority of laser vision
correction surgeons in the United States in preference to the initially
approved PRK.

This is because it has been found to be better patient care and although
participation in such studies is not without a price, these are
resources well spent when spent within the CRS study. It is a study of
excellent quality. Its findings speak for themselves. Please give the
CRS study and its findings, as well as its request for a PMA your most
favorable review. It deserves this on all counts as do the surgeons who
perform LASIK and the patients who benefit from this advanced
technology.

Thank you.

DR. MC CULLEY: Thank you, Dr. Arrowsmith.

Do any of the members of the Panel have a question for Dr. Arrowsmith?

Seeing none, Dr. Liang?

DR. LIANG: I am Dr. Keith Liang. I was previously on the Advisory Panel
for LDC. I am no longer on the Advisory Panel, and I have no other
conflicts of interest.

Good morning. It is a pleasure to be here. I want to echo my sentiments
with the previous two speakers. Intraocular implants, clear corneal
cataract surgery, macular pucker membrane peels, trabeculectomy and
minomicin(?) an LASIK, all these advances in our field by innovative,
thinking physicians, as physicians we are encouraged to think outside
the box in order to continue advancement in our field of ophthalmology.
The ability to solve problems, create solutions attracted many of us
into medicine. The challenge to invent new instruments, refine surgical
techniques, design new drugs provides an ongoing stimulation in our
careers and our lives.

It is this innovative thinking that benefits our patients\' vision, and
this continued innovation led me to explore LASIK as a better
alternative for my patients. The ability to make a difference attracted
me to join the clinical study for LASIK. As a resident at LSU, we were
one of the original Taunton(?) and VISX sites taught me the value of
research by clinical trial.

The firsthand experience allowed me to appreciate the effort,
determination and time required to bring a good idea to clinical
application. During the involved process it became evident that a
variation of the original PRK protocol could be beneficial or more
beneficial to our patients. When at 2 am in the morning I have to call
in Demerol shots for PRK patients, control their high pressures from
post-op steroid regimens and also explain corneal haze to higher
corrective myos, I realize that better alternatives must exist. I began
to hear and explore alternatives from my international colleagues called
LASIK which alleviated many of the patients\' undesirable effects such
as pain, slow visual recovery and haze from higher corrections.

I realized the effort to bring this innovative idea to the US would be
in the best interests of the patients. After observing the procedure
firsthand in 1995, and examining the patients I realized this would be
an effort that I wanted to put forth in helping bring this technique to
the United States.

The CRS study for LASIK continues this innovative thinking and allows
physicians to regain some autonomy in the direction of refractive
surgery. It enabled us to study a procedure which we felt was best for
our patients and allowed us to validate what we felt clinically. The
study allowed for an efficient enrollment of patients in a timely
fashion. The study protocol and the reporting of information allowed
quick and easy review to allow feedback to the investigators in a
continuing fashion.

The Panel\'s expedited review of the CRS data and possible approval
encourages us that we can still make a significant difference and a
contribution to the current health care system, that our continued
innovations will benefit the advancement of our surgical specialty and
the benefit of our patients.

Thank you.

DR. MC CULLEY: Thank you, Dr. Liang.

Do any of the Panel members have questions for Dr. Liang?

Seeing none, we now have a few minutes remaining in our 30-minute open
hearing discussion. One individual did call in and make a request. I,
therefore, will give that individual precedence. Anyone else, time
allowing, we will allow further comments. The time restrictions will
continue on individual speakers, and I would now like to offer Dr. Ron
Link the opportunity to speak.

PARTICIPANT: You put an MD after his name.

DR. MC CULLEY: Mister, sorry.

MR. LINK: For clarification purposes, yes, I am a consumer, not a
doctor.

DR. MC CULLEY: Thank you. I was going to say either that or you are
British, and if you will state any interests, conflicts that you might
have, financial interests?

MR. LINK: I have no financial or other conflicts with any proceedings
here today.

DR. MC CULLEY: And you paid your own way here and home?

MR. LINK: Absolutely. Good morning, members of the Ophthalmic Devices
Panel and members of the audience. I am thankful to be here today. I am
here as a representative of the Surgical Eyes Foundation, a grassroots
organization formed by consumers whose eyesight was needlessly damaged
by the refractive surgical procedures of ALK, RK, PRK and now, LASIK.
Our goals are simply these, to raise awareness of the issues, identify
lasting solutions and provide support for the post-refractive surgical
failure. It is our committed stance to work with the industry, not
against it. The phone book version of our web site rests here under my
hand. Our web site in its current form just had its 50,000th visitor
since its inception just over 2 months ago. During this period I have
answered over 1250 e-mails, a significant percentage from people who
have had negative outcomes from LASIK.

There are some of you here today who may be thinking, of course, there
are going to be negative outcomes. No surgical procedure is without
risk. We agree. We are here to work in concert with the medical
community and I say, again, not against it. That being said we are
compelled to call attention to the hard-earned larger truths that we,
the casualties of refractive surgery have learned and will have to live
with for the rest of our lives.

The standard of care in refractive surgery must be raised. How? In two
fundamental ways. No. 1, using new modalities to determine what
qualifies as a successful outcome, meaning in clear English that
potentially debilitating complications be defined to include ghosting,
polyopia, starbursts, glare, haze, blur, halos and any other symptoms
currently not acknowledged in contemporary and historical complication
rates.

You will most probably hear talk today of BCVA, best corrective visual
acuity. The ability to recognize symbols of our language in the
controlled static high-contrast environment of a doctor\'s office,
letters of the alphabet on an eye chart, a device invented in 1862. The
time is now to include other modalities besides an eye chart invented
more than a century ago as a primary indicator of post-refractive
surgical success as represented to the public through print, radio and
other media.

No. 2, better pre-op evaluation, namely, identifying counter indications
to surgery meaning sharing with the patient how the consent form applies
to their own unique set of eyes and expectations, measuring pupil size,
contrast sensitivity testing before and after, glare testing before and
after, testing for predisposition to vitreous detachment, keeping up
with all the latest scientific journal literature, identifying
pre-existing ocular conditions like eye muscle imbalances which might be
exacerbated, warning the high myo that the chance for complication is
greater. Thirty-five cents from every contact lens sold goes into R&D,
research and development. There ought to be a fund set up which comes
out of refractive surgery profits to study and develop lasting solutions
for the post-refractive surgical failure.

Many of the hundreds of negative outcomes which have e-mailed our web
site were, in fact, preventable had there been an aggressive mechanism
for identifying and sharing all complications. Given the proliferative
success of current procedures like LASIK is there even less of an
industry inclination to study and acknowledge poor outcomes? If there is
substantive help, why are hundreds of failures in the just 2 short
months of our existence ending up at our web site? We are just ordinary
people. Clearly something is wrong.

Why isn\'t there a national industry or surgeon association maintained
database of agreed-upon complications that include those crowding at our
door? Is it the responsibility of the patient to have to form and join
an organization like ours? If the post-refractive failure only tells
their surgeon, and that is as far as it goes, how can anyone say that
they have accurate complication rate figures? Of the stats that have
been maintained by different laser centers complication rates vary from
zero to 15 percent and there is the lack of agreement on what qualifies
as a complication.

Quoting the doctor who spoke here previously if the data is good, the
data is not complete. As a former career firefighter I used to drive a
hook and ladder and put up 100 foot aerial ladder during a late night
thunderstorm within inches of a peak of a roof where men\'s lives
depended on it. Today because of my refractive surgery I cannot even
parallel park a small Toyota once the sun goes down. Since my surgery I
see five traffic lights instead of one, and oncoming traffic looks like
an approaching phalanx of exploding stars. My eyesight is a success
according to techniques promulgated by a manual taught to thousands of
surgeons from coast to coast. I am defined a success. Despite the
published scientific journal of Drs. Applegate and Holiday who clearly
warned in published results years before and after my specific surgery
that pupil size was of critical importance, there was no mention of
pupil size by Dr. Case Baird, the author of the manual on which the
parameters of my surgery were based.

For the sake of the future of LASIK and the welfare of patients who have
the right and the expectation of good eyesight I hope and pray that what
is offered here today will indeed raise the bar for the standard of care
as it applies to LASIK. We strongly encourage the FDA and all ophthalmic
professionals to do what is necessary to prevent the recent and present
history of refractive surgery from becoming the thalidomide of tomorrow.

In this bag, all the contact lenses, devices and drops that I have tried
since my surgically created visual deficits. Members of the Panel and
audience, thank you for your time.

Mitch Farrow who is a member of our board of trustees is, also, here,
and if there is an opportunity wold like to speak for just a few
minutes.

Thank you.

DR. MC CULLEY: Thank you, Mr. Link.

Are there any questions of Panel members for Mr. Link?

Dr. Bullimore?

DR. BULLIMORE: Thank you for your comments. Just for clarification,
which procedure did you have?

MR. LINK: I had radial keratotomy April 7, 1995.

DR. BULLIMORE: Thank you.

MR. LINK: I have copies which go into further detailed, culled from our
web site which I will leave on the table outside.

Thank you very much.

DR. MC CULLEY: Thank you, Mr. Link.

We are nearing very closely the end of the 30-minute open session.

Are there any other people in the audience who would like to speak very
briefly?

Okay, you have, can you do this in 2 minutes?

MR. FARROW: I will try my best.

DR. MC CULLEY: That is what you have.

MR. FARROW: My name is Mitch Farrow. I thank the Panel for the
opportunity to speak today. I, also, do not have any conflict of
interest or any financial interest in laser vision correction. I am,
also, representing a consumer of LASIK. When I drive to work every day,
fighting the DC traffic I hear lots of great advertisements including
the advertisements from the center that did my surgery talking about 95,
98 percent, whatever the percentage is of their patients who achieve
20/20 or 20/40 or better vision, and they consider that a success. I am
considered a success by that criteria as well.

However, in anything but extremely bright daylight I am visually
impaired by starbursts, halos, multiple ghost images because of LASIK
done on my 8-millimeter pupils. I am not asking you today to not approve
these devices or to not advance refractive surgery. In fact, I want to
see advancements so that they can improve my conditions. What I am
asking you today is to consider all the issues with respect to visual
quality in assessing these devices. Specifically I ask the FDA to
consider the following: No. 1, expansion of required clinical trials,
study parameters to include contrast sensitivity testing, both pre- and
post-op, glare testing, pre- and post-op, incidence of diplopia and
third-party independent assessment of vision.

When I go to my surgeon and they refract, do testing on me, they test me
at 20/20. When I go to other third-party independent objective medical
professionals the test me at 20/30, and they do refract me as well. No.
2 is FDA approval of devices should include not only approval within a
certain range of myopia or astigmatism or hyperopia but within a range
of pupil sizes such that any use of that device outside of that pupil
size should be considered against the FDA approval of that device, and
finally, and I am trying to make this short because I have 2 minutes,
third of all, the FDA should create and enforce guidelines regarding
advertising and marketing of these devices. I do see a guideline here
that was included in the packet. I found out about this meeting last
night, went home, opened my Newsweek, and there is an ad for, I guess
Crylosak(?) with about a paragraph of benefits, a couple of paragraphs
of side effects, an entire page of warnings and indications. There is an
ad here for ZOFOR(?) again with a couple of paragraphs of complications,
side effects, an entire page of contraindications and side effects, and
finally, an advertisement for laser vision correction with a paragraph
of how this is doing to improve your visual acuity, you know, great
things and no indications of any potential side effects. If I read your
guidelines here, the marketing of RKPRK LASIK to consumers should not
contain express or implied claims that are false or unsubstantiated or
omissions of material information. I think my inability to see in the
lighting in this conference room is an omission of material information,
and I respectfully submit that to you today.

DR. MC CULLEY: Thank you. Are there questions from the Panel members?

Seeing none, we thank you, and this concludes the open public hearing.
We will now begin the open committee discussion with Dr. Rosenthal
giving a division update.

DR. ROSENTHAL: Thank you, Mr. Chairman.

I will take the opportunity to thank the Panel for coming and knowing
that they have 2 rather arduous days and four applications, and we very
much appreciate all the effort that they put in as primary reviewers and
all the advice that they will be giving us.

I have some news about personnel to the Division of Ophthalmic Devices.
We have added four members, three who are on board and one who is coming
on board next week, Joel Glover who is a biomedical engineer who has
arrived from the NIH, the National Eye Institute, with a long history of
ophthalmic research behind him, Eva Rohrer who is a medical officer who
has just finished her fellowship at Johns Hopkins, Eric Selfontz who has
arrived to do some of the technical administrative work and is a CST. I
never can remember what it means, but consumer safety technician, and
Karen Copeland who will be a secretary who will be joining us on August
1.

I should like to, also, inform the Panel that the Division of Ophthalmic
Devices has been enlarged by an additional branch called the Ear, Nose
and Throat Branch and one day we will rename the Division which will
appropriately designate that ear, nose and throat is, also, part of the
Division of Ophthalmic Devices, but we will not ask this Panel, probably
to rule on EMT devices in the future.

I, also, would like to make a statement concerning bioresearch
monitoring. I think when most of the Panel members are indoctrinated
into the system they are given some information about bioresearch
monitoring, but many of the new members may not know what it really is
and many of the members of the Panel who have been around for a while
may have forgotten. So, I would like to refresh your memory in a generic
way.

The Food and Drug Administration\'s bioresearch monitoring program or
BIMO was established in 1977 by a task force that included
representatives from all the FDA Centers. Congress mandated that FDA
develop and implement an agency-wide program. BIMO monitors sponsors,
IRBs, clinical investigators and non-clinical laboratories involved in
the testing of investigational devices.

The objectives of BIOMO are twofold: One, to ensure the quality and
integrity of data and information submitted in support of an
investigational device exemption, and IDE, premarket approval
applications, PMA, and premarket notifications (510(k)s); and two, to
ensure that human subjects taking part in investigations are protected
from undue hazard or risk.

The Division of Bioresearch Monitoring\'s operations are directed toward
several program areas. These include: (1) audit of clinical data
contained in PMAs prior to approval; (2) data audits of IDEs or 510(k)
submissions; (3) inspections of non-clinical laboratories that perform
medical device related safety testing for inspection of IRBs that
monitor investigational device studies; (5) enforcement of the
prohibition providing education, training and guidance to regulated
industry and (6) implementation of FDA\'s Application Integrity Policy.

If you would like additional information about bioresearch monitoring,
please contact Charma Konnor who is the Director in the Division of
Bioresearch Monitoring. That applies to all PMAs.

Another item I would like to bring to the attention of the Panel
concerns some of the complaints we have received about the sunrise PMA
which we will consider this afternoon. FDA and Panel members received
several complaints that Sunrise\'s clinical investigators held
significant amounts of stocks, options or warrants in the company and
that by virtue of these equity positions the data generated by these
investigators was, therefore, biased.

One of the faxes contains complaints about the design and execution of
the study as well as the question of bias in the study. The issues
raised by these complaints are not on the agenda for Panel
consideration. FDA advisory panels were established to advise the agency
on scientific and clinical issues that arise during the consideration of
applications and other clinically related issues. They are not intended
to deal with conflict of interest or data integrity issues.

If we find that data in an application suffers from such infirmities
that application may not be presented to the Panel until all such issues
have been resolved satisfactorily. In fact, when issues related to the
integrity of the data are discovered appropriate action may be taken at
any time prior to or after Panel review or at any time prior to or after
FDA approval of the application.

FDA is concerned about the integrity of the data or the design and
conduct of the studies in all of our applications, and we have a very
active and effective program to assure our decision making is based on
accurate, complete and unbiased data and information.

Our staff takes very seriously any allegations concerning these matters,
and we will look into these allegations and take whatever actions are
appropriate. However, our investigations are discussed in camera and not
discussed with the public or with the informants from whom we have
received information.

Thank you, Mr. Chairman.

DR. MC CULLEY: Thank you, Dr. Rosenthal.

We will now begin deliberation on PMA P990010. We will begin with a
60-minute sponsor presentation, and again if each person who speaks for
the first time will identify yourself and your position relative to the
PMA?

DR. KEZIRIAN: Good morning, ladies and gentlemen. Thank you very much
for allowing me to appear before you and thanks to the FDA staff for a
lot of cooperation and courtesy during this. I am Charles Casebeer. I am
Chairman and founder of CRS Clinical Research, the applicant for this
PMA. I am the senior medical monitor of the CRS LASIK studies and so you
know I have no financial interest in any of the products that are
involved, I guess, other than the fact that I am the Chairman of the
company that is sponsoring the PMA.

I thought it might interest you to know a little bit about CRS before we
really get into it. So, we are going to present you with this agenda,
the goals of the study, the history and evolution of CRS and this study
done by myself, then the study logistics, monitoring and results by Dr.
Guy Kezirian and then a few concluding comments at the end by myself.

CRS started in March 1996 to look at what was going on with LASIK when
we became aware that although the laser had been approved for PRK, it
seemed and it turned out to be true that the majority use was going to
be in LASIK, and it brought up some issues about the public welfare,
performance of the lasers in a procedure that had not really been
studied before. So, we formed this small group, at that time totally
independent of anybody with the surgeon-funded study before it became an
IDE to study this procedure.

We formed an affiliation with the International Society of Refractive
Surgery and our goal really was to try to validate or invalidate for
that matter the use of the lasers in LASIK.

In the summer of 1996, we had a meeting with the FDA, and it was
requested that we convert this to a federal IDE which we have done. The
letter of approval was received in October. There is an explicit letter
of understanding about how it will be performed and frankly at that time
we didn\'t know or even expect that we might have the opportunity to
submit or participate in the submission of a PMA, and we are very
grateful to have that opportunity.

What we wanted was for the American ophthalmologists, the people in the
trenches who have a lot of skill and interest to participate in the
validation and refinement of this procedure and based on early
experience we knew that we needed to study the application of the PRK
algorithm to LASIK.

Mostly what we wanted was to make the procedure safe for the public and
discourage unproven application of laser technology beyond the limits
that were known to be valid. So, what we really hope that this will lead
to is validation or approval of LASIK with the technology that is
available in America today through the normal FDA approval policy and
that it will be for all doctors and all of the public rather than for a
few doctors or a small sector of the public, and we have given a lot of
interest in software-specific matters for LASIK and of course, we hope
that labeling now will allow the technology to be LASIK specific.

We set the study up, and Dr. Kezirian will tell you much more about it
to be practical, to be compatible with the practice of ordinary
practitioners. He will tell you that we taught them how to be clinical
investigators but we did not want it to be onerous, and of course, we
obviously wanted to study standards of care and affect standard of care,
make nomogram adjustments and ultimately as we are with this application
establish performance criteria for higher myopia and allow which we have
been this interactivity between ourselves and the investigators to
become aware of things that either are problematic or that might improve
the safety and effectiveness of the procedure.

This application involves a combination of two CRS studies, one LASIK
and the range for which the lasers are approved for PRK and then what we
designated substudy A which includes high myopia and astigmatism. Our
company has multiple other variations with both VISX and the Summit
laser relating to hyperopia and other variations of that, and we are
conducting a similar study on behalf of the Nidek laser.

The study has been open to qualified ophthalmologists. The
qualifications are clear but we do hope that it is a reflection, and we
think it is a reflection of LASIK in general use as opposed to smaller
areas, research centers, companies or other things. We do have IRB
oversight and of course, we do conduct it as an IDE.

So, I am very grateful to be here with you, and I will introduce Dr. Guy
Kezirian.

DR. KEZIRIAN: Good morning, and thank you for this opportunity to
present to you this morning. I am Guy Kezirian. I am a consultant to
CRS. I have been from the beginning of the study and work for CRS in a
capacity as such. I have been involved with the study from the point of
view of helping to write the protocols, liaison with FDA, helping to
recruit investigators, organizing the meetings, personally crunching the
data, the database involved with that, personally, with assistance
preparing the applications. So, I have a thorough exposure to the study
from its beginning to today.

The data collection process was one of the things that empowered the
study to actually work. We had a program called data site which allowed
for remote data entry at each clinic directly in and avoided a whole
layer of paperwork and a whole layer of logistics for us and allowed us
to impose these things called data entry filters which are simply range
filters on the data to prevent 100 being put in for 10, for example.
What it didn\'t do, what these data filters don\'t do is to take two
plausible entries and know that one of them is wrong, for example,
saying that a patient is a plano(?) and uncorrected acuity of, or let us
put it the other way, patients of minus 10 and uncorrected acuity of
20/20. It didn\'t have that ability to do those relational things.

So, those problems that did exist, dates being juxtaposed, that sort of
thing that weren\'t caught were hand picked out through a systematic way
that we developed and have been listed in the application for your
perusal.

But overall that program was very, very helpful to us in limiting data
entries and allowing us to accumulate a rather large database in a
rather quick fashion.

We were very careful to have the sites conduct the study in a uniform
fashion and to do that took a certain amount of time, but Dr. Casebeer
and/or myself visited every single site as it got going and spent time
educating and presenting to the staff and the surgeon about study
conduct, requirements for logistics and compliance and exactly what we
expected of them.

We performed ongoing data monitoring for reporting compliance, adverse
events, nomogram development and other things that will come up a little
bit later in the presentation and that occurred on a continuous basis,
and we presented those results three to four times a year in public to
our presenters, to our investigators and to the affiliate society, ASRS.
So, we obtained a large amount of feedback as we progressed with the
study.

The studies inclusion criteria have been listed in your handout, and
they are for bilateral pre-existing, naturally existing spheroequivalent
myopia of minus 1 to minus 15 diopters with .25 to 6 diopters of
astigmatism in a stable eye. Gas permeable contact lenses were required
to be out for 3 weeks and soft lenses for 3 days, 18 years or older or
enrollment and signing an informed consent and able to complete the
6-month follow-up.

The exclusion criteria are listed here in summary. The eyes were
required to be normal, no previous surgery, diseases. The last item,
diagnosed autoimmune disease as an exclusion criteria is something that
I believe will come up in the FDA\'s comments. We were able to exclude
patients on medication, system medications for autoimmune disease by
excluding the disease per se.

Operative parameters with the VISX STAR laser were an ablation zone of 6
millimeters, confluence of 160 milliJoules per centimeter squared,
repetition rates of either 5 or 6 Hertz. One keratome was used in this
entire study which is the Chiron ACS. We currently are using other
keratomes, but the data were cut off at such a time that those keratomes
hadn\'t yet been introduced. So, your data are pure with the Chiron ACS
keratome, and the calculations pre-operatively were required to predict
at least 250 microns residual corneal tissue to remain after the
ablation.

Nomograms were used and encouraged. We found very early on that the
difference between the PRK and LASIK algorithms with the VISX STAR laser
are significant, and in fact we suspect that our ability to recognize
through collaborative databasing and our ability to publicize that as we
did may have saved the overcorrection of many eyes around the country.

Nomograms were developed in conjunction with CRS. We would actually
participate and actually crunch the numbers for them and help them to
understand what nomogram adjustment to make to their particular
procedures based on their own outcomes. Fellow eye treatments were
permitted same day if everything went well in the first eye, but if it
didn\'t then not until the first eye had been recovered to best
corrected acuity of the pre-operative level and then it would be
permitted at that point.

Reoperations were allowed but only after 3 months which allows us to
present to you in a 3-month time period only single procedure outcomes,
and as you will see they are quite strong and speak for the single
procedure success of LASIK but by no means suggest that second
procedures aren\'t a part of LASIK because they clearly are in some
eyes.

We froze the protocol for June 1, 1998, to allow us to present to you
completed patients from the study. Follow-up was required at 1 day, 3
months and 6 months. A 1-month exam was optional but was provided from
many centers to allow us to accumulate stability. Investigators
consisted of 11 surgeons at 11 centers and overall there were 1276 eyes
submitted in the PMA application, in the overall cohort. We chose to
divide the cohort into two subgroups, what we termed the PMA cohort
where we took the data from any investigator whose compliance was 80
percent or better at the 3-month observation and we had in that group
723 eyes and 11 investigators that were used for the safety and efficacy
evaluation. That allows us to satisfy good accountability at 3 months
and have reliability on the efficacy rates.

The remainder cohort was the rest of the investigators whose 3-month
compliance level did not meet 80 percent. These were, also, submitted in
the PMA and used to verify safety. We had eight investigators and 553
eyes in that group. We examined them rigorously as requested by FDA in
several different ways for differences between the two groups and found
no statistical differences between the two cohorts, with the exception
of a slight trend, not statistically significant for the remainder
cohort, the one that was not used for efficacy to have better results,
the explanation being that from the investigators anyway that the
patients with the good outcomes were difficult to bring back for the
3-and-6-month exams.

Study results. Accountability is shown here with 90.3 percent at 3
months, dropping to 76.3 at 6 months. We had 90.3 percent Caucasian, .7
percent black, 4.9 percent Asian and 4.1 other in a demographic race
distribution, a slight preponderance of females to males in enrollment
and right and left eye distribution rather symmetric.

The age distribution mirrors the age distribution seen in most
refractive study reports, with the preponderance in the middle-age
range, a mean age of 41 plus or minus 9 years which is almost exactly
what other people seem to report. A range of 18 to 65 years was reported
in the study. Attempted corrections averaged 5.85 diopters in sphere
only corrections with a range of 1 to 13.76 diopters. Spherocylinders
averaged 594, quite close with a range of .25 to 14 and a mean attempted
correction of cylinder of 1.19 diopters. Now, these were the attempted
corrections, amounts actually attempted to be achieved as opposed to the
pre-operative refraction which differed slightly, people sometimes
attempting to correct less than the full amount.

These are reported here with a distribution that mirrors somewhat the
general population. We have a little bit higher representation in the
upper refractive ranges about 20 eyes above 12 diopters a little bit
higher representation than you see in the general public which we
thought would be good for evaluation in that range.

Pre-operative cylinder distribution focus is mainly up to 3 diopters.
Beyond that we have 11 eyes. This actually exceeds the distribution in
the general population again. It helps us to evaluate outcomes in that
range.

Pre-operative best corrected visual acuity was 20/20 or better in 92
percent of the eyes and worse than 20/20 in 8 percent with the
corrections under 7 diopters.

One of the protocol requirements, if you recall was best corrected
acuity of 20/40 or better. So no one was worse than 20/40. In the higher
group 78 percent were 20/20 and 22 percent fell below 20/20 and better
than 20/40. So, that perhaps impacted our later results a bit.

We present safety results first. The targets that are listed here are
the targets that are provided in the October 10, 1996, FDA guidance
document. Our actual risk protocol predated that guidance document. We
came close on most of the targets and in fact, I was serving on the
refractive technology forum at that time and had some ability to try to
match them, but what we did with our subsequent protocols is to exactly
match them. So, what we are doing today in that request of FDA is to
present to you our results against the published guidance documents.

They are listed here, and I am sure you are familiar with them. On the
loss of two lines or more best corrected visual acuity the target rate
is 5 percent, and in all eyes for either of the refractive subgroups we
fell within the 5 percent level, getting up to 1.4 percent in the over 7
diopter group at 3 months but that actually improves at 6 months to .7
percent.

Best corrected visual acuity of worse than 20/40 the target is 1
percent. We meet it for all eyes but exceed it for the over 7 diopter
group and we do so slightly both at 3 months and 6 months although with
a trend toward improvement. The less than 7 diopter group did not
experience this complication, remembering again that some of those eyes
were close to 20/40 when they began.

Best corrected acuity worse than 20/40 in the higher group was a
question to us because we were concerned that perhaps it was a trend
that the higher you went the more best corrected acuity loss you would
achieve. So, we look at it in terms of 1 diopter stratifications and
find that in fact it is not a trend. There is this little cluster
between 9 and 11 but no trend for loss of best corrected acuity was
apparent as you went higher, and remember that the number of eyes
although we probably were better than the general population the number
of eyes in the higher ranges was very low. So, any given eye has a
significant weighting of percentage rates of outcomes. We actually had
four eyes at 3 months that met the target of 20/40 or worse and two eyes
at 6 months but because of the dwindling Ns toward the higher refractive
ranges those two eyes and four eyes end up exceeding the target.

Inducing greater than 2 diopters of cylinder and spherical corrections,
in other words causing cylinder where there was none did not occur at
all in this protocol either at 3 or 6 months either for low or higher
myops, and adverse events occurred with these rates. The black numbers
are within the target of 1 percent. Interface epithelium was reported at
1.2 percent rate but we found that we looked at each of these eyes and
none of them were beyond trace, so a little nest, a small nest of cells,
none with best corrected visual acuity of 20/25, worse than 20/25 in
this group.

So, although that existed and as an absolute on a rating scale, none
were worse than trace.

Operative complications, intraoperative complications existed at these
rates with some of these being more observations than complications, for
example, a free cap isn\'t understood to occur at its given rate, but
there have been reported here in detail overall .1 percent of procedures
were aborted because of an intraoperative complication. That was related
to a keratome. There were no procedures aborted due to a laser failure,
and despite again that list of complications that is up again, surgery
did not have to be aborted except for in .1 percent of eyes.

Complications reported at 3 and 6 months are listed here, and because we
did not control for dry eyes in the study they had to have a normal
ocular exam, we suspect that the staining that is reported here at 2.3
percent may be related somewhat to a dry eyed population but we cannot
verify that. It is pure speculation.

Cumulative complications reported, how many eyes experienced any
complication at any time point was 4.1 percent, whether in the low or
high group, treatment group and again that similar complication rate was
reassuring to us that by going higher we weren\'t automatically causing
more complications.

We did not find a significant ability to predict what would happen to
IOP after LASIK. We did find that overall the trend was for the
intraocular pressure to decrease. We had a small group of eyes that
increased between 1 and 5 points, but we didn\'t find any eyes that or
we didn\'t find any trend to the pattern of overall IOP reduction. We
looked at it from every point of view and tried to regress against
everything at FDA\'s request to try to obtain a formula by which we
could predict in the future how much IOP change would occur, but we were
unable to do so. However, we did meet the requirement for not having IOP
elevations above 10 in this series. So, IOP is not a complication of
LASIK in this area which is a significant benefit in my mind.

To summarize the efficacy results again using the FDA targets listed
here, you will see that we actually add an extra slide because it often
comes up what was the 20/20 rate. So, we provide that information as
well, but it is not a stated FDA target in the guidance.

We showed using the mean measurement method to evaluate stability the
mean spheroequivalent in a paired eye analysis, you understanding that a
paired eye analysis is to use the same eyes for measurement at each
interval as opposed to whoever shows up for one interval against whoever
shows up for the other interval to allow you to have tracking of
patient-to-patient what happened in those eyes. This is a paired eye
analysis and in all eyes we show very little change in the mean sphere
of equivalent from 1 to 6 months, the same in the 7 diopter or less
range and the same in the 7 diopter to 14 range with less than .2
diopter drift in the mean spheroequivalent. However, if you look at it
in the other way of looking at stability how many eyes showed less than
1 diopter sphereoequivalent change in two observations we show with a
target rate of having 95 percent of the population showing less than 1
diopter change, we show that for all eyes we almost make it at 94
percent. We do exceed it at 96 percent in the under 7 diopter group, and
we fall short in the over 7 diopter group at 3 months, 1 to 3 months.
Going 3 to 6 months we meet it in all eyes. We meet it in the under 7
diopter group again, and we still fall short in the over 7 diopter
range.

So we show that the mean change in the population was minimal after 1
month. Stability was achieved beyond 3 months per the FDA definition for
the overall cohort and beyond 1 month for the less than 7 diopter group,
but the rates of stability were slightly less and took longer to occur
in the over 7 diopter group, and we were, also, able to show that there
was no difference in stability occurring whether it was a spherical or a
spherocylindrical correction.

The target of uncorrected acuity 20/40 or better, the target is 85
percent. We meet that target in all eyes in under 7. We are a little
short in the over 7 diopter group at 3 months. We meet it across the
board by 6 months with 86 percent in the greater than 7 diopter group
and 95 percent overall.

Uncorrected acuity of 20/20 or better, of course taking out the eyes who
didn\'t have 20/20 or better pre-operative best corrected acuity, so you
weren\'t asking an eye that was best corrected 20/40 to see 20/20,
looking just at those eyes we find that the 20/20 rates were 53 percent
overall and 59 percent in the under 7 diopter range and 39 percent over
7 diopter range, improving a little bit in the under 7 diopter group
between 3 and 6 months but staying fairly stable in the over 7 diopter
range of 39 percent.

One day visual acuity probably accounts for a great deal of the
public\'s acceptance of this procedure and their enthusiasm for it, and
we show why here. One-day acuity of 20/20 is 43 percent in the under 7
diopter group and 20/40 or better in the under 7 diopter group is 92
percent and that is quite remarkable and allows people to return to
functional vision quite rapidly. Even in the high myops it is 72 percent
in the 20/40 level on the first postoperative day and clearly presents a
relief for the practitioner and the patient alike coming from previous
procedures.

The plus or minus 1/2 diopter target is 50 percent. It was met across
the board at 3 and 6 months with the rates reported here.

The plus or minus 1 diopter target is 75 percent and it is reported
again with everybody except for the over 7 diopter group at 3 months.

Nomograms were used and encouraged in this study and I think are
essential in LASIK. We developed them in a process that allowed us to
look at the overall laser behavior over the full range of refractive
correction. We would create that profile, take an individual\'s
outcomes, compare them to that profile and mean adjust the entire
profile to the investigator\'s outcomes. It allowed us to generate a
nomogram with maybe 20 eyes from an investigator but based on thousands
of eyes from everyone pooled together looking at the overall behavior of
the laser and we were able to monitor how those were occurring and
control them because they reported to us what they were doing in each
operative report.

You can see how necessary they were when you look at the
no-nomogram-adjusted results when I take the amount that was programmed
into the laser versus the amount achieved, a mean of 11 percent extra
correction compared to what was expected, and if you look at the plus or
minus 1 diopter line which is depicted here, you can see that a
significant trend especially toward higher correction of overcorrection
that would have been unacceptable.

Nomogram-adjusted outcomes eliminated that tendency for overcorrection.
You can see that our regression line falls toward the minus 1, in the
plus or minus 1 range, and that was intentional. We wanted to avoid
overcorrections. This protocol existed before we had access to hyperopic
corrections to come back if you wanted to, and we felt that it was
better to leave people under corrected with a second treatment
possibility than to all them to be overcorrected and untreatable, and
you can see how effective it was in avoiding overcorrections. The trends
for spheres and spherocylinders reports are just taken out of these and
they exactly mirror these trends. There wasn\'t any significant
difference in those two groups.

To summarize we found significant differences between PRK and LASIK
treatment algorithms about 11 percent on average with a range that went
far beyond. It was revealed by our ongoing data monitoring, and we
provided constant feedback and were able to impact significantly the
outcomes that we achieved by doing so, and it allowed us to obtain more
accurate treatment. It demonstrates, I think this was a vivid
demonstration of how important it is that software can be adjusted by
the user and that individual nomogram adjustments can be made for any
laser that is used for LASIK.

This group heard a discussion 6 or 8 months ago about what is the best
way for us to look at cylinder outcomes, and this has been a topic that
has gone around for a long time. The one thing I heard from that meeting
was the SIRC-to-ERC ratio, the surgically induced refractive change, how
much you achieved versus the intended refractive change, what you were
attempting to achieve, that ration of what did we want versus what did
we obtain, provided a nice summary of how much correction the laser was
delivering for what it was asked to do, and we present that ratio here
on a percentage basis as it is requested in the FDA format, and we show
that the ratio was very close to 100 percent across the board. The
standard deviation line is presented. The confidence intervals I should
mention for all of the things that we are reporting, stability or these
or any of the others are extremely small, .1 diopter range or less
because of the large numbers in the study which was helpful to us.
Rather than report those which don\'t show up on the graph, I am
reporting standard deviation numbers which provide us with a little more
information.

You can see that in the low corrections, the very low corrections, less
than 1 diopter the small denominator, half a diopter attempted, achieved
a 1 diopter. You have 100 percent overcorrection. So, the standard
deviation tends to be heightened by the small denominator in the low
group, and it gradually tapers off as you go higher, and you can see
that across the board the accuracy was quite good.

The stability of the cylinder correction coming again out of the FDA
guidance was very good at 99 percent, the definition of 1 diopter of
change between the two observation intervals, and we had that in 99
percent of the eyes across the board.

We did perform a patient subjective questionnaire and say what you will
about our ability to measure contrast sensitivity and our ability to
measure glare and nighttime complaints, patient questionnaires provide
us with a very powerful tool to measure these outcomes and the actual
performance in visual function of a patient. We found them very
valuable, and we learned a great deal of information about LASIK.

We administered pre-operatively and at 3 months so that we obtained two
snapshots in time. How are you doing with your visual function before
the procedure, and how are you doing at 3 months, and for symptomatic
questions related to glare and halo responses improved after LASIK
compared with the pre-operative level.

We are reporting them here in a little bit different format than I have
seen, but it is familiar to you in the sense that the same way we report
best corrected visual acuity we take a paired analysis. So, we take an
eye and if it improved it goes to the right, and it is worsened it went
to the left. So, we looked at the scores, and we said with glare the
question was how much glare do you experience in your daily activity,
and the patients that reported better were over here, and the patients
that reported worse were over here. You see a fairly gaussian
distribution which is great news compared to some of our previous
procedures which would certainly have gone the other way. We had a mean
pre-op of 3.4 and a mean postop of 3.0 and a very significant although
not clinically a big number changing 1/2 point on average statistically
very significant improvement on the amount of glare that was
experienced. So, if anything in our population we found that glare
improved after LASIK.

The story with halos was less dramatic. We had more of a scatter and
more of a smattering of responses. We had very similar pre- and
postoperative mean outcomes and we did not have a significant difference
pre- and postoperatively. That is not bad news. They didn\'t get worse
when compared to their pre-operative appliances to postoperative LASIK,
but clearly one of the frontiers in LASIK is to actually try to improve
quality of vision than what people were able to achieve beforehand, and
we aren\'t there yet with that.

Vision fluctuation, again, was not a significant change. A higher score
is better with vision fluctuation but we didn\'t show that to a
significant level to occur. So, in summary the first, the glare
improved. The other two didn\'t change statistically and we weren\'t
making them worse on our patient subjective questionnaires which was a
very, very positive note for LASIK compared to what we have been doing
in the past.

We feel, and we encountered reoperations are a significant part of
LASIK. We report the rates here based on pre-operative refraction, what
the likelihood was to go on to reoperation. It is nearly a 1.0
correlation at .98. It is clearly related to, the reoperation rate is
clearly related to your pre-operative refraction. We did not find it to
depend on whether or not you underwent a sphere or a spherocylindrical
correction. So, cylinder correction didn\'t increase your likelihood of
reoperation, and we were pleased to see that if we looked at the best
visual acuity and the worst visual acuity and they were basically the
same, 11 percent lost one line, 11 percent gained some lines.
Seventy-eight percent didn\'t change, and that was I think a very
heartening testimony for the safety of performing a reoperation in
LASIK.

I have heard an anecdote where LASIK may be the only operation where the
reoperation is safer than the original operation, and it could be that
because you are not using the keratome, but we sure report here that the
loss of visual acuity was not pronounced with patients undergoing the
reoperation.

We did show a clear trend toward improving the visual outcome. We went
up to, 98 percent of the eyes that underwent a reoperation achieved
20/40 or better, and 63 percent of them achieved 20/20 or better, and we
show that compared to the pre-reoperation levels that was a significant
improvement. We show that both in terms of the scatter and the mean the
mean spheroequivalent improved to very close to a zero target and so the
accuracy of reoperation seems to be quite good, and they are effective
at reducing refractive error and so in conclusion on reoperations we see
that they are more common as the primary correction amount increases,
that they have effective result in reducing refractive error and
improving uncorrected visual acuity and that the risk of best corrected
acuity loss is minimal for reoperations and that underscores the
widespread clinical practice of having a certain rate of reoperations
exist in a clinical practice of LASIK.

With this I will turn it over to Charles Casebeer.

DR. CASEBEER: This will just take 1 minute. I just wanted to review for
all of you how this works out compared to the FDA guidelines, and I
don\'t need to bore you with reading all of these things, but we were
just extremely pleased to see that when we looked at the guidelines that
we were able to put a check in every box, and that of course was the
goal of the study and something that is pleasing, very pleasing to us.

So, in summary, we feel I think it is clear that the study exceeded the
published FDA safety guidelines for safety and effectiveness and clearly
nomogram adjustments with this particular laser are essential in LASIK
and I feel and the other people at CRS feel that the approval of this
very popular, very exciting procedure is in the best interests of the
public and of ophthalmology and again, thank you very much for allowing
us to make this presentation before you.

DR. MC CULLEY: Does this conclude sponsor\'s presentation?

DR. CASEBEER: It does.

DR. MC CULLEY: I would like to thank you for a very clear presentation.
I would like to poll the Panel now. Would you like to take a break now
or would you like to wait and take a break, a break, one break this
morning?

Break now, all those in favor?

(There was a show of hands.)

DR. MC CULLEY: It looks like the break wins. Prior to the break I would
like to say something. We must be very cautious as we all know about
conflicts of interest. That can go to the extent of a perceived conflict
of interest. So, I would like to suggest or just remind the Panel that I
am sure everyone knows that we are not to discuss PMAs under
consideration in this or any others in this session with anyone
including FDA staff or amongst ourselves, and certainly not with anyone
who is not on the Panel would be included in that additionally.

There can be the perception of a conflict, and I am not certain exactly
how I personally feel about this, but with heightened concerns I would
caution you against having extended conversations with individuals who
are not on the Panel that might be perceived as a part of a conflict of
interest or a conflict.

I am sorry, quite honestly to have to be making that comment but I think
that given the environment as it is right now for individual protection
that is probably something one needs to take to heart.

So, with that, my watch, and I may be wrong. Sally and I aren\'t the
same, even. We are going with my watch. I have nine-forty-three. We will
take a 15-minute break. We will reconvene at 3 minutes before the hour.

(Brief recess.)

DR. MC CULLEY: We are delaying just a bit while there is an AV hookup
for overflow.

We will now begin deliberation once again on PMA P990010 with FDA
presentation.

Dr. Waxler?

DR. WAXLER: Good morning. I am Morris Waxler, Chief, Diagnostic and
Surgical Devices Branch, and I am limiting my comments to introducing
Jan Callaway, the team leader, and she will have a few more comments.

MS. CALLAWAY: Good morning. I am Jan Callaway, the team leader for the
CRS PMA for the VISX STAR Excimer Laser System. CRS Clinical Research,
Incorporated of Scottsdale, Arizona, submitted this application which
was filed on February 23, 1999. The sponsor is requesting approval for
LASIK for the correction of myopia between minus 1 and minus 14 diopters
with or without astigmatism corrections ranging from .25 to 6 diopters.
The primary panel reviewers for this application are Dr. Mark Mannis and
Dr. Mark Bullimore. Panel input is required in this ares because
clinical judgment is required to evaluate the data. Your comments from
the discussion today will help us in evaluating the safety and efficacy
of the device for this indication for use.

The FDA team evaluating this PMA included the following reviewers: for
engineering and Operator\'s Manual labeling Dr. Bruce Drum; for patient
information labeling, Ms. Paula Silberberg; bioresearch monitoring was
supervised by Dr. Jean Toth-allen; statistical reviews were done by Ms.
Phyllis Silverman; and, clinical reviews were done by Dr. Bernard Lepri.
I would like to thank those team members for the outstanding job they
have done in review of this document.

At this time I would like to introduce Dr. Bernard Lepri, the clinical
reviewer for this application.

DR. LEPRI: Good morning, Mr. Chairman, members of the Ophthalmic
Advisory Panel, CRS members, FDA colleagues, industry representatives
and public representatives. Today, I am going to present to you PMA
990010 LASIK for myopia and astigmatism applicant at CRS Clinical
Research, Inc.

The information that I am going to present to you consists of specific
concerns that FDA wishes to obtain the Panel\'s expert opinion in
consideration of this PMA. Information specific to these concerns will
be presented to assist the Panel in addressing FDA\'s questions. The
device under question, under consideration was the VISX Excimer Laser
Model C STAR.

A brief description of the investigation is up on the screen. It was a
6-month investigation of LASIK for myopic correction both with and
without astigmatism.

Question No. 1, do the clinical data in this PMA provide sufficient
patient follow-up of LASIK for the correction of myopia with and without
astigmatism in the ranges indicated?

Next I will present a different picture of the stability data that
provides you a little more information in making your consideration. The
stability was calculated for both low and high myopic corrections for
all eyes, spheres and spherocylinders. This table presents all eyes
attending all follow-up visits specified in the protocol. The change in
MRSE of less than or equal to 1 diopter between the 1 and 3 month and
the 3 and 6 month intervals was calculated along with the appropriate
standard deviations and the 95th confidence intervals.

To support the calculation of the percent of eyes demonstrating less
than or equal to 1 diopter change in MRSE the sponsor, also, provided
the mean differences as you can see here. I will give you a moment to
review that.

The next slide represents all visits for all eyes in the 3-to-6-month
interval.

My question to you is what are the Panel\'s recommendations regarding
the sponsor\'s presentation of stability data for LASIK in the
refractive ranges indicated in this PMA?

The following information is presented in support of Question 3 which
will follow the following review charts of data. The total number of
eyes whose spherical error was greater than 11 diopters was 33 or 4.56
percent of the total number of eyes in the PMA cohort. The number of
eyes less than or equal to 11 diopters was 690, and the total was 723.

The total number of eyes demonstrating a cylindrical component of their
refractive error was 579. Of those 579, only 11 were over 3 diopters of
cylinder. This comprised 1.9 percent of all eyes exhibiting cylinder. A
specific stratified analysis of the spherocylindrical corrections
reveals the following: In the category of greater than 3 to less than or
equal to 4 diopters of cylinder 1.6 percent, a total of 9 of 579
spherocylindrical corrections ranged anywhere in sphere from greater
than 4 diopters to less than or equal to 13 diopters.

In the category of 4 to 5 diopters of cylinder 0.3 percent or 2 of 579
corrections were in the range of greater than 8, so less than 9 diopters
of sphere.

A stratified summary of the MRSE of plus or minus 1 diopter at 3 months
indicates that 70 percent are within 1 diopter for the greater than 7
diopter category of refractive errors and 95.8 percent for those less
than 7 diopters. This graph portrays a comparison of the diopter
stratifications for myopic corrections over 7 diopters and the
proportion of eyes achieving an MRSE within 1 diopter, their intended
outcome at 3 months. The Ns are noted on the bars for further
information for you because the percentages don\'t tell the whole story,
and the next slide portrays a similar analysis for the 6-month postop
interval. Both graphs demonstrate the lower number of eyes in the higher
refractive categories.

Question 3. Do the Clinical data in this PMA provide reasonable
assurance of the safety and efficacy of LASIK for the correction of
myopia with or without astigmatism in the ranges indicated?

You have been told that there was the use of individualized adjusted
nomograms and this was unique to this protocol. Specifically the
individualized nomograms utilized CRS providing the original nomogram.
After the first 20 cases the achieved correction at 3 months was
compared to the programmed amount for each eye. The average difference
between the investigator\'s outcomes and those predicted by the group
nomogram over the entire range was called the personal calibration
factor.

The surgeon then used an adjusted group nomogram called an individual
nomogram which was adjusted by the PCF. Individual nomograms result from
adjusting the group nomogram, not just the surgeon\'s outcomes directly.
The group nomogram reflects the behavior of the laser over the full
treatment range. The mean outcomes were adjusted to approximately one
standard deviation below plano to avoid overcorrections. This resulted
in an actual target of minus 0.3 diopters. The sponsors proposed the
following labeling regarding the nomogram. The programmed amount
indicates the average correction that can be anticipated but actual use
may require individual adjustments of this amount. Tracking of clinical
outcomes is recommended.

Question 4. What are the Panel\'s recommendations regarding the data on
the individualized nomogram used in this investigation of LASIK, and No.
5, does the Panel recommend including warnings in the labeling regarding
post-LASIK corneal ectasia? And I would like to thank the sponsor for
providing us with a very cooperative and detailed report of their data
which facilitated our review in a timely manner.

Thank you.

DR. MC CULLEY: Does that conclude the FDA presentation?

DR. LEPRI: Yes, it does.

DR. MC CULLEY; Should we give the Panel the opportunity to ask questions
of FDA at this point? We will bring sponsor back again after primary
review. Does the Panel have any question for clarification of the FDA
presentation?

DR. YAROSS: This is Marcia Yaross. I have a question for clarification
as to precisely what is the product under review here? Is it labeling
for this group of clinical investigators or is it labeling for the
manufacturer of the laser? Could you clarify?

DR. MC CULLEY: In other words what is the device under review?

DR. YAROSS: Precisely.

DR. LEPRI: The device under review is the VISX STAR Excimer Laser Model
C for the correction of myopia via LASIK.

DR. YAROSS: Thank you.

DR. MC CULLEY: This is not site specific as one other IDE PMA had been?

DR. LEPRI: Could you repeat the question?

DR. MC CULLEY: This is not site specific laser model serial number
specific?

DR. LEPRI: No.

DR. MC CULLEY: Dr. Bullimore?

DR. BULLIMORE: This is Dr. Bullimore. Is it, also, microkeratome
specific?

DR. LEPRI: It is microkeratome specific. They only used one
microkeratome.

DR. MC CULLEY: So, this is specific to the model of the microkeratome
not as one other or as it might \-- I have to be careful how I word
this, as it might be worded that an approved microkeratome. It is
specific microkeratome model specific.

DR. WAXLER: I think a little more clarification is I can try. It is true
that the Chiron ACS microkeratome was the only one used in this trial,
but I do not believe that the approval will read specifically that the
LASIK was approved with this specific device. There will be generic
descriptions in the manual for a microkeratome. Otherwise we would be
labeling somebody else\'s medical device for LASIK which I think would
not be appropriate.

DR. MC CULLEY: Your opinion overrides.

DR. WAXLER: For the moment anyhow.

DR. MC CULLEY: Your clarification overrides. Listen, life is tenuous
even though you wear a flower in your lapel. It doesn\'t protect you
always.

Does that answer your question, Dr. Bullimore?

DR. BULLIMORE: Yes, thank you.

DR. MC CULLEY: Dr. Pulido?

DR. PULIDO: I would like some clarification from Jan Callaway about the
patient accountability concerns and how she feels about the fact that
there was 43 percent exclusion of the data.

MS. CALLAWAY: I would like to bring up the statistician, Dr. Phyllis
Silverman.

DR. SILVERMAN: I am Phyllis Silverman. I was the statistical reviewer
for this. I labored long and hard over this exclusion, and I don\'t
really consider it an exclusion as much as a stratification of the data.
The results were stratified by the group of investigators that had more
than 80 percent follow-up and the group that had less, and all the data
that was available for both of those strata were presented so that it is
not that we ignored all of those other sites. There was a statistical
comparison done of safety and efficacy for the PMA cohort versus the
remainder cohort and there were no statistically significant difference,
and if anything, as was mentioned this morning the remainder cohort did
better. So, there certainly was no bias in favor of the device by doing
this stratification.

So, I don\'t think you should really look at it as an exclusion as much
as a stratification.

DR. MC CULLEY: Does that satisfactorily answer your question, Dr.
Pulido?

DR. PULIDO: Yes.

DR. MC CULLEY: I am going to get it right. You have turned it so I
cannot see it.

Oh, Rick Ferris.

DR. FERRIS: This is Rick Ferris. I have a question regarding this
approach of dealing with clinics with inadequate follow-up, and it is a
design issue and then maybe we can get to the problem I have with it. I
have suggested even on this Panel before that it isn\'t necessarily a
bad way of dealing with clinics that promise to perform but then don\'t
perform provided two things, I think provided two things.

One is that the randomization is done within clinic, and I assume that
was probably correct, and the second is that the cut point of which
clinics were going to be included and which were going to be excluded
was decided prior to looking at the data, and if those things are true,
then I think you still have a randomized comparison and as you say, you
have a stratified, you can, also, do a stratified look both at those in
that follow-up group and those with less good follow-up.

The problem I have with all of this is there is no statistical way of
handling missing data that I know of. I think the quote is the only way
to handle statistically to handle missing data is not to have any, and
anything else makes presumptions, and the usual presumption is that the
data missing is similar to the data that you have. You actually said
something just a second ago that suggests that may not be true. What you
said was, I believe, and I believe the data says the same, that the
group that has less follow-up actually looks a little bit better than
the group with more follow-up. Is that correct?

DR. SILVERMAN: No, the centers that had less than 80 percent
accountability, those patients that did return to those centers looked
better than the other ones, and the underlying premise is that the
reason those centers didn\'t have complete follow-up is that their
patients that were doing well tended not to show up for their follow-up
treatments.

DR. FERRIS: Maybe you have to say that again for me because I don\'t
quite understand it. If they look better with less follow-up, it must
mean that the missing information is worse because that would \--

DR. SILVERMAN: No, it is not that they had less follow-up. It is just
less patients came back for the 6 and the 12 month follow-up. It is not
that they just came back for \--

DR. FERRIS: The concern is that the patients who are having problems \--
my concern here with all of this is not on the efficacy side. I don\'t
think there is any doubt that this laser does something. It is just to
me that cannot be the issue. It obviously does something. The question
is, and it is pretty effective at doing it. The question is, and as we
heard earlier if we have a small amount of harm and we are trying to
balance the benefits with the risks or give some assessment of the
risks, the most conservative assessment of risk is that all of the
people who didn\'t come back had a problem. Well, if you took that point
of view then you could have a fairly large problem. I think that is a
ridiculous assumption. I don\'t think all of the people that didn\'t
come back had a problem, but what you look for is is there some
suggestion that those who aren\'t coming back aren\'t coming back
because they are having a problem or is it just that the people who are
really doing the best are so happy and why bother coming back, and then
you worry less about it, but we don\'t have any way of handling that,
and I think that is the concern that the bigger that portion is that we
are missing if we are looking for balancing a small negative effect or
at least trying to allow the patients to know what the degree of
negative effect is, when there is a lot of missing data it is very
difficult to assess that.

DR. MC CULLEY: Let me interrupt here? We are getting our agendas mixed.
I think what we want to do right now is, I mean you bring up a very
valid point that we need to have as part of the Panel discussion. What
we want to do right now is if you want to challenge or have a question
or any of us for FDA to respond to, this is the time for that.

DR. FERRIS: I have three questions. Question 1, and I saw some nodding.
So, I think I know what the answers are.

DR. MC CULLEY: Let us get FDA response. State your question briefly.

DR. FERRIS: Question 1 was did they pre-specify that 80 percent was the
cut-off and clinics that had less good follow-up than that would not be
included, and the reason that that is a problem, it ought to be obvious
\--

DR. MC CULLEY: You could move the cut-off. So, answer that. That is a
simple question, yes or no?

DR. LEPRI: Bernie Lepri. To the best of my knowledge they did not
pre-specify, and they can correct me on that. This was established when
they observed the compliance rate of the investigators.

DR. MC CULLEY: Okay, we will discuss that when sponsor comes back then.

Second question?

DR. FERRIS: Second question, did they randomize by clinic? I assume they
did, but I don\'t know. Within clinic they have a randomization
schedule, and you can randomize \--

DR. MC CULLEY: There was no randomization.

DR. FERRIS: Oh, I am sorry. So, everybody got treated. Boy, I did
clinical trials too long. So, I mean that would be the other issue, and
the third question, well, we will get to it later. That is part of the
discussion.

DR. MC CULLEY: Right. The issue I would have with this would be what did
the data look on the missing patients that weren\'t there at 6 and 12
months.

DR. LEPRI: That I can address. I mean they did provide a last visit
carry forward analysis and there were no glaring differences in outcomes
between those presented in PMA cohort and remainder cohort. They
provided a complete detailed information on those patients.

DR. MC CULLEY: Questions for the FDA to answer?

Dr. Wang?

DR. WANG: Ming Wang. I have a question for the statistician of FDA. I am
struck by the lower numbers above minus 11, minus 12 and if you have
only a couple of patients the very little statistics that can be talked
about. Does FDA feel that there is need to be someone look at that
particular group separate because results also, fall off sharply at
minus 11, minus 12 or higher? Does percentage eigne anything in that
specific group with such a small number in terms of quality of
statistics?

DR. MC CULLEY: I am not a statistician, but I can answer that. Does the
statistician want to answer that?

DR. SILVERMAN: I didn\'t see any glaring differences, but I felt that
was really more of a clinical issue than a statistical issue.

DR. MC CULLEY: Dr. Rosenthal?

DR. ROSENTHAL: This was one of the questions asked about the range. So,
you are asking the Panel\'s recommendations concerning this?

DR. MC CULLEY: I think when you have such small numbers we are not going
to be able to answer it statistically. It is going to be clinical
judgment. That is why we are here with our minds.

Any other questions for the FDA to answer?

Dr. Macsai?

DR. MACSAI: Was the 80 percent cut-off set by you or the sponsor, going
back to the accountability question?

DR. LEPRI: It was set by the sponsor.

DR. MACSAI: Was it, also, looked at at a 90 percent accountability
cut-off?

DR. LEPRI: We will have to ask sponsor. Sponsor said it will have to ask
sponsor when sponsor comes back to the table.

DR. MACSAI: I was wondering if the statistician had looked at it like
that? No? Thank you.

DR. MC CULLEY: Dr. Higginbotham?

DR. HIGGINBOTHAM: This is a question for Ms. Silverman. In your report,
you noted that there was a poor success rate for the 7 high myops in the
smaller centers and that was 15 out of 36 or 41.36 percent. Was there
additional data provided that would suggest that over time those
patients improved or was this the ultimate that you actually noted, this
41.36 percent?

DR. SILVERMAN: Was that with the centers that had the combined centers
that were \--

DR. HIGGINBOTHAM: Yes, there were seven myops treated at center 22099.

DR. SILVERMAN: Right and they had a \--

DR. HIGGINBOTHAM: It was the high myops at the combined centers.

DR. SILVERMAN: At the combined centers?

DR. HIGGINBOTHAM: Exactly, and you noted \--

DR. SILVERMAN: I felt that that probably was due to a learning curve
effect, that that was a combination of about four or five centers that
had very few patients treated and I felt that was probably a learning
curve phenomenon, and I didn\'t see any additional follow-up on them. It
might have \-- the sponsor may have it, but I didn\'t. I am not aware of
that.

DR. HIGGINBOTHAM: So, there was no additional follow-up. That was my
question. Thank you.

DR. FERRIS: One last question for FDA. Is there any differentiation in
the data between the patients that were treated, the first 20 patients
treated by a given investigator and those done after the nomogram was
individualized or are they all pooled together?

DR. LEPRI: Bernie Lepri. They were all pooled together.

DR. MC CULLEY: We will have opportunity for further questions
subsequently. We are going to pause in place for 3 to 5 minutes for an
audio hook-up to be accomplished. We are not going to break because
breaks tend to expand.

Are the folks who want to do the audio hook-up ready to do it? Okay, so
there is going to be minor distraction. So, official business will be
paused for the moment.

If you will tell me please when you won\'t be a potential distraction we
will proceed, audio folks, please? Let me know when you are not going to
be going back and forth in front of us, please let me know so we can go
ahead?

(Brief recess.)

DR. MC CULLEY: We have given them quite a few minutes. They are still in
the process of hooking up. We are going to proceed with our
deliberations. We have a new procedure in that one of the primary
reviewers will be asked to keep track of recommendations, concerns that
the Panel will specifically be making. So, we will have a designated
scribe for PMA, and Dr. Bullimore, I saw you raise your hand.

(Laughter.)

DR. MC CULLEY: I saw something waving down there. So, I assume that you
were asking to be designated. Would you please do that for us?

DR. BULLIMORE: My mother is in the audience.

DR. MC CULLEY: She will be proud, I hope. That means you have got to do
a good job. We will now begin with the committee deliberations, and we
have two primary reviewers, Dr. Mannis and Dr. Bullimore, and we are
going to ask Dr. Mannis to go first.

DR. MANNIS: Thank you, Dr. McCulley. You chose the right Mark. First, I
would like to thank the FDA for the usual businesslike manner in which
these matters are handled, and this represents information for the
sponsors and for the American public.

I would, also, like to extend my thanks. As you all know this process is
a series of distillations. The FDA is presented with a mass of data from
the sponsor. The FDA\'s staff then goes through this data and does a
clinical and statistical review for the primary analysts, and it is our
job then to reassess that distillation and try to put it in a meaningful
form for the Panel.

Sally has asked us to be brief, and you all have my own distillation in
comments in writing in front of you, but I would like to make a few
points and prior to that I would, also, like to thank Dr. Lepri for a
really masterful compilation of this data. It made it very, very
understandable, and I would, also, like specifically to thank Phyllis
Silverman whose analysis I thought showed a great deal of insight and
clarity. In terms of the primary issues at hand we are dealing with
issues of efficacy and safety. The data based on FDA guidelines
certainly suggests that the procedure is efficacious in terms of the
goal sought in terms of predictability, in terms of stability over the 6
month observation period and in terms of effectiveness in the modulation
of corneal astigmatism.

Five parameters as pointed out by Dr. Kezirian were used to assess
safety in terms of less than 5 percent loss of greater than 2 lines of
best spectacle-corrected visual acuity. Essentially all groups met the
target. In terms of the goal of less than 1 percent of best corrected
spectacle visual acuity of less than 20/40 there was a division and
unless I misread the statistics 7.1 percent of patients in the greater
than minus 7 diopter group had a best spectacle-corrected visual acuity
of less than 20/40 at 6 months. So, in this case the safety parameter
was not met. Haze and induced astigmatism as pointed out were not an
issue and in terms of adverse events the only adverse event that
significantly was outside of the FDA parameters was a 1.6 percent
incidence of interface epithelial inclusions which were felt to be
non-significant clinically.

If you look at this data overall, I think there are two issues which
bear significantly on the way the Panel should label this application.
First is that the groups need to be divided and looked at carefully into
between that group of patients equal to or less than minus 7 diopters of
myopia versus those greater than 7 diopters. Not only was at least one
safety parameter exceeded in the greater than 7 diopter group but in
addition, if you look at the rates of uncorrected visual acuity in the
below minus 7 diopter group, 54 percent had 20/20 at 3 months, whereas
in the above 7-diopter group 35 percent had 20/20 vision.

If you look at 20/40 vision as a parameter, 94 percent of those under 7
diopters had 20/40 and 79 percent in the group above minus 7 diopters.
So, clearly there is a dividing line in both efficacy and safety at the
7-diopter level. I think that this should probably be reflected in the
labeling recommended by the Panel.

In addition, the sponsors indicated to us that symptomatically based on
questionnaires the two groups were equal. However, doing some quick math
this morning during Dr. Kezirian\'s presentation 20 percent of the
patients were subjectively worse in terms of glare. Now, we weren\'t
told at what level, whether that was dysfunctional glare or noticeable
glare but there was clearly a 20 percent incidence of some visual
dysfunction and although not mandated one does give pause to concerns
that perhaps non-acuity parameters should be evaluated over the entire
range of refractive errors in this procedure.

Overall, my impression of the study design was that it was both well
designed and executed, that the cohort was of a suitable size and that
unless the Panel determines that the deletion of the 43 percent in the
non-PMA group based on compliance at the 3 months becomes an issue of
pre-selection, I feel that the data in the PMA cohort justifies the
overall safety and effectiveness of the procedure.

I think that in deliberating the label I would say that the degree of
myopia should be an important consideration and the issue of a nomogram
should be important. The nomogram in this study was based, the group
nomogram was based on a non-IDE database which was then modified by this
personal calibration factor after 3 months when each investigator had
done 20 cases, and I think that the data suggest that this is useful way
in which to construct a nomogram, but that nomogram construction has to
be reflected in the labeling.

In summary then I would recommend approval of the device as safe and
effective for the treatment of myopia with or without astigmatism in the
indicated range. Because of the small numbers in the study, I feel that
patients with spheres or spherocylindrical corrections of greater than
10 diopters may experience complications that were not elucidated, and
this needs to be clear in the labeling. I feel that iatrogenic corneal
ectasia which is obviously one of the most serious complications needs
to be specifically cited particularly in the higher myopic group.

Because of the nomogram issue which is as pointed out necessary in the
clinical performance of all refractive surgery, LASIK included, the
labeling should include that the programmed amount of treatment indicate
an average anticipated correction but that actual use will require
adjustments based on tracking of clinical outcomes by the using surgeon,
and finally, that in patients over 7 diopters of myopia the accuracy
cannot be as clearly guaranteed as in lower myopic patients.

Thank you.

DR. MC CULLEY: Thank you, Dr. Bullimore?

DR. BULLIMORE: Thank you, Mr. Chairman. This is Mark Bullimore. I don\'t
want to go into the data too much since both the sponsor and the medical
officer have already given an excellent overview of that.

Like Dr. Mannis I believe the PMA is approvable with some conditions
that relate to product labeling and the range of approval, but there are
a number of things that I would like to bring to the Panel\'s attention
for discussion.

The biggest is this issue of accountability, and Dr. Ferris has already
raised this, and it already has had some discussion among the Panel. One
characteristic of the PMA is the very variable accountability of these
clinics. Overall the accountability is less than 75 percent at 3 months
and less than 63 percent at 6 months, and if you look at the data, one
surgeon actually enrolled 179 patients which actually represents 10
percent or more of the entire cohort but did not report any 3-month
examination. So, at least in that particular surgeon\'s case there is no
bias, but the sponsor addresses the issue by dividing the whole cohort
into this PMA cohort and this remainder cohort.

I was, also, intrigued to note that of the three people who made
presentations to the Panel, the three physicians, one of them wasn\'t
included in the PMA cohort and a second actually just made the cut.

So, this is a constant source of concern for me because as indicated by
Dr. Ferris, we know something about the people who do return for the
visits, the follow-up visits, but we never know anything about the
people who don\'t return. We can say that the PMA cohort that return are
reasonably equivalent to the people in the remainder cohort, but the
individuals that are included ultimately in both cohorts and taking the
cohort as a whole we don\'t know anything about the 30-something percent
who are not seen at 6 months.

So, the potential for patient bias or surgeon bias or investigator bias
is considerable because of this at best mediocre accountability.

I was interested to hear the comment made that when you do compare the
PMA cohort, that is the good clinics with the remainder cohort
henceforth referred to as the great unwashed, that does suggest that
there is some bias there on the part of the physicians, and I don\'t
want to sort of target them or be accused of slander, but the fact of
the data they are reporting, given their lower accountability is
slightly better than the group, the PMA cohort, suggests that the bias
actually runs in that direction. So, that is all I have to say about
that, and we have an industry representative on the Panel, and I
wouldn\'t expect that many of the investigators would get a call from
Dr. Yaross for her own company\'s investigations given some of these
rates of follow-up.

In terms of efficacy, I think that is the strongest part of the
proposal, both in terms of sphere and SIL(?) the laser clearly does what
it is intended to do. The question remains whether it should be approved
for the higher ranges of myopia.

Although the sponsors request an approval for up to minus 14 diopters, I
believe that is spherical equivalent but I would like some
clarification, but by their own admission the distribution of refractive
errors tapers off beyond minus 11. We only have 29 patients reported at
3 months in the minus 11 or greater range and only 17 with more than
minus 12 diopters of myopia.

The problem is just as acute and maybe more acute for astigmatism.
Approval is being requested for up to 6 diopters, but only 11 cases are
reported over 3 diopters and only 2 patients had greater than 4 diopters
of astigmatism.

So, in summary I would ask my colleagues on the Panel to consider what
the entire range for approval should be.

The range of approval, also, has relevance to the question of corneal
ectasia, and there are a number of reports and comments in the
literature by very distinguished people in the field about the risk of
corneal ectasia above minus 10, and minus 10 seems to be a line drawn in
the sand, and I would have difficulty based on the data here going
beyond minus 11, certainly not minus 12.

Stability refraction seems to be okay. There seems to be little average
change although the patients with higher degrees of myopia seem to take
a little more time to reach stability.

I would point out the potential for long-term changes in refractive
error does still exist. Only going to 6 months would not, for example,
demonstrate the long-term hyperopic shifts that we saw in the Perk(?)
study. So that possibility remains given the limited amount of
follow-up.

Frequency of loss of visual acuity is low, and that is within
guidelines. As Dr. Mannis pointed out, there are a number of people who
in the higher myop group end up worse than 20/40 and I will accept the
sponsor\'s observation that many of these started with visual acuities,
best corrected vision acuities of close to 20/40, but they, also, of
course, do have the benefit of the magnification induced by moving the
refractive correction from the spectacle plane to the corneal plane.

Sixty-four of the PMA cohort were excluded due to, from the 6-month
visit, due to retreatment. Since retreatment does occur in a significant
proportion of the cohort some analysis of the safety in this group which
I think has already been presented is appropriate, and should be
included in the labeling.

It is, also, unclear to me from the original proposal how stable
pre-operative refractive error was defined. So, some clarification would
be useful there, and as I have said at a previous meeting there is still
need for a standardized questionnaire or instrument to be used for the
assessment of patient satisfaction following these procedures.

Interpretation of data from different sponsors would then become a
little more meaningful.

Thank you.

DR. MC CULLEY: Thank you.

Just an editorial comment. It seems like the accountability here is an
issue as it has been in other situations and we have a standard that is
set. This isn\'t a brand new device in one sense, and it is not our
first experience with it, and I think that to me a real question is the
patients that weren\'t present at 6 and 12 months with us seeing
stabilization in general toward 3 months, what is the accountability at
3 months, and if we have good accountability at 3 months given the
appearance of stability at 3 months, given the overall experience that I
think we bring to the table, then I would be less concerned about the
accountability from a practical standpoint but from an idealistic
standpoint I certainly would not want to send a message that long-term,
when there are issues, this kind of accountability is acceptable.

Is that fair?

DR. MACSAI: Dr. McCulley?

DR. MC CULLEY: Dr. Macsai?

DR. MACSAI: This is Dr. Macsai. In your statement you just that as long
as stability is established at 3 months. I am not sure \--

DR. MC CULLEY: I said, \"Stability appears to be established at 3 months
in this\" \--

DR. MACSAI: If accountability is inadequate and stability is established
by measuring two different points at a set time period and comparing
those two how does one establish stability?

DR. MC CULLEY: I don\'t want to argue the point, Marian, but what I am
saying is that if we have stability established at 3 months, if that
appears to be the case, part of my statement was a question. If indeed
stability appears to be established by 3 months and we have good
accountability at 3 months, I am less concerned about the drop-off in
accountability at 6 and 12 months with this particular device or with
Excimer lasers that we now have a good deal of experience with. It is
not a device coming in that is not in the market that we don\'t have
experience with and that many of us have experience with. That was my
comment because I think we can slam dunk this PMA based on
accountability.

So, what I am trying to do is let us get to a meaningful discussion
about accountability or else we can go on forever about it because it is
not good as we get into the later time points, and we need to use our
time effectively and decide how we are going to deal with that issue.

I said one way that to me I thought was a reasonable way to deal with
it, with this particular device. The biggest risk I see in that is that
being interpreted as setting some kind of precedent where we don\'t have
any degree of comfort level or knowledge that we do have here, and I
just want to be absolutely clear that we don\'t do that and quite
honestly that would affect how I would feel if I thought that would
establish something that would come back to haunt us in carrying out
effective deliberations in the future.

Dr. Pulido?

DR. PULIDO: Jose Pulido. First, Jim, for the remainder cohort the
accountability was 57.5 percent at 3 months. So, even there the
remainder cohort had \--

DR. MC CULLEY: What about the other cohort?

DR. PULIDO: The other cohort was 90 percent. For the record I just would
like to state the following. I agree that the data from the PMA cohort
shows very good safety and efficacy in patients with astigmatism up to 3
diopters in myopia up to 10 diopters but I have strong concerns
regarding accepting the study as a whole because of the data set and if
the FDA accepts this kind of study where accountability is only 57
percent, only because there was a large number of patients where will we
stop? If there is a subsequent study where enrollment was 10,000 and
there was good follow-up on 1000, will this be accepted? The doctors
should be chided for bad science, and if they enroll patients into a
study, they should be ethically bound to follow up on these patients.

DR. MC CULLEY: I think we need to continue to discuss this issue a bit
now because I think this is the most critical issue.

Dr. Wang?

DR. WANG: Ming Wang. Along the argument of this issue, since I first
raised the issue about whether this was preset or not obviously there is
the question of bias on whether the 80 percent was set depending on
where the lever was set, and since the primary data is all there, the
elements are all there, could we ask the sponsor to look at whether say,
set at 70 percent or 65 percent will a totally different type of
conclusion be drawn, and we can determine whether this setting is
somewhat a sensitive issue?

DR. MC CULLEY: Dr. Bullimore?

DR. BULLIMORE: Yes, this is Dr. Bullimore speaking as a primary
reviewer. I think that is an intriguing idea from a scientific point of
view, but the fact that there is no difference in the safety and
efficacy outcomes between the two cohorts when the criterion is set at
80, I don\'t expect the change in the cut point is going to provide us
with illuminating information. It might be useful, but I think it would
appear as sort of busy work or punishment for the sponsor rather than
being illuminating for the Panel or the FDA. So, I would discourage that
particular line of pursuit..

DR. MC CULLEY: Dr. Ferris?

DR. FERRIS: I think going in that direction you already have a pretty
good estimate of what is going to happen because you looked at the two
cohorts. So, as you lower the bar further it doesn\'t hurt the
assessment. In fact, it is in favor of saying that it is safe and
effective. The concern is what happens if you raise the bar and look at
only those clinics with 90 percent or 95 percent. I assume if it wasn\'t
predetermined, the 80 percent that they way they determined 80 percent
was the balance between the N and as you take that bar higher, now the
standard errors around all these estimates are going to become more of a
problem, and I presume that that is why they did this.

This application to me is interesting in that I think the surgeons have
done a marvelous job in one sense. I mean on their own they have gone
ahead and done this at their own expense.

The unfortunate part was that at least some of them and maybe most of
them didn\'t really understand how important it was at the beginning to
make sure that those patients they entered in the trial understood that
they needed to come back, that if they didn\'t come back it was going to
really jeopardize the whole program, and that is my view, that it
jeopardizes the whole program.

I sort of agree with what you said, Jim that in this case it is a little
bit different than the usual kind of situation we have. I would find it
very disturbing if people went away from here if this was approved and
they thought that we only need 80 percent follow-up because I don\'t
want to be part of lowering that bar. I think the bar ought to be
raised, if anything.

On the other hand, the last time I \-- actually driving in here I heard
a number of advertisements for this procedure. So, I am not sure. I
thought to myself well, people little note nor long remember what we do
here because as near as I know this train is moving.

DR. MC CULLEY: I think that the risk to us is exactly what you and Dr.
Pulido said. If we can rationalize this that the core had 90 percent at
3 months and at 3 months we had stability we bring our reason to the
table rather than our ruler to measure risk with; then we can
rationalize it if we are comfortable with everything else, and I think
we have to decide whether that is what we want to do now or not because
that is what everything else hinges on.

DR. YAROSS: This is Marcia Yaross. I think you spoke a moment ago, Dr.
McCulley about the message that goes forth from this Panel. I think one
of the messages that intended or not is sometimes perceived is that
there are different standards for investigator-sponsored PMAs brought to
this Panel than for industry-sponsored PMAs, and I think that is
something the Panel should be aware of.

DR. MC CULLEY: I think that is very good that you stated that. I can
tell you from my perspective I try to be as consistent as I possibly can
be, but we wouldn\'t need to be here, and we could have computers in our
place if we weren\'t meant to bring our reason with us and our
experience. So, that may be the perception, but I guarantee that sure is
not the intent, and people aren\'t paying attention, to me, if they
think that.

Dr. Van Meter?

DR. VAN METER: There is another data issue that clouds the results for
me, and since you mentioned experience, I take this time to bring it up.
We have spoken for years about the importance of learning curves and the
idea that some experience is helpful in doing this procedure. We, also,
have an admission, by the way, that sponsors have gathered data that
after 20 cases an individual fudge factor is necessary to alter some of
the treatment parameters and yet all of this is pooled, all the patients
before and after the, you know, first cases and last cases are all
pooled together, and I think it is fairly important to look and see if a
learning curve is important because I think this is critically important
in determining how you are going to train surgeons to do this procedure
because everybody is going to have a learning curve.

DR. MC CULLEY: The reality is that there are LASIK training courses
going on now, and my impression is how those are dealt with is that
surgeons until they get their own information, I mean the nomogram in
effect is somewhat surgeon surgical technique dependent. It is
environment where the laser is housed dependent. It is laser dependent
and then those we can kind of deal with with our experience, but it is
somewhat patient and eye dependent and the approach, taking everything
possible into consideration is to aim to under correct and then as one
gets personal experience with that laser in that environment with that
surgical technique to start to move upward and the incidence of
retreatments decreases. If we remember previous data we have had
retreatment rates in the 40 percent range.

We now have a retreatment rate, I don\'t remember the number, but it is
somewhere in the 10 percent or less range. So, I think that that is
where we come back to, if we get over the accountability issue, we have
to address the labeling on the nomogram.

DR. MANNIS: Jim, just a point of clarification. I am sure we all
understand this.

DR. MC CULLEY: Dr. Mannis, please, always identify yourself?

DR. MANNIS: Mark Mannis. These were not their first 20 LASIK cases. They
were the first of the 20 cases they did in the study. I think that is
important for the record, that the surgeons who participated were all
experienced LASIK surgeons.

DR. MC CULLEY: Okay, I think we need to \-- yes, Dr. Pulido?

DR. PULIDO: I understand that as anterior segment surgeons you have all
had the experience that this is a good technique, that it needs to be
accepted. On the other hand, and Rick Ferris can correct me, and you are
going back to the experiences saying, \"Well, we can accept this data
because our experience says that it is so,\" but Rick Ferris may correct
me if I am wrong, when the original DRS was going to come out, they
polled the doctors as to what the results were going to be about laser
photocoagulation which we know is efficacious now for diabetic
retinopathy and the experience of each doctor was the majority thought
that the study was going to show that laser photocoagulation was of no
help in these patients. So sometimes experience may not be the right
role in large studies like this.

DR. MC CULLEY: Dr. Ferris?

DR. FERRIS: Rick Ferris. It was actually in a macular photocoagulation
study, and I think the difference there was that the treatment effect is
relatively small, and so, it is easy to make a mistake.

In terms of the treatment effect here, I assume that that mistake isn\'t
being made, that if you ask these surgeons and the DRS, by the way, I
think one of the clinics thought the treatment wasn\'t helpful, and the
others thought it was, but there it was a 50 percent treatment effect
compared to a smaller effect although the short-term effect with macular
photocoagulation is about 50 percent.

The issue remains though as to whether we are sending any message, and
maybe at the very least we have to make it clear that this decision is
based not just on this data, that it is a serious fault, that there is
this much missing data. In fact, I got very frustrated reading this and
thought to myself, why don\'t they just bring up patients and have
little anecdotal reports because this data in my view as a scientific
study is something in between anecdotal reports and what you would call
an adequate scientific study, and the fact that there is even the 15 or
20 percent missing information when we have bars that say you cannot
have more than 5 percent of this or 1 percent of that, that missing
information makes it very difficult to interpret whether you have really
made that or whether you have somehow with regard to bias excluded the
worst cases and if anything I still believe the data tend to suggest
that the worse the follow-up is the more likely that sort of the better
the group is and you know, when you look at that remainder cohort versus
the, unless I have it wrong, versus the main cohort the remainder cohort
does better and what that tells me is that as you added more patients
you are reducing the mean and suggesting that the missing information
might be in the direction of harm or at least less efficacy and that is
the concern, and there is no way of dealing with that missing
information that I know of.

DR. MC CULLEY: Dr. Matoba?

DR. MATOBA: Alice Matoba. I am relatively new to the attendance at these
meetings. So, excuse me if this is already known, but does the FDA set
these criteria for accountability up front?

DR. MC CULLEY: In the guidance document there is a target, yes.

DR. MATOBA: Ninety percent. So, okay.

DR. MC CULLEY: But it is not an absolute. I mean it is a guidance.

DR. MATOBA: Shouldn\'t there be some absolute number that should, also,
be set?

DR. MC CULLEY: In a perfect world, yes, but it doesn\'t seem to work. I
don\'t know that I can rationalize that or make good sense for you, but
just to tell you it doesn\'t seem to work. It would be nice to have an
absolute, that if it doesn\'t reach that we are not asked to add our
knowledge and wisdom to it.

Dr. Bullimore?

DR. BULLIMORE: In the interests of moving the discussion along, I am
happy to accept the data as they are presented and move on from this
accountability issue. I know I made some fairly strong statements about
it, but I think they have been made, and we can move forward to address
the question raised by the agency.

DR. MC CULLEY: Is there disagreement with that position and if so I
would like for you please to state it now?

Dr. Macsai?

DR. MACSAI: In response to Dr. Matoba\'s inquiry in the checklist for
information usually submitted in an investigational device exemptions
application for refractive surgery lasers dated October 10, 1996,
accountability is as follows: The loss to follow-up typically should not
exceed 10 percent at 1 year, and I have a great deal of difficulty with
an accountability of 50 to 76 percent at 6 months.

DR. MC CULLEY: Okay, Dr. Macsai has basically as I understand your
statement stated disagreement with Dr. Bullimore\'s assessment.

Does anyone else have a disagreement with that?

MS. MORRIS: Lynn Morris. I guess I just have a question. How if you
accept this level of accountability is it not setting a precedent?

DR. MC CULLEY: Again, I said that before. I can restate it. Basically we
are asked to bring our experience, knowledge to the table. I am not
trying to argue one side or the other here, but if we have 90 percent
accountability at 3 months, stability established at 3 months given all
of the information available to us that that is it is possible for us to
consider that as a reason to consider the data as presented otherwise.
We have to decide whether that is reasonable or not, and everything else
hinges on that, and we need to decide that. Otherwise, well, we need to
decide that.

MS. MORRIS: So, I guess my question to take it to the next level is if
you determine that now when we come back to make a determination on
another PMA in the future, isn\'t there, I mean couldn\'t the sponsor
argue that we accepted this level of accountability?

DR. MC CULLEY: Not really. I think we have to \-- PMAs are not done one
in comparison to the other. It is a sticky point, and yes, I mean it is
risky, and I see that as the biggest risk in accepting the data. I agree
with that concern, and it is just a matter in the minds of the members
of this Panel as to how they weigh that, but each PMA stands on its own
bottom as I understand it, and we do not compare in making decisions
about a PMA we are not making comparisons to others. We are bringing a
set of knowledge to a set of data and the experience of a group of
people to the table. All of those change from one PMA to another. We
change. Dr. Bullimore pointed that out once, that when something was
being said to us, that he wasn\'t at that particular meeting or
something of the sort, but the people change. We are not on this until
the day we die and even if we were, we would still die and have to be
replaced.

Dr. Van Meter?

DR. VAN METER: Woody Van Meter. Because the sponsors have adequate data
for the main cohort is because they have carved out the additional
cohort. Even though it looks like the patients in the additional cohort
did well, I think that that is not science to carve out data that is not
compliant. I don\'t think, it is not, I mean I think in the past we have
asked the sponsors to come up with data to meet that criteria and I
believe that since there is such an effect here that whether it is by
telephone or letter or what not, that data is out there.

DR. MC CULLEY: And we have done that, and we have accepted funny
statistical machinations that are beyond my ability to understand in the
past as well. What we need to get is a sense of where we are going.

Dr. Rosenthal?

DR. ROSENTHAL: I would just like to make two comments. The first is that
the guidance is guidance, and as you know the office has I think quite
publicly stated that in general for the Office of Device Evaluation an
80 percent level is generally acceptable of accountability.

The second is an issue that when you consider your deliberations in the
PMA you do it based upon all the information, not only that is presented
to you but that is going on in the outside world.

Now, this is a procedure that is being, and I am not arguing one way or
the other. I am just presenting something to you. This is a procedure
that is being done quite extensively throughout this country in which
there is no information publicly available except what doctors want to
give to patients based upon off-label use. It is the practice of
medicine. It is not being done one or two times. It is being done
thousands of times, and I think part of your deliberation has to be you
have to weigh the issue, that is it important to have some information
even though it is not perfect science, and that is your decision that
one has to make.

DR. MC CULLEY: Dr. Sugar?

DR. SUGAR: Joel Sugar. While I abhor the exclusion of a substantial
number of patients and think it is inappropriate, the accountability,
also has to be seen in light of the safety and efficacy, and if there
were serious questions about safety and efficacy, the level of
accountability that we would demand I think would be higher. I think
that the data presented plus as Ralph mentioned the experiential data
that is available outside of this application suggest that it would be
wrong I think to disallow this PMA based on the accountability as it is
presented and that we should proceed to move forward and have some
impact on this procedure by approving this with modifications and move
beyond this issue.

DR. MC CULLEY: Dr. Wang?

DR. WANG: Ming Wang. I would like to echo some of those things already
expressed. I agree that we should be very careful not to set a precedent
but overall as an anterior segment surgeon who has done 2000 LASIK cases
myself I have a basic hunch this is a good procedure with adequate
efficacy and safety. I would recommend to go beyond this issue but do
make some kind of language so that to specify the FDA is not totally
happy with the accountability in this particular study and restress our
need for a good scientific study that higher accountability is required.

DR. MC CULLEY: Dr. Mannis?

DR. MANNIS: Mark Mannis. I have a question that may be naive, but is it
possible for the FDA to request the sponsors to provide us with
follow-up information on the 43 percent non-PMA cohort even though it is
not at 6 months? Could they resurrect those patients and so to speak and
could we get that information? Could it be conditional upon that?

DR. MC CULLEY: Dr. Rosenthal, would you like to answer that?

DR. ROSENTHAL: Certainly if the Panel deemed it so it could be a
condition of approval.

DR. FERRIS: This is Rick Ferris. I was happy to hear what Dr. Rosenthal
said because it seems to me that the public health issue here is as
great as the issue as to whether this laser works or not. I have heard
advertisements suggesting that there are no side effects to laser and I
take it that if this was approved and there are documented levels of
side effects that those advertisements would no longer be appropriate.
So, I think we have to be careful about going too far in the other
direction and trashing this because there is a public health implication
of saying nothing, and if we defer saying something the only comment I
would have is that my concern is that I don\'t know what the
complication rate truly is lurking out there. You know, we had
suggestions this morning that it may be higher than we think. As a
retina person I have to see the data, and the problem is that this data
cannot tell me what that rate is. It can tell me what I think the lower
limit of that rate is but not what the higher limit is and whatever we
say I think might be that to me the complications that we see here may
well be the lower limit of the complications. They may be somewhat
higher.

DR. MC CULLEY: In my experience the complication rate that they reported
is what others are reporting in other venues.

DR. FERRIS: But even there the problem, I don\'t know whether, I assume
that the rate of people coming back for them is similar to the rate of
people coming back for new and so nobody may know what the lurking
complication rate is, if the disgruntled don\'t come back, and that is
the issue.

DR. MC CULLEY: Okay, we need to stay on this, and there may or may not
be those issues with the other reportings. I don\'t want to get off on
that. They are not necessarily there.

Dr. Van Meter?

DR. VAN METER: What we could do is fine with me. I mean the issue is
whether or not we want to get more data, and we can discuss that at the
tail end, but there are lots of other issues about safety and efficacy
especially in the higher groups, and if you want to summarize what the
Panel thinks about this issue, would you want to \--

DR. MC CULLEY: We will do that when we come back to the specific
recommendation. At least my sense of this which I guess unfortunately we
have to rely on to a degree is that we more or less have the issue
fairly well dealt with and we will formally deal with it when we come to
answering the question for the FDA, and I think now we need to move on
to other issues, but I think that what I would like to do now is invite
sponsor back to the table for Panel to ask the sponsor questions about
data that they have presented.

Would sponsor like to return? This is a time for clarification. Sponsor
is not to take this as an opportunity to present other data. It is a
time for Panel to ask the sponsor for clarification on issues that have
been presented.

So, Dr. Sugar?

DR. SUGAR: Joel Sugar. Dr. Kezirian, you stated that 7 to 8 percent, 7
percent in the lower and 8 percent in the higher myo group had
reoperations. How many of those were for refractive purposes only and
how many were for wrinkles, epithelial ingrowth or whatever?

DR. KEZIRIAN: It was approximately two to one were for refractive errors
and the rest were for epithelium or wrinkles, caps and that sort of
thing, two to one for refractive.

DR. MC CULLEY: I thought that, Mark in your review you said that the
epithelium was minor and that they weren\'t reops for epithelial
ingrowth. So, I am confused.

DR. MANNIS: That is what I understood. I must have misunderstood.

DR. KEZIRIAN: No, there were some that were lifted for epithelium.

DR. MC CULLEY: What percentage?

DR. KEZIRIAN: I would have to get back to you in the next section on
that to give you the absolute number.

DR. MC CULLEY: Does the FDA have that data at hand from your analysis,
that piece of information, percentage of flaps lifted for treatment of
epithelial ingrowth?

DR. LEPRI: Mr. Chairman, Bernie Lepri. I do not have that data
available. We would have to look it up.

DR. MC CULLEY: That was not in our package, the best that I could tell.
One other question. Was pupil size looked at apropos of the public
comments?

DR. KEZIRIAN: Pupil size was not one of the considerations in this
protocol.

DR. MC CULLEY: Dr. Wang?

DR. WANG: Ming Wang. A question for sponsor. The pockets in the results
in the above minus 7 correction range that fall out of FDA guidelines
even though most of the data fit the guideline and there is obviously
good statistics at minus 7, poor statistics at minus 15 or 13, let us
say. I guess it was upper limits of 14. Do you have a feeling what is
the threshold in which the statistics become not good, somewhere around
10 or 11 because that will give a basic measure of confidence in the
data.

DR. KEZIRIAN: I appreciate the opportunity to address this issue because
I think that there are a few considerations that have not been brought
to light that should be in order to consider this well. First of all the
one target that wasn\'t met which was the best corrected acuity
exceeding 20/40 in the greater than 7 diopter group did not occur in
many eyes. We had four eyes we were looking at it, but the N tapers off
toward higher corrections as you noted. So, that becomes proportionally
heavier weighted. So, it wasn\'t something that occurred in a large
number of eyes, and it wasn\'t something that occurred in a trend. If I
saw it occur in a trend that you know you had one in the 7 diopter bin
and two in the 8 diopter bin and three in the 9 diopter bin even
percentage-wise was increasing as you went higher I would have much more
concern than I do when I see it occur in four eyes that were clustered
between 9 and 11 diopters and did not occur in the eyes that were higher
than that. So, I don\'t know that I accept de facto that a safety risk
for best corrected acuity loss as we measure it occurs in a trend with
higher corrections.

Now, why? Perhaps because it was protected against with some of the
things that were done in the exclusion and inclusion criteria. It may be
that we are guarding against them, and we are protecting as we should be
against those things. So, regarding safety I don\'t have a clear answer
for you. My feeling is that through the range of the study we were safe.
Effective, I think efficacy again has to be considered in the issue of
this nomogram that Dr. McCulley talked about a moment ago.

We intentionally as you saw in the scattergrams geared toward under
correction in the higher corrections. We did it intentionally knowing
that yes, that is going to compromise efficacy but frankly just reality,
nothing about this Panel or this process we weren\'t doing this to
obtain FDA safety and efficacy. We were doing this to study and validate
LASIK. So, as a group when we came together our goal was not to shoot
for 100 percent efficacy which we could have done by overcorrecting
everyone by 1/2 diopter and we would have great vision, but we would
have terribly unhappy patients. We did it for long-term benefit of the
patients and the long-term validation of LASIK and the nomogram still
intentionally under corrects people understanding that reoperations are
a fundamental part of the procedure and as we showed reoperations can be
performed safely. So, that is how I would answer your question. I don\'t
know that it is fair to look at efficacy that falls off at 14 diopters
because you are trying to under correct as being an absolute criticism
against this.

DR. MC CULLEY: What were final results after retreatment in that group?

DR. KEZIRIAN: We improved the uncorrected visual acuity in the retreated
group. We had \--

DR. MC CULLEY: In the higher range?

DR. KEZIRIAN: In the higher range we had, I am sorry, I want to give you
the exact number. The uncorrected visual acuity pre-enhancement 20/40 or
better went from 43 percent in the pre-reoperation to 98 percent in the
post-reoperation. Efficacy was good. So, I just think that we have to
consider this thing in the context of how it is being offered and how it
is being practiced and because we are trying to certainly barter some
efficacy in order to gain safety, I don\'t think that that is
necessarily a negative thing about the way the study was done or that
LASIK is performed.

DR. MC CULLEY: Dr. Wang?

DR. WANG: I just want to clarify my question. I think in addition to
safety and efficacy there is a basic question of confidence in the data
irrespective of what the merit or what is the point we are trying to
show using the data, and since we are talking about very high percentage
success and very low percentage of failures and if you only have three
patients the relative error of one patient may have probable 30 percent.
So, I am trying to get a sense where is the \-- obviously minus 7 has
good statistics. Minus 13 is terrible. Where do I \--

DR. KEZIRIAN: Why is it terrible?

DR. WANG: Because of the sample size. So, somewhere along the line let
us say minus 11 where we can say that gives us a reasonable statistic in
terms of error is comparable to what we are talking about in terms of
safety and efficacy and so, at a range lower than that we can draw
conclusions more confidently. At a range higher than that we have to use
more intuition and others because we cannot rely on these percentages
anymore. The statistics itself is of little significance at the
threshold.

DR. KEZIRIAN: I agree with you and have the same feeling about wanting
to have huge numbers. I agree with you, and I think Dr. Casebeer has a
comment he wants to make as well but my reaction to that as a
statistician is that our distribution in the higher ranges actually far
exceeded by multiples what the natural distribution of higher refractive
errors are in the population, and so, I think that our data do
adequately reflect what would be encountered in practice and I think
they do adequately reflect what exists.

So, while I would like to have each bin chock full, that will never
happen no matter how long we wait. Those patients just aren\'t out there
in enough numbers. It is important to give them information about
safety.

It is important to give them information about efficacy, and it is
important to prevent those patients from being treated with double
carding and other innovations which would be required should they not
have access to the technology because they are going to be treated. I
think Dr. Casebeer had a comment to make about the patient satisfaction.

DR. CASEBEER: No, it is really the same thing. I don\'t know how you
could ever study in large numbers anything that has an occurrence in the
population of 1 or 1-1/2 or 1/2 percent. I don\'t think it is possible,
and I think since the patients are satisfied in the patient
questionnaire that probably it is an inherent problem with a study like
this where there is a big drop off, but I agree with Dr. Kezirian
otherwise.

DR. MC CULLEY: We have addressed the issue before in the Panel of this
inability to get large numbers in high ranges of myopia and in the
higher ranges of astigmatism, and we have accepted lower numbers in the
past weighing again the real world and the benefit, potential benefit to
the patients and their options or alternatives. So, we have addressed
this before, and I think dealt with smaller numbers than these more
commonly encountered situations.

Dr. Pulido?

DR. PULIDO: I really would like your help because if I can get over this
accountability problem this accountability hurdle, I would be very happy
in accepting and approving this FDA submission, but here is my
conundrum. If we go to Page 196 of Volume 1, our 3-month accountability
range is from 0 percent in at least two cases in two centers to 100
percent. Okay, your argument thus far is that those people that didn\'t
come back it was because they were so happy they didn\'t come back. So,
just taking a polarity then if that is true through all centers then if
some centers had no patients coming back and therefore they were all
very happy, then the ones that had 100 percent return, they were all
unhappy, and is that how we should interpret the findings, that the more
accountability there was the more unhappy these patients were? I am just
using the flip of the argument that you are using.

DR. KEZIRIAN: Okay, as I pointed out, the points that you have brought
up are, I think largely done away with, with the observation that we did
provide a last visit carried forward analysis, Table 8 for eyes that
missed visits in both cohorts, and they don\'t differ from the rest of
the group. FDA looked at it. We looked at it, and you know, the people
have asked, \"Show us the data on the eyes that don\'t come back.\" We
have done that, and it is in the application, and they don\'t differ
widely. So, you know, we have only conjectured that it is more difficult
to get the satisfied young active patient back into the practice.
Clearly some of our investigators had more sway with their patients or
more commitment to the study and were able to get them in. I don\'t know
that that so much parallels the patient satisfaction as the
effectiveness of that investigator\'s commitment to the study to get the
patients in. The two centers that had zero, the one with the large
number of eyes had a change of doctor. The doctor was no longer at the
clinic, and they couldn\'t participate. In fact, they withdrew from the
study, but because the patients were enrolled they were submitted but
actually that center is not an active center in the study.

So, that center was effectively removed because the doctor no longer was
at the clinic to follow the patients. So, that looks terrible to have a
zero follow-up, but the zero follow-up was there because the doctor was
no longer there.

So, when we look at those things and at Dr. Ferris\' question the answer
is that the exclusion was randomized before we looked at the results. We
did look at the N because we wanted to have the 90 percent level at 3
months, and we set it at 80 percent because it so happens that 80 and
100 average out to 90 and it gave us the answer that we are looking at,
but it was done before we ever looked at the results, and in fact, at
times we have regretted that because some of the other results were
better, and it was a randomized thing, and it was preset. It was preset
to come up with the 90 percent.

The other thing is that because we provided that last visit analysis we
feel that some of the anxiety is misplaced because we did give you those
results and they are there, and they are fine, and having done that we
feel like we have satisfied our obligation to integrity to give you
everything.

We aren\'t giving you 57 percent of the applications. We are giving you
100 percent of the applications. We consider them both from safety and
efficacy. We have given you safety and efficacy on both, but when we
know that issues like stability want to be evaluated against the cohort
with good follow-up and other efficacy issues want to be evaluated
against a cohort with good follow-up we broke down the cohort that had
good follow-up so that we could do that, but we did provide all results
for all eyes.

DR. MC CULLEY: That is not the issue. The issue what you weren\'t able
to provide that wasn\'t there, I think, just very simply put. It is not
a question of you massaging what you have.

DR. KEZIRIAN: Right, well, that wasn\'t the question.

DR. MC CULLEY: It is the fact that you don\'t have the follow-up on some
that is the concern. It is not an integrity issue, nothing of that. I
have heard no sense of that. It is that you have a bunch of patients who
didn\'t come back.

It is as simple as that.

Dr. Sugar?

DR. SUGAR: A corollary question then, when we discussed earlier if we
could make a recommendation that you get more data, is that a realistic
thing from your standpoint? Have you pushed as hard as you can to get
the patients that you want to get and if we made a requirement for a
follow-up, I guess, requirement for approval that you get more patients,
do you think you realistically could do that?

DR. MC CULLEY: Let me ask for just a point of order here? It is a good
question. I am not sure it is one that is appropriate for us to ask
sponsor to respond to where it would affect, I am not certain, okay? I
don\'t want to get in trouble in later.

PARTICIPANT: It is quite appropriate to ask the sponsor whether or not
they feel they can get the information that you feel might be required
to make a decision.

DR. MC CULLEY: Please answer the question.

DR. CASEBEER: Let me comment on that? We don\'t like that any better
than you do, obviously, and we did monumental things in terms of Fed Ex
packages, certified letters, phone calls, faxes, any type of
communication already to try to solve this problem because clearly we
wanted it solved, and I think we have extracted what we can out of the
investigators and a future effort would not reveal very much because we
have been very, very difficult to the point of myself threatening people
to be out of the study if we didn\'t get what we wanted.

DR. SUGAR: You are talking about pursuing the surgeon or pursuing the
patient?

DR. CASEBEER: We are talking about pursuing in most cases the surgeon.

DR. MC CULLEY: He is saying that he doesn\'t think it would yield much.
That does not preclude us from having that as a condition though. It
doesn\'t mean we put it in. It doesn\'t mean we have to take it out.

Dr. Wang?

DR. WANG: I just want to follow-up on the question that Dr. Pulido just
raised 10 minutes ago or so. Just along the lines of thinking of this
process and trying to resolve this issue from our intuition and clinical
experience my personal clinical experience is that it tends to be in
terms of direction of whether those patients who failed to show up they
tend to do better or worse. Just from personal experience they tend to
do better. Usually and particularly in LASIK in this particular type
procedure if they have problems they tend to come back. So, I guess that
sort of relieves some of your anxiety maybe to some extent.

DR. MC CULLEY: Dr. Bullimore?

DR. BULLIMORE: Just an observation. I mean this one clinic where there
were 179 patients enrolled and nobody was followed up to any extent, you
have my sympathies and what would have been useful for me in my review
and my comments would have been had you emphasized the fact that the
doctor had left the office and basically that clinic site had to be
closed down. If you had made that more clear in your application I would
have \-- you would have had more sympathy up front. You basically with
that one individual\'s behavior, whether intentional or whatever, you
were concerned about 86 percent. Your ceiling was set at 86 percent. So,
in terms of guidelines you had a big hole in your ship right there. I am
prepared to put this issue to bed and let us move on.

DR. MC CULLEY: Dr. Rosenthal?

DR. ROSENTHAL: I just want to remind the Panel that in the past they
have required additional information from another PMA holder which the
agency then sought to obtain and in fact was brought back to you and in
another instance, two instances you actually have requested as part of
the conditions of approval general information.

DR. MC CULLEY: So, that is an option available to us when we bring our
wisdom to words.

Dr. Macsai?

DR. MACSAI: Though I think we are not finished with the accountability
issue I have just a few questions for the sponsor, and I assume this is
the time to ask them. Regarding the nomograms you stated in your
presentation that a paper was published in the Journal of Op Tech Cat
Refractive Surgery, and I am not familiar with that journal. Could you
tell me is that \--

DR. KEZIRIAN: It is a Williams and Wilkens publication out of
Philadelphia. It was begun about a year ago, and I don\'t know how
successful it has been, but the paper was included in the application.

DR. MACSAI: But it wasn\'t in the bibliography, and that is why I was
confused.

PARTICIPANT: The paper is in there.

DR. MACSAI: Okay. Did you, you said you looked at a lot of different
identifying factors, sex, etc., did you look at age stratified by sex to
see if there was a difference in outcome and did you, also, look at
women on hormone replacement therapy?

DR. KEZIRIAN: We looked at all the factors you mentioned including age.
In fact, a nomogram that we did find a significant correlation with age
and used age and pre-operative refractive error to formulate the actual
nomograms. We did not find a sex differentiation on a statistical basis.
We did not consider hormonal therapy versus none in that analysis.

DR. MACSAI: Another question I have is in your presentation, Dr.
Kezirian you talked about the stability with your paired analysis which
was a very nice presentation. What overall percentage of patients did
that represent?

DR. KEZIRIAN: About 35 that came in for the visits to be able to analyze
it.

DR. MACSAI: Also, in your presentation you had a, you walked us through
your graphs, your bar graphs for patient symptoms including glare, halos
and visual fluctuation and Dr. Mannis did some quick math noting 20
percent of patients complained of worsening of glare and is it
statistically fair to summarize those numbers because if it is then I,
also, would add that I calculated that 26 percent of the patients were
complaining of halos on the worst side and 26 were complaining of visual
fluctuations?

DR. KEZIRIAN: Right, you just brought up the point I think that is
really important and that is that this is a change pre-op to post-op So,
it is not an absolute do you have halos. It is do you have halos pre-op
and do you have halos post-op and comparing your two scores. If you get
better you fall on the better side and if you get worse you fall on the
worse side and that was the way this was structured.

We find, I don\'t know about the math. I think you might have been
looking at the wrong side of the chart. There were 5 percent of the eyes
that were worse more than, 3 points or more.

DR. MACSAI: No, all points is what I am asking, not 3 points or more.

DR. KEZIRIAN: Right, there were 15 percent that were worse 3 points and
so that adds up to 18. Fifty percent were no change, and the rest were
better which was about over 30 percent. So, you know, the shake-out
between minus 1 and plus 1 is questionable statistically because of the
way that the questionnaire was administered. They had no number clue.
They just made an X on a bar and we graded it afterwards with numbers.
So, if you look at that there was some worsening, but if you consider
that moving a point or two may not be as significant as moving 5 points
the number that really became worse in glare was very small.

Now, I am sorry?

DR. MACSAI: Did you validate your questionnaire to determine if a
movement of 1 point was significant?

DR. KEZIRIAN: We did not perform a statistical analysis asking that
question, no, whether or not 1 point was significant. We could, but it
would all be, you know, frankly, it would be conjecture.

The other question you asked was about halos.

DR. MACSAI: Halos and visual fluctuation. You presented three different
slides.

DR. KEZIRIAN: Right, and because we had a mean that didn\'t change, a T
test that showed no statistical significance in the before and after
answers and a distribution that was gaussian we just interpret that as
meaning there is not a significant measurable effect of this procedure
on those symptoms.

DR. MACSAI: But if you add all the numbers on the worse side, when I
added them is it fair to say that 26 percent complained of worsening of
halos whether it be mild, moderate or severe?

DR. KEZIRIAN: That is a true statement. Yes, it is. That is a true
statement and it would be balanced by the same if that many get better.
Why? I didn\'t find out.

DR. MACSAI: I didn\'t ask you why.

The other question I have is you talked about re-operations and the
effect on uncorrected visual acuity which was very impressive and I was
wondering how far out you had followed those patients. Was that effect
at 1, 3, 6 months after \--

DR. KEZIRIAN: For that analysis we used the last visit analysis. We
looked at the last time they had come in. For some patients that was as
short as a month and for some of them it was as long as almost a year.
We used the last visit analysis on that.

DR. MC CULLEY: I have three people I know that are queued up. Rick, you
were first, then Eve, then Janice.

DR. FERRIS: My comment actually goes back a long time ago to what Ming
was asking about with regard to the ability to look at the higher levels
of myopia and make some determination as to whether they should be
included or excluded. I am sure if you did the math to say what power
you had to show that this, what you observed there was the same as at
the less than 7 level of myopia you could get a number that would tell
you you don\'t have very good power to say that at least within a narrow
confidence interval that they are the same.

On the other hand, it seems to me that this is what Dr. McCulley was
talking about earlier that to some degree we are going to have to use
some clinical judgment because this kind of generalizability problem
extends in any study. If you start looking at minority populations
within the study, minorities in any way that you are talking about it,
your power to say that the treatment effect in that subgroup is the same
as the overall treatment effect is inevitably killed by the sample size.
So, you have to look within there to see if there are any clues for
differences, and I think you addressed that point fairly well with
regard to where the differences occurred and how we might address that.

Now, in the end we are lacking data. So, we are going to have to make a
clinical judgment. The second question has to do with the issue of the
missing people that we have been perseverating about, the ones that you
don\'t have information on and we understand that that is a particular
problem when people aren\'t sick. These people don\'t have any good
reason to come back necessarily and the question is whether you had ever
tried administering the questionnaire, for example, over the phone or
because I suspect that the people that came to the podium earlier today
would have no problem answering that questionnaire over the phone as to
how they liked this procedure. I haven\'t given them the questionnaire,
but I can predict what their response might be, and the issue here is
whether the people that you don\'t have follow-up on have similar
responses to the questionnaire as the people that you do have follow-up
on making you believe that the cohort that you are missing data on is
similar to the ones that you have data on and making it more easy to
swallow the idea that you are not missing some terrible bit of
information that is lurking out there that we just don\'t know about.

DR. MC CULLEY: Questions for the sponsor continue. Dr. Higginbotham?

DR. FERRIS: Can I get a response to that or not.

DR. MC CULLEY: What was the question?

DR. FERRIS: The question is whether they have thought about doing a
questionnaire over the phone.

DR. MACSAI: Which was my first question.

DR. KEZIRIAN: For a variety of reasons we haven\'t and resources clearly
is one of them but it is my understanding that that has been done with
some of the manufacturer\'s studies and it is my understanding that in
those manufacturer\'s studies specifically with this laser with VISX
that when that was done the mean responses mirrored or were better than
what was actually done, and I think that to a certain extent these are
the same people we are surveying again, but the only way I can respond
and answer is we haven\'t done it.

DR. MC CULLEY: If appropriate at the appropriate time, would we want to
make that as a condition?

Dr. Higginbotham?

DR. HIGGINBOTHAM; Yes, thanks for asking my first question, Dr. Ferris.
My second question relates to the comment we heard earlier today that
there was a poor success rate in the combined centers for the higher
myops and that was thought to be related to learning curve but as I look
at some of the clinics and the remainder cohort I see there are as many
as 139 patients and one of these, I mean this doesn\'t sound as if it is
an inexperienced surgeon necessarily and my question therefore is
whether or not this is probably not necessarily learning curve but
related to the fact that these are higher myops and there is a greater
risk that you are going to have some difficulty in meeting your goals.

DR. KEZIRIAN: The pooling analysis I generally would agree with your
comment except that the experience wasn\'t lower, I don\'t think in any
of the clinics. I think it was pretty even across the board, and I think
that that conjecture was made by the statistician who did, I think, a
wonderful job looking at it but didn\'t know the clinics and just
conjectured that, and it was plausible, but I don\'t think it was
accurate.

Your comment about risk, I would simply say that the outcomes that we
compared for poolability were efficacy outcomes, and it wasn\'t for best
acuity. So, I don\'t know that that would be presumably could risk, just
success. The success rate was lower. I am not sure the risk rate was
higher.

DR. HIGGINBOTHAM; Okay, I accept that amendment but it is probably
related, therefore, to the high refractive error.

DR. KEZIRIAN: Right, and therefore we agree.

DR. HIGGINBOTHAM: Yes, thank you.

DR. MC CULLEY: Dr. Jurkus?

DR. JURKUS: Going back to the patient survey could you please tell me
when that was given to the patients, at what visit?

DR. KEZIRIAN: Yes, it was provided pre-operatively and at the 3-month
follow-up visit.

DR. JURKUS: Then as the second question on that the people that reported
a change for the worse in terms of halos and vision fluctuation and
glare, was there any breakdown between the higher, greater than 7
diopters surgery and the less than 7 diopters surgery?

DR. KEZIRIAN: Not that we provided in the analysis. We have done that
informally but not in exactly the same data set. It appears that there
is a little bit more in the higher group.

DR. MC CULLEY: I don\'t think that we should be working under the false
assumption that the higher ranges do as well as the lower ranges.

DR. FERRIS: Of course not.

DR. KEZIRIAN: They don\'t.

DR. MC CULLEY: They are gaining more in refractive error, but they do
not \-- it is not, they do not do as well in whatever analysis one wants
to apply.

DR. FERRIS: How about are they happier?

DR. MC CULLEY: That would come in in the patient survey. Are they
happier or \--

DR. FERRIS: I mean they might be.

DR. MC CULLEY: They are gaining more, but they are risking more. They
are not going to do in general as well by most measures, but you have an
indication of \-- and they are in the range as best we can tell of
acceptability, but in terms of satisfaction are they happier or
unhappier?

DR. KEZIRIAN: We found that the higher patients tended to answer happier
than the patients in the midrange and the patients in the low range
tended to answer happier than patients in the midrange.

DR. MC CULLEY: Who was the happiest, high or low?

DR. KEZIRIAN: The high.

DR. MC CULLEY: So, high, low, intermediate?

DR. KEZIRIAN: Exactly.

DR. MC CULLEY: Dr. Wang and again, these are questions to sponsor. So,
questions to sponsor and then we need to allow sponsor to retire from
the table.

Dr. Wang?

DR. WANG: Ming Wang. I have a question about visual quality, and this
will pertain to the labeling later to be discussed. Specifically
regarding halo, we know that clinically the halo experience after LASIK
tends to be more visually significant and affecting the quality of
vision than halos that occur naturally in patients without ever having
surgery. From a physics standpoint we know that has some rationale if
the pre-op the halo come from asphericity of corneal lens combined
optics where post-op comes from this artificial excavation of cornea
just like volcano on surface of the cornea, but off sharply at 6
millimeters. Have you attempted to assess the degree of halo because
from my clinical experience those halos that occur after LASIK tend to
be more significant?

In other words if you just assess whether you have halo better or worse
pre- and post-op you may not address a more important hidden question
that is the degree of halo which may more potentially reverse their
post-LASIK visual quality compared with naturally occurring mild halo
pre-op without surgery.

DR. CASEBEER: The only way that I think you could have a judgment about
that is it would seem like people who said that they had one for halos
pre-op and they thought it was really worse or really different they
would grade it higher in the other, and it would show up to the left
side on that bell curve, but we didn\'t exactly say, \"Is this halo
better than that halo?\"

DR. MC CULLEY: Dr. Bullimore?

DR. BULLIMORE: A couple of very quick questions while he is still at the
table. Firstly, do you think pupil size is an important factor in
patient satisfaction with this procedure?

DR. CASEBEER: As a personal matter, I mean do I, personally, think that?

DR. MC CULLEY: No, I don\'t think we want personal \--

DR. BULLIMORE: Does the sponsor believe that pupil size is an important
determinant in \-- okay.

DR. CASEBEER: I want to answer, but it doesn\'t seem appropriate.

DR. MC CULLEY: No, I think you told us before you did not assess pupil
size.

DR. CASEBEER: Correct. So, we have no opinion.

DR. KEZIRIAN: So, we don\'t have a company opinion if you would. It
would only be personal.

DR. BULLIMORE: That is fine. The other issue was in terms of the
indications for the device do the numbers you give there refer to
spherical equivalent or sphere?

DR. KEZIRIAN: Say the question again?

DR. BULLIMORE: In your indications for, your proposed indications for
the procedure you are asking for up to minus 14. Is that spherical
equivalent or sphere?

DR. KEZIRIAN: Sphere.

DR. BULLIMORE: Is that minus cylinder form or plus cylinder form?

DR. KEZIRIAN: Minus cylinder form.

DR. MC CULLEY: Dr. Pulido?

DR. PULIDO: Proceeding with what Dr. Ferris said you said that trying to
get 100 percent follow-up on this by phone on this remainder cohort
would be almost insurmountable. What about randomly selecting 20 percent
and making sure that what you suspected was that they are doing very
well is truly the case? Would you still feel that that is
insurmountable?

PARTICIPANT: That is not appropriate.

DR. MC CULLEY: I don\'t think we care whether they do if we think that
is appropriate. It may be a very good suggestion, but whether they think
that they can do it or not or it is appropriate on their part is not
relevant. We decide.

Mr. Macsai?

DR. MACSAI: We discussed that you had different shapers but that this
data is all with one shaper. Is that correct?

DR. CASEBEER: That is correct.

DR. MACSAI: That is the diameter of the flap that the shaper in this
study lifts?

DR. CASEBEER: It is keratometry dependent with steeper corneas giving
larger caps. Probably with the Chiron ACS at around 43 or 44 diopters a
8.4 or 8.5 millimeters, someplace around in there. We do have other
keratomes in the study but they are not in this database. They are at
another time, and we are not asking clearly for some kind of an approval
for the Chiron ACS. It just happens to be \--

DR. MC CULLEY: We got that well clarified before.

DR. MACSAI: One other point, one last point of clarification. You said,
\"Minus 14 sphere and 6 diopters of cylinder and minus cylinder.\" Do
you mean minus 14, minus 6 at say 90 or 180? What indications are you
asking for? Because I was equally confused as Dr. Bullimore.

DR. CASEBEER: It is in two different parts really, sphere and cylinder,
so that theoretically that could occur, minus 14, minus \--

DR. MACSAI: Because that is the spherical equivalent of minus 17.

DR. CASEBEER: Yes, certainly it is, ma\'am.

DR. BULLIMORE: But you don\'t have any patients in that range to present
to us.

PARTICIPANT: It seems to me if I can make this statement more of a
labeling issue than anything. I mean there have been warnings suggested
and everything else about higher ranges, and I think that the hazard is
in requiring the only alternative for treatment of such eyes to be
individual innovations such as double carding. I think it is very
hazardous.

Okay, questions to sponsor, sponsor only answers to questions. No
editorial comments, sorry.

If there are burning questions for sponsor still, please so indicate?
Dr. Matoba, did you have one or yours isn\'t burning.

DR. MATOBA: It is labeling.

DR. MC CULLEY: I see no further questions for sponsor. We will ask
sponsor to depart the table. We thank you for your responses.

Okay, Bernie you need to get your questions ready to give to us. Are
there any other comments, questions statements, whatever variations on
the English language that we need to do before we put the questions up
to respond to?

Dr. Matoba?

DR. MATOBA: Alice Matoba. Just a comment about the labeling. In their
study the exclusion criteria included active ocular disease, anterior
signal pathology and also, any type of intraocular surgery but in their
proposed labeling that is not \-- previous intraocular surgery is not
mentioned either as a potential contraindication or as a caution that
efficacy has not been proven for those patients, and I think that the
labeling should be consistent with what they use as exclusion criteria
in their study.

DR. MC CULLEY: Good point. Thank you. Any other comments?

I think what we will do now is Bernie will present his questions to us
one at a time. Dr. Bullimore is going to scribe as we raise issues and
be sure you have Dr. Matoba\'s issue that we will bring up again as
well.

DR. LEPRI: Mr. Chairman, there is one point I would like to address one
of the questions regarding the labeling in pupil size. The current VISX
labeling states that astigmatic patients between the ages of 21 and 30
should be reminded that due to their larger pupils they are more likely
than the over 30-year-old population to experience a degradation in
visual performance under these conditions.

DR. MC CULLEY: Do the Panel agree with accepting that as an addition to
the labeling.

PARTICIPANT: It is already in the labeling.

DR. MC CULLEY: But we are going to have separate labeling for this so as
to carry forward and not have lost \-- it is an operational point that
the FDA can probably figure out, but we don\'t want that lost I don\'t
think.

DR. BULLIMORE: Correct, we want to add it for the spheres.

DR. MC CULLEY: So, you have that appropriately indicated?

DR. LEPRI: No, that is not the problem. There is a computer problem.
That is the screen.

DR. BULLIMORE: If it pleases the Chair, why don\'t I read the first
question while Dr. Lepri is recovering his computer?

DR. MC CULLEY: Good.

DR. BULLIMORE: Do the clinical data in this PMA provide sufficient
follow-up on the stability of the safety and efficacy of LASIK for the
correction of myopia with or without astigmatism in the ranges
indicated?

DR. MC CULLEY: Okay, I think we have, there have been stated issues. Let
us do sphere initially. What range is the Panel comfortable with \--

DR. BULLIMORE: This is the \--

DR. MC CULLEY: Oh, follow-up, accountability, okay, sorry. I fixated on
the word \"range.\" Accountability. Would you like to make a
recommendation, Dr. Mannis or respond to that question initially, take
the first shot at it?

DR. MANNIS: I must say that I am, Mark Mannis, I am waffling a bit. When
I came to the meeting I didn\'t feel as uncertain about the missing 43
percent as it were as I do now, and I would like to recommend that the
obstacles notwithstanding that the sponsor turn back to its cohort and
try to provide us with additional follow-up data.

DR. MC CULLEY: Dr. Pulido had a specific recommendation. Let me ask him
to state that and see if there is Panel concurrence with that?

Dr. Pulido?

DR. PULIDO: Proceeding from what Rick Ferris had said my suggestion had
been to randomly select 20 percent of that remainder cohort and calling
those patients and seeing how truly satisfied they had been and using
just that 20 percent of the remainder cohort.

DR. MANNIS: Mark Mannis, but you are talking only about a satisfaction
survey. I am actually talking about measuring objective parameters,
visual acuity.

DR. PULIDO: I would be happy with just a satisfaction survey.

DR. MC CULLEY: Dr. Rosenthal?

DR. ROSENTHAL: Twenty percent of those whom they have no data on?

DR. PULIDO: Correct.

DR. MC CULLEY: Then what percentage of that percent do they have to get
responses from? We have requested in the past that sponsor by whatever
mechanism gets whatever information sponsor can get by whatever means,
always legal, to get a response, and I don\'t recall how we worded that
before, but I think something along those lines seems to be, I hear from
just trying to interpret all of the various things that have been said
that that is the compromise that the Panel would be most comfortable
with and the question is how are we going to state that, that the
majority of the Panel will be most comfortable with, and the question is
how to state that.

Dr. Ferris?

DR. FERRIS: Rick Ferris. I am not going to suggest how to state it but I
had a question with regard to, that relates to whether this is
sufficient information or not, and it has to do with my concern of is
this sufficient information; does it stand alone to justify approving
this PMA or not, and as an alternative, and I don\'t know whether it is
possible, so I am raising this as a question, it might be that to say
that this is equivalent to an already approved procedure is different
than saying that on its own it stands alone, and I don\'t know whether
that is an option for us to say that this is \-- I see some shaking
heads like it is not an option.

DR. MC CULLEY: I don\'t think we can go the substantial equivalence
route. If they could we probably wouldn\'t be here.

DR. FERRIS: I withdraw the suggestion.

DR. MC CULLEY: Dr. Morris?

DR. MORRIS: This may be a really elementary question, but I thought I
heard the sponsor say that they used every human possible means to get
feedback from these patients, and \--

DR. MC CULLEY: They said that they worked principally with the
physicians. They didn\'t go directly to patients.

DR. MORRIS: Right. So, are you suggesting that the sponsor now go
directly to the patients around the surgeons?

DR. MC CULLEY: As a possibility. I am not trying to suggest anything.
What will make the Panel comfortable?

DR. MORRIS: That doesn\'t make me comfortable. I mean I am taking their
word for what they said. They said that it was impossible to get this
feedback, and now to force them to go back and get feedback so that we
feel better about it doesn\'t make me feel better.

DR. MC CULLEY: Is this an attempt to feel good and just a smokescreen or
is it real, and I don\'t know.

Dr. Macsai?

DR. MACSAI: I think the impossible has been done before, and I don\'t
think that the Panel ever has intended to do any sort of smokescreen nor
has any sponsor. I mean it is just a matter of establishing safety and
efficacy with acceptable accountability. That is all.

DR. MC CULLEY: Okay, Dr. Higginbotham?

DR. HIGGINBOTHAM: I guess my greatest concern rests with those clinics
that have 0 percent follow-up at 3 months, and perhaps one could do a
more targeted questionnaire or survey of those patients by phone just to
get a sense of their level of satisfaction and perhaps 20 percent of the
cohort of those centers might be a reasonable compromise to get us off
this issue.

DR. MC CULLEY: So, 0 to 20 is really going to answer the issue?

DR. HIGGINBOTHAM: Well, no, at least to sample those patients, at least
a reasonable sample of patients that at least three of the centers that
have more than two patients enrolled in the study.

DR. MC CULLEY: It seems to me crudely put those are bad actors, those
centers. They weren\'t responsible investigators for whatever reasons.

DR. MACSAI: Historically I think this is not under the Panel\'s purview.
If the Panel feels that the accountability is inadequate, then we either
decide if this PMA is acceptable or approvable, approvable with
conditions or not approvable.

DR. MC CULLEY: Okay.

DR. MACSAI: And then we set what accountability we feel is appropriate
and how a sponsor meets it is under a sponsor\'s purview and it is
inappropriate for us to dictate.

DR. MC CULLEY: It is not necessarily inappropriate. I mean we can
dictate things that we would want them to do. I mean basically what you
have done is called the question on this issue, and I am going to ask
for a vote on that, but Dr.Bullimore\'s hand got up before I said that.

DR. BULLIMORE: I am happy just to vote.

DR. MC CULLEY: All right. So, the question is that we are going to vote
on is do the clinical data in this PMA provide sufficient follow-up, and
I think it was changed a little bit, of the follow-up of the LASIK for
the correction of myopia with and without astigmatism in the ranges
indicated for voting members of the Panel, and there are 11. I know it
is not a formal vote, but it is a consensus vote at this time, but I
would like to take that straw vote as to the answer to the question.

DR. MANNIS: This is conditions or without conditions.

DR. MC CULLEY: It can be yes. It can be yes, with conditions. It can be
no, I suppose. This is a tough one to get over.

DR. ROSENTHAL: This is Dr. Rosenthal. You obviously have an issue with
accountability.

DR. MC CULLEY: That you is the plural.

DR. ROSENTHAL: I mean you, plural, many of you and when you make your
final recommendations you can recommend how you feel that should be
altered, as you have done so in the past.

DR. MC CULLEY: Okay, ordinarily what we do is answer the questions as we
go. I am trying to figure out how we can answer this question.

DR. ROSENTHAL: I think the agency understands that you have a problem,
you, collectively have a problem and that we will wait until the end of
the questions and the final decision to \--

DR. MC CULLEY: So, the Panel is uncertain as to how to answer this
question at this point.

Let us go to the next question.

Yes?

DR. YAROSS: Mr. Chairman, I would just propose that you ask it in terms
of the data in front of the Panel today.

DR. MC CULLEY: That really is what the question is. I mean that
clarifies the question. I don\'t think that is going to help the Panel
answer it.

Okay, is there a sense for a straw vote?

Do the data in the PMA provide sufficient follow-up of LASIK for the
correction of myopia with and without astigmatism in the ranges
indicated in the opinion of the individual Panel members?

DR. FERRIS: A point of clarification. This is Rick Ferris. That is by
itself, not using other clinical information?

DR. MC CULLEY: No, this is not in isolation. This is given all
information that each of us brings to the table, the data, our
interpretation of the data, our knowledge base, our sense, what is the
individual \--

DR. ROSENTHAL: Sorry, Dr. McCulley, this is Dr. Rosenthal. I think
actually Dr. Ferris is more correct. It is does the data that the
sponsor has presented in support of their application provide sufficient
patient follow-up.

DR. MC CULLEY: All right, okay, but our assessment \--

DR. ROSENTHAL: And I think we have gotten the sense that the Panel has.

DR. MC CULLEY: All right. So, what \--

DR. ROSENTHAL: I don\'t know if you need a straw vote.

DR. MC CULLEY: Okay, so just for data as presented does the Panel feel
like there is sufficient follow-up for the correction of myopia with or
without astigmatism in the ranges indicated?

All of those that think that it is, raise your hands?

(There were two hands.)

DR. MC CULLEY: All of those that do not, raise your hands?

(There were six hands.)

DR. MC CULLEY: Okay, the majority think that it is not.

Okay, go to the second question. Would you like to read the question for
us?

DR. LEPRI: What are the Panel\'s recommendations regarding the
sponsor\'s presentation of stability data for LASIK and \--

DR. LEPRI; Excuse me for interrupting, Dr. Rosenthal. There was another
part of that question, and I am sorry, part of it is my fault for not
having emphasized it, and that is is the 6-month follow-up assuming they
had not 100 percent at 6 months, are you happy with the 6-month data
because are retreating slightly from previous decisions where sometimes
6-month data was, you wanted something beyond 6-month data.

DR. MC CULLEY: We have wanted 2-and-3-month data.

PARTICIPANT; In the guidance document it is 1 year, 90 percent at 1
year. I mean is that what you are getting at?

DR. MC CULLEY: No, that has been clarified at another meeting before. I
thought the same thing, but the way it reads and it was Morris that
corrected it, it was that stability at two points 3 months apart.

DR. BULLIMORE: I think what we are saying is have they demonstrated,
assuming that they had all the accountability issues intact, have they
demonstrated that 6 months is all they need.

DR. MC CULLEY: For stability?

DR. BULLIMORE: No, for everything? Are you willing to accept the data at
6 months?

DR. MC CULLEY: At their level of accountability?

DR. BULLIMORE: No.

PARTICIPANT: If the accountability was perfect would 6 months be enough
follow-up?

DR. MC CULLEY: Okay, so this is a theoretical question in a sense.

DR. BULLIMORE: Yes, follow-up could be follow-up in terms of
accountability and it could be follow-up in terms of time, duration and
so I just want both of your inputs on that.

DR. MC CULLEY: As far as accountability that is what we \--

DR. BULLIMORE: We have gotten that input. Now, \--

DR. MC CULLEY: Minimum follow-up time with good accountability at that
time point, what is that time point set at?

DR. BULLIMORE: Yes, for what procedure?

DR. MC CULLEY: For this particular PMA?

DR. BULLIMORE: Yes.

DR. MC CULLEY: Relative to stability or all data?

DR. BULLIMORE: All data.

DR. MC CULLEY: All data.

DR. BULLIMORE: I mean the stability data are the data upon which we base
the duration of the study.

DR. MC CULLEY: But once you have stability then the other data is
useful.

DR. BULLIMORE: Is used to ensure that the safety and efficacy is
supported.

DR. MC CULLEY: To me the absolute time is a float depending on other
data, but, okay, Mark, you are frustrated.

DR. BULLIMORE: I am frustrated. I am unclear whether the FDA is asking
us to vote on this particular PMA or whether they are asking us to make
recommendation for the future. I am confused.

DR. YAROSS: May I try restating it? This is Marcia Yaross. I think the
question was if you had this data set with 90 plus percent
accountability would you feel that you had sufficient follow-up in terms
of time?

DR. MANNIS: Is 6 months enough is the question.

DR. MC CULLEY: At 6 months. You didn\'t give a number, but at 6 months.

DR. YAROSS: With the 6-month data set you have if the accountability \--

DR. MC CULLEY: If we had 90 percent accountability at 6 months would we
feel that this data was acceptable data in the \--

DR. YAROSS: To determine refractive stability.

DR. MC CULLEY: No, he said, \"Everything.\"

DR. YAROSS: To determine safety and effectiveness given that the data
came out the same out as they were but you had accountability that
satisfied you, is that the question?

DR. FERRIS: And I take it this is an issue because the guidance suggests
1 year. Is that right?

DR. ROSENTHAL: It is an issue because the sponsor has come in with
6-month data and I think if they have difficulty getting information up
until 6 months I want to be sure that the Panel is happy that they will
accept the 6-month data set. That is really what I am asking.

DR. MC CULLEY: I think it would depend, I mean we can look at the
6-month data set. Whether it is acceptable or not depends on what the
data is.

DR. ROSENTHAL: You have been given the 6-month data set. So, I am asking
you \--

DR. MC CULLEY: If the accountability \--

DR. ROSENTHAL: Obviously the accountability alters your decision, but
\--

DR. MC CULLEY: Okay, what you want us to answer for you is if there were
acceptable accountability in this particular PMA at 6 months would this
data be acceptable to us?

DR. ROSENTHAL: Correct.

DR. MC CULLEY: All of those that it would be acceptable raise your
hands?

(There was a show of hands.)

DR. MC CULLEY: All of those that it would not be raise your hands?

(There was a show of hands.)

DR. ROSENTHAL: Thank you, Mr. Chairman. I am sorry to have been
confusing. It was my fault in writing the question.

DR. MC CULLEY: I was confused. I am glad you are accepting the
responsibility.

Okay, next question, Question 2.

DR. LEPRI: What are the Panel\'s recommendations regarding the
sponsor\'s presentation of stability data for LASIK in the refractive
ranges indicated in this PMA?

DR. MC CULLEY: Dr. Bullimore?

DR. BULLIMORE: Would you entertain a motion or an informal motion?

DR. MC CULLEY: How about a suggested \--

DR. BULLIMORE: Basically that we accept these data, but I would like to
see in the conditions some wording be included in the labeling about
stability being poorer in the higher refractive ranges.

DR. MC CULLEY: How would you specifically state that?

DR. BULLIMORE: Refractive stability may be poorer above minus 7 diopters
of correction.

DR. MC CULLEY: Is there agreement?

DR. MACSAI: Can I make a friendly amendment that refractive stability
was only studied up to 6 months post-op.

DR. BULLIMORE: I accept the friendly amendment.

DR. VAN METER: I have several things to bring up about the higher
refractive ranges. We have seen less efficacy. We have seen less safety
in the efficacy issue that is at 79 percent 20/40 versus 94 percent
20/40. When we set up the original guidance documents it was really with
the specter of PRK on the horizon, and I think most surgeons think that
LASIK is better than PRK for a number of reasons. Yet the bar has not
been raised any. So, looking just at the subset of the greater than
minus 7 we see less efficacy and less safety both of which are below the
guidance document even though the bar has not been raised. In addition
there are other treatment modalities out there even outside of
spectacles to correct these patients and this doesn\'t mean that they
cannot have LASIK, but I am not sure that we should approve the higher
range based on the information that we have now.

We can get around this with appropriate informed consent.

DR. MC CULLEY: What we decided before when we discussed whether to add
specifics to the guidance document for the higher ranges is that we
would not try to create artificial numbers but take into consideration
our realization and the reality that those patients typically do less
well, and we would make a judgment as to what the performance was
whether it was acceptable or not.

So, we left it soft so that we would bring judgment to it and did not
change the guidance but with the understanding that those patients would
typically not respond as well as the lower ranges.

DR. VAN METER: With LASIK.

DR. MC CULLEY: With anything.

Dr. Pulido?

DR. PULIDO: I would like the labeling to say that there were too few
cases above 10 diopters of myopia and/or 3 diopters of astigmatism to
determine the safety, to completely determine the safety and efficacy.

DR. BULLIMORE: Mr. Chairman, a point of clarification here. The question
No. 2 that is on the screen which is the one I made a motion about
refers specifically to stability. It actually is No. 3 on the Panel\'s
handout. So, this may be leading to some confusion.

DR. MC CULLEY: Yes. The handout No. 2 it No. 3. No. 3 is No. 2. Sorry.
So, the response to this question, Dr. Bullimore suggested the response
and accepted Dr. Macsai\'s friendly amendment to that. Would you state
that now?

DR. BULLIMORE: Basically that the sponsor has shown adequate stability
with the conditions that stability may be poorer above minus 7 diopters
and stability has not been studied beyond 6 months.

DR. MC CULLEY: Okay, is there agreement? Okay, next question, No. 3,
which is No. 2 on the written handout.

No. 3, do the clinical data in this PMA provide reasonable assurance of
the safety and efficacy of LASIK for the correction of myopia with or
without astigmatism in the ranges indicated.

Dr. Pulido?

DR. PULIDO: Now, I would propose a motion that the labeling say that
there were too few cases above 10 diopters of myopia and/or 3 diopters
of astigmatism to completely determine the safety and efficacy in this
range.

DR. MC CULLEY: Does that meet with approval?

DR. VAN METER: That is just a fact, and then we don\'t approve safety
and efficacy above minus 10. That is not a labeling issue.

DR. MC CULLEY: You stated it as a labeling and that is a good point,
Woody, thank you. We want to set range, a recommendation for approvable
and as I looked at things between 10 and 14 there were questions that
you would address with the labeling as you have suggested, but there
were no patients above 14 and there were no patients with astigmatism
greater than 4 in the study. So, I don\'t see that we can approve
something where we have zero data. It seems like with no data above 14,
no data above 4 in cylinder that we cannot assess that because we have
zero data to try to assess.

Dr. Macsai?

DR. MACSAI: Jim, we have I think two patients. It wasn\'t zero patients
over 4 diopters. It was just two patients over 4 diopters. So, it was
\--

DR. MC CULLEY: Let me ask the table. How many patients above 4 diopters
of astigmatism?

PARTICIPANT: Two.

DR. MC CULLEY: Were there two between 4 and 5?

DR. ROSENTHAL: Mr. Chairman, excuse me. Dr. Waxler cogently reminded me
there are indications in which you would name the range and then there
is the labeling which would make certain statements about those outside
the range.

PARTICIPANT: Here are the numbers you requested. There were 9 between 3
and 4 diopters and 2 between 4 and 5 diopters of cylinder.

PARTICIPANT: Nine between 5 and 6.

DR. MC CULLEY: Okay.

Dr. Bullimore?

DR. BULLIMORE: Do we have a motion before us at the moment? If not, I
would like to make one.

DR. MC CULLEY: We are not to formal voting, but if you would like to
restate our consensus answer to the question that would be good.

DR. BULLIMORE: I will restate the consensus. I think the indications
should say that the range should be up to minus 10 for sphere and the
cylinder should be up to 4 diopters, minus 4, but I will accept friendly
amendment.

DR. MC CULLEY: Is there agreement with that or should it be, but I am
confused by what you said before that we can have indications but then
we can have labeling that allows going beyond the indication. I thought
we would have ranges and then there would be labeling warnings about
areas within the range. So, let us go with ranges and warnings within
the range because that is more like I think we have done it before.

DR. PULIDO: I second Dr. McCulley\'s motion to have ranges and labeling
within the range.

DR. MC CULLEY: Dr. Macsai?

DR. MACSAI: I agree with you but since there are no patients over 5
diopters I would feel very uncomfortable with that range.

DR. MC CULLEY: That is fine. We are trying to get a principle set here.
So, if you agree with the principle, then we will try to set the ranges.
Okay?

DR. ROSENTHAL: Excuse me, if I am not mistaken you have in fact set a
range and the made a recommendation above the upper level of the range.

DR. MC CULLEY: Let us do it this way.

DR. ROSENTHAL: You can do it either way you want and we are happy to
take your recommendation.

DR. MC CULLEY: Let us do it this way today and then you can deal with it
however you want to. What do we want the range to be, up to what in
sphere? I heard Dr. Mannis before say, \"Up to 14 with label warnings\"
or label warnings above 10 anyway. Maybe you didn\'t say, \"Fourteen.\"
They had data to 14.

DR. MANNIS: I didn\'t say, \"Fourteen.\"

DR. MC CULLEY: Okay, he said, \"Above 10 warnings.\" So, I got the 14
from another piece of it.

DR. MANNIS: Actually mine was lower. It was above 7.

DR. FERRIS: I would recommend up to minus 12.

DR. MC CULLEY: Minus 12 on the sphere.

DR. BULLIMORE: Mr. Chairman as the secretary is it my responsibility to
take a weighted mean for this?

DR. MC CULLEY: You are going to lose more hair.

PARTICIPANT: Is that spherical equivalent or sphere? I didn\'t hear what
you said.

DR. BULLIMORE: Sphere.

DR. MC CULLEY: Okay, Dr. Wang?

DR. WANG: I would say just minus 12 and minus 4 cylinder.

DR. MC CULLEY: Woody?

DR. VAN METER: That than allows a minus 16 plus 4 which I think is
outside the intent of what we mean. So, a patient who is minus 16 plus 4
would be correct by letter of the law but not by the intent.

DR. MC CULLEY: That is not necessarily true with the manner in which
this laser treats myopia. You will not be removing a minus 16, 17 amount
of tissue.

DR. VAN METER: I understand, but I mean should we add a spherical
equivalent?

DR. MC CULLEY: We were talking about sphere minus 12 and cylinder 4. Is
there general agreement with that?

DR. ROSENTHAL: And again Dr. Waxler reminds me that is what the laser
that you are currently considering is labeled for PRK.

DR. MC CULLEY: Isn\'t it amazing how consistent we are?

DR. ROSENTHAL: Isn\'t it amazing.

DR. MC CULLEY: Up to minus 12 and a minus 4 cylinder; is there agreement
with that, and that is nice to hear that it is consistent with the
current labeling.

Dr. Macsai?

DR. MACSAI: Maybe the sponsor cannot tell me because I think it is out
of order, but maybe the Panel members, someone could answer the question
for me, what are the microns of tissue removed at a minus 12, minus 4
correction?

DR. MC CULLEY: At a 6, I can tell you what I have in my memory bank that
you are removing roughly 11 microns per diopter at a 6-millimeter zone.
The zone is going to be less in treating the cylinder.

DR. ODRITCH(?): I am Mark Odritch. I am the sponsor \--

DR. MC CULLEY: You are out of order, Mark.

DR. WANG: So, focal equivalent in that case is minus 14 and 12 microns
per diopter. So, 12 times 14 is total microns tissue removed.

DR. MC CULLEY: But we are going to come to the critical issue here. We
are going to come to the critical here on the untouched posterior
stroma. That is the issue, and we are going to get that issue, that
concern dealt with otherwise. So, I don\'t think that the exact answer
to that question is relevant. So, we will deal with it otherwise. I am
not going to recognize anyone from the audience.

DR. SUGAR: Assuming that we just agreed to that, the minus 12, minus 4,
can we as a corollary to that request that the labeling have specific
tables showing outcomes for the different ranges?

DR. MC CULLEY: We have done that before that in the labeling that there
be stratified and I think that is a suggestion that we have agreed was
good in the past, and I think it is good in this setting as well.

Dr. Macsai?

DR. MACSAI: Dr. McCulley, could I add that that be stratified by 1 or 2
diopters, not by less than 7 and greater than 7?

DR. MC CULLEY: Yes. Does the Panel agree with that? That is what we have
done. That is consistent with prior. So, it would be stratified by 1 or
2, Marian. You have to pick.

DR. MACSAI: One.

DR. MC CULLEY: By 1 diopter. That is recommendation. If reality proves
that that is not practical, the FDA can deal with that. We are making
recommendations for FDA.

DR. PULIDO: Dr. McCulley, does the Panel feel that adding further
verbiage besides just a table saying that cases above 10 diopters, there
are too few cases above 10 diopters and 3 diopters of astigmatism to
completely determine the safety and efficacy in these ranges?

DR. MC CULLEY: I think that is reasonable. Others, I think Mark had that
actually in his written review.

Is there concurrence with that?

Okay.

DR. MACSAI: May I ask a question regarding the range? Within the range
are we going to specify the 250 microns of tissue or \--

DR. MC CULLEY: Marian, that is his question.

DR. MACSAI: Okay.

DR. LEPRI: Question 4, what are the Panel\'s recommendations regarding
the data on the individualized nomogram used in this investigation of
LASIK?

DR. MC CULLEY: Can you read for us exactly what the sponsor is
requesting the labeling to be relative to the nomogram?

DR. LEPRI: The programmed amount indicates the average correction that
can be anticipated but actual use may require individual adjustments at
this amount. Tracking of clinical outcomes is recommended.

DR. MC CULLEY: I have a question for you on that. That implies that the
software in the laser is going to be changed for LASIK as opposed to a
PRK setting.

DR. LEPRI: My understanding is that the software isn\'t changed but the
amount \-- they have specific settings in software for LASIK. However
they are going to change the amount of intended correction that is
cranked in based on an analysis of the beginning patients.

DR. MC CULLEY: Of the nomogram?

DR. LEPRI: Of the nomogram.

DR. MC CULLEY: So, what they are saying is that there will be \-- that
doesn\'t address the nomogram. How does one get to the programmed
amount? That is the nomogram that gets you to the programmed amount and
then based on individual experience one may have to adjust that. What is
said about getting to the programmed amount?

DR. LEPRI: There is a look-up table included in the PMA that shows in 1
diopter stratifications the results of this clinical investigation for
each area of spherocylindrical correction, what should be cranked in and
what the standard deviations were. So, they had to write in mean values.

DR. MC CULLEY: And that will be part of the product labeling?

DR. LEPRI: Yes. That is my question. Should it be part of the product
labeling?

DR. MC CULLEY: Absolutely.

DR. BULLIMORE: I think we are in agreement there.

DR. MC CULLEY: And that you may have to make individual adjustments from
that. Okay.

Yes, if what I understand you to be saying is what you are saying that
sounds appropriate.

Is there agreement with that?

DR. FERRIS: Was it may require individual adjustments or did require
individual adjustments.

DR. MC CULLEY: May require.

DR. LEPRI: It will depend on the \-- it is an outcome-based nomogram
program adjustment. There were varying amounts of adjustment and someone
may out there in the world, but my understanding is, not need to make an
adjustment.

DR. MC CULLEY: I guess what Rick is saying was there indeed a person who
did not have to make adjustments. So, should it be may or will?

(There was a chorus of \"May.\")

DR. MC CULLEY: All right. Dr. Wang?

DR. WANG: I have a suggestion for amendment to this based on I overall
agree with the way this is approached. You can take advantage of the
large generic nomogram based on 1000 patients, yet, also, take into
account the patient-specific techniques and whatever. However, there is
an intrinsic assumption in this approach, that is assuming the
surgeon\'s ratio to the generic population remains constant, in other
words personal calibration factor always stays at .9 for Joe Smith, the
surgeon. So, therefore, I don\'t know whether the surgeons may not
really understand that. It has to be very important that the surgeon has
to keep the same surgical technique, room humidity, temperature, various
conditions so that within the surgeon that he or she will be operating
with the same personal calibration normalizing factors. So, maybe a
language or two stressing the need that the surgeon has to maintain
intrasurgeon consistency in order to use this ratio consistently.

DR. MC CULLEY: If we are going to take it to that degree one would have
to say that the surgeon has to be aware that this is surgeon technique,
that that individual surgeon\'s technique has laser dependency, has the
laser exactly as at the time and the environment must not change. So, I
think we can leave that to the FDA as to whether those additional
factors would need to go in there. That is a good point.

DR. LEPRI: It could be added to have continued tracking of clinical
outcomes it is recommended, so that some \--

DR. MC CULLEY: Or you can state what the variables are. Dr. Wang is
correct, that the nomogram can change, if the same surgeon everything
being the same changes his technique somewhat.

Mark?

DR. MANNIS: Mark Mannis. Is recommended in this statement a strong
enough word? Should we perhaps say, \"Necessary\" or \"Mandatory\"
because the only way you can modify your nomogram is to track your
clinical outcomes? So, it really is saying that in order to do this
accurately we shouldn\'t just recommend that they track clinical
outcomes. If you want to have an accurate system of delivery you have
got to monitor your outcomes.

DR. MC CULLEY: This gets into management issues for the FDA. I think,
can we leave that as you guys think about that rather than us coming
down on it? That has implications I think beyond \--

DR. FERRIS: Rick Ferris. I just want to go back to the word \"may\"
because I know you cannot write a sentence that everybody understands,
and this one I don\'t understand in a way that may be different than
other people don\'t understand it and that is I view in this PMA that
they presented it did require individual adjustments and they showed us
data that showed that each individual had to adjust their machine. Now,
that adjustment may be close to zero or zero, but they had to look at it
and adjust it, and the may to me means, well, maybe you don\'t have to
do that.

DR. MC CULLEY: May I suggest, \"Will probably\" or something of, I think
will probably require. I don\'t know if that is \-- you understand our
concern about this, and I think we all agree with Dr. Ferris. You have
words that I am sure you are more allowed to use or otherwise. Get the
point? Okay.

DR. LEPRI: Stronger language.

DR. MC CULLEY: Stronger language.

Next question?

DR. LEPRI: No. 5, does the Panel recommend including warnings in the
labeling regarding post-LASIK corneal ectasia?

Dr. Sugar, would you like to suggest the wording for that?

DR. SUGAR: I suggest that the labeling contain a statement in that
regard.

DR. MC CULLEY: Okay, Dr. Mannis had in his review, I believe it was
Mark\'s, a \--

PARTICIPANT: In Dr. Lepri\'s Page 11.

DR. MC CULLEY: Okay, iatrogenic corneal ectasia is a possible
complication of LASIK. Clinical data suggest that this complication is
uncommon with residual and I inserted there untouched or posterior
corneal stroma, stromal thickness of at least 250 microns. Residual
stromal thickness could be to the uninitiated, one could take into
account the thickness of the flap. It is the posterior portion that is
untouched. So, it needs to be wording that makes that clear that cannot
be misinterpreted. So, it is not total. It is posterior untouched.

Dr. Wang?

DR. WANG: Ming Wang. I have a suggested amendment to that statement. I
feel it is probably not strong enough, maybe something to the FDA
recommends against performing this procedure, something to that effect
while the residual point is the posterior stroma is less than 250,
rather than state it is uncommon.

DR. MC CULLEY: I don\'t have a problem with that.

DR. MACSAI: I agree with that because if you are treating a minus 14
spherical equivalent to have a 250-micron bed you need a corneal
thickness of 580.

DR. MC CULLEY: Right.

DR. MACSAI: Five hundred and eighty microns and you may not have that in
some individuals.

DR. MC CULLEY: That is right. That is why we have, and that was, I think
that needs to be strongly stated that the posterior 250 microns not be
invaded because of the fear of second corneal ectasia, and one has to be
very careful and the safest way to do it is run the thing on the laser
to see how many microns it says it is going to take off and create a
table, and you have the table there with you, and you can look and see
and look at how much corneal thickness there is, that is pre-op to know
whether you can do it, but that is the safest way to do it rather than
doing it with calculations and formula.

Okay, so we have answers to all of your questions. Do you have any other
questions, and Dr. Rosenthal, no confusing questions.

Okay, Dr. Sugar?

DR. SUGAR: Can we have additions?

DR. MC CULLEY: Yes.

DR. SUGAR: I would like to add that there be a statement concerning the
possible adverse effect of pupil size on patient\'s symptoms and that
this be taken into account and this be placed both in the patient
brochure and the physician labeling.

DR. MC CULLEY: Okay, and Dr. Bullimore you had, we had a couple that you
were scribing. Dr. Matoba had one, and then we had one other that
brought product labeling in line. You didn\'t write it, huh? Okay, he
will write it this time, Alice.

DR. MATOBA: My suggestion was that the labeling be modified to be
consistent with the exclusion criteria that were used for the clinical
trial, specifically previous intraocular procedures, surgery. Patients
with that indication were excluded.

DR. MC CULLEY: Why?

DR. MATOBA: I don\'t know why, but I think that there should be a
warning. It shouldn\'t necessarily be an exclusion criterion in the
labeling, but it should be a caution that this procedure was not
investigated for those subgroups.

DR. MC CULLEY: And the why is you can blow the wound, but anyway let us
not. I should just shut up.

Dr. Wang?

DR. WANG: I would like to suggest in the same paragraph Dr. Sugar
suggested adding a sentence saying that cautionary statements such as
for high range of correction visually significant halo or glaring may be
present.

DR. MACSAI: Dr. McCulley?

DR. MC CULLEY: Is there agreement with that?

DR. MACSAI; I would like to expand on it.

DR. MC CULLEY: I will recognize you in a moment, Dr. Macsai.

Is there agreement with that?

Okay, Dr. Macsai?

DR. MACSAI: I think we need to expand upon that and actually include the
percentages that were shown in the study of glare and halos that
patients experienced.

DR. MC CULLEY: Is there agreement with that?

Okay. Any other additions?

I will ask the consumer rep, do you have any other additional comments
you would like to make?

MS. MORRIS: Lynn Morris. I wanted to be clear that pupil size was
included. I thought I heard the sponsor say that that wasn\'t part of
the study. They didn\'t collect that data.

DR. MC CULLEY: That is correct. They did not study it, but the fact that
they did not study it does not alleviate our concern that it might be an
issue. So, we are saying that we want that in.

MS. MORRIS: Oh, no, I want you to assure me that that is going to be in
the labeling.

DR. MC CULLEY: Yes, that was added.

Are there any other additions?

Before a motion is entertained the Chair will open the floor for open
public comment. The period will not exceed more than 30 minutes and
individual speakers will be limited to a maximum of 5 minutes.

Is there anyone from the public that would like to come back and make a
comment? Are you public or are you sponsor?

PARTICIPANT: I am public, really.

DR. MC CULLEY: I know who he is. Yes, you may return to the podium.

DR. STONECIPHER: Just real quick, my name is Dr. Karl Stonecipher, and I
just want to clarify a couple of things. I think you guys have answered
that the higher myops, they tend to be more happy, and those patients
tend to have less out- \-- better outcomes. So, I think you stated that,
and I think that is good. One thing that I think has been brought up wit
everybody, you have got to remember this is a mobile population. I mean
it is a very mobile and this was written as a 6-month study, and correct
me if I am wrong but that was the way that the informed consent was
read, and the higher myops tend to sometimes have this anatomic
disparity, and we included that, whether they had 20/40 vision or
whether they had 20/30 vision, but they were still based on that
original 20/20 guideline and then one thing that is very important and I
think that we missing and we haven\'t seen it in the discussion of the
Panel, Mr. Link\'s comments earlier are very important. I agree that
glare and halos are very important. We need to look at pupil size
although we didn\'t do that and maybe you want to do that in your
labeling, but the most important problem that is brought up here is that
we have some ethical guidelines that we need to look at and be a
patient\'s advocate that need to be addressed, that like Dr. Ferris
brought up aren\'t going to be addressed. I mean whether you guys
approve it or not, they are still going to keep doing it, and if you put
some kind of guidelines out there then whatever governmental agencies
will be able to put those guidelines into place.

Thank you.

DR. MC CULLEY: Anyone else who would like to make a comment from the
audience?

Seeing none, the \-- I didn\'t see your hand, sorry.

Identify yourself?

MR. LINK: Ron Link. I just wanted to say that it was very good to be
here today, and I am coming away with a much better feeling to go back
to my rank and file, if you will of the willingness to listen to our
concerns and address them and I think one thing that is clear to me is
that LASIK is a procedure obviously that is here to stay and I have
friends who have had success with it. I am very happy for them. At the
same time the people who have poor outcomes, there needs to be more
research as to what to do with these people in terms of fixing them, you
know in just really blunt terms because their experiences, they go back
to the doctor and they are met with well you should maybe wait until the
technology improves or we will send you up to Canada or any number of
suggestions.

So, a lot of them are in holding patterns and some for years, and I
think given the overwhelming success of the industry and the money that
has been generated it would be an ethical imperative to donate some of
that profit to research to help those who didn\'t have the good outcome.

DR. MC CULLEY: Thank you for your comments. You realize we have no
control over that?

MR. LINK: Absolutely. I just wanted to make it a matter of public
record.

Thank you.

DR. MC CULLEY: Any other comments from the public?

Seeing none, the open public hearing is now closed.

Does the FDA have any closing comments?

(No response.)

DR. MC CULLEY: This is new. Does the sponsor have any closing comments?

You have 5 minutes.

DR. ELDRIDGE: Sorry for that interruption, Mark Eldridge. I represent
VISX. I am the medical monitor to VISX and a paid consultant to VISX.
Several concerns were brought up by the Panel. We are here with, we
being VISX, not me. VISX is here with this sponsor, and we would like to
point out a couple of things. The concern regarding the minus 16, plus
4, I would like to answer numerically so the Panel is comfortable with
it. A minus 14, minus 4 ablates 140 microns of tissue. Monolin\'s(?)
formula is based on a 12-micron per diopter ablation at 6 millimeters.
Ours is a multizone ablation. So, it has less than the numeric guide
that you see if you just did the math.

Secondly, our technology uses a set of slits that affords us to create a
shape that does not ablate any deeper whether you are doing a minus 12
sphere or a minus 12, minus 4. So, when you program in minus 12 sphere
it is 140 microns. When you program in minus 12, minus 4, it is 140
microns. Interestingly when you go to 6 there is a little bit more of an
adjustment which has to do with a nomogram factor internal in the laser.
It only goes to 147. So, if you program in minus 12, minus 6 it will be
147 microns of tissue that are ablated. Minus 12 which is, the issue
that we are talking about is 127 microns of tissue. So, minus 14 is 140.
Minus 12 is 127 and adding sphere up to 4 does not increase the ablation
depth. I am sorry, cylinder, up to 4 does not increase the ablation
depth which is the reason the spherical equivalent does not make sense
in this particular device. It becomes cumbersome and very difficult for
the clinician to figure out. It is not quite straightforward. So, I
applaud you if you should elect to go with a minus 12 sphere or minus 14
sphere and whatever cylinder, but understand that that is a minute
increase. That is issue one.

Issue No. 2 has to do with asking the sponsor, in this case CRS to go
back. I can tell you having been the monitor for VISX when we had to go
back for PRK and several other times that every time we have gone back
we have had significant problems and the problems have to do with the
fact that the investigators are the ones who have a moral, ethical and
medical-legal responsibility to the patients. We do not, okay? And as a
company, a sponsor, it is very hard to go back directly to a patient,
and I think CRS is to be applauded for having attempted to motivate
their surgeons. Additionally every time we have done it, it has only
shown and verified exactly what CRS has showed you, that those patients
are doing better. It is when they don\'t do well they show up at your
doorstep.

Guy?

DR. KEZIRIAN: In my 1 remaining minute I just wanted to thank the Panel
for your discussion and your consideration of the application. We have
worked very hard to try to present it in a way which was understandable,
and I think you perceived that our approach has been to lay forward our
work on the table for you to observe, and we did not start this with the
understanding or intention of being able to affect a labeling change. If
we can, we have succeeded more than we wanted to. Our attempt was to
validate LASIK, and we feel we have.

Now, with the issue about the patients that we couldn\'t show you
through 6 months, I hope that you have had the opportunity to look at
Table 8 which is this last visit carried forward analysis. It basically
takes the last time we saw them and says how they were doing.

Seeing that patients haven\'t changed in any other part of this cohort,
we did see them postoperatively, almost all of them were seen
postoperatively, I would say that all of them were seen postoperatively
and reported. So, they are all in there, and the results didn\'t vary
very much. So, I just wanted to point that out that the information is
there as much as we could possibly generate it and again, thank you for
your consideration of this work.

DR. MC CULLEY: Thank you.

Ms. Thornton will now read the voting options for us.

MS. THORNTON; The Medical Device Amendments of 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 own merits, and the Panel\'s 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 use and
conditions of use when labeled will provide clinically significant
results.

The Panel\'s recommendation options for the vote are as follows: No. 1,
approval. There are no conditions attached.

No. 2, 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 the conditions are discussed by the Panel and listed
by the Panel Chair.

No. 3, 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.

Thank you, Dr. McCulley.

DR. MC CULLEY: Dr.Bullimore, would you like to make a motion?

DR. BULLIMORE: I will try. This is Dr.Bullimore.

I move that the PMA be deemed approvable with the following conditions,
that the range be limited to minus 12 diopters sphere and 4 diopters
cylinder and that the labeling include the following: No. 1, safety and
efficacy data be presented, stratified in 1-diopter steps and a clear
statement included to indicate that poorer outcomes should be
anticipated in refractive errors above minus 10 diopters.

Two, that stability though established is poorer in corrections above
minus 7 diopters and has not been studied or established beyond 6
months.

Three, there is a need for a nomogram to determine the correction as
worded by the sponsor on the slide.

Four, that the residual posterior corneal stroma of a depth of 250
microns not be invaded by either the laser and/or the microkeratome.

Five, caution be exercised in patients with prior intraocular surgery.

Six, some patients will experience significant visual symptoms such as
glare and halos. These may be worse in patients with larger pupils or in
conditions where the pupil is dilated.

Have I missed anything?

DR. MC CULLEY: That is your motion?

Is there a second to the motion?

DR. HIGGINBOTHAM: Second.

DR. MC CULLEY: Is there further discussion on the motion?

DR. HIGGINBOTHAM: Just a minor refinement and a friendly amendment.
Incisional intraocular surgery, just to not include within that
cautionary statement laser surgery.

DR. BULLIMORE: I accept that friendly amendment.

DR. MC CULLEY: Dr. Macsai, I thought I saw your hand or was it Woody?

I saw a hand down there.

DR. VAN METER: It was the question of accountability was not mentioned
among the provisions, is that correct?

DR. MC CULLEY: The motion on the table did not have \--

DR. VAN METER: Was there not a straw vote that \--

DR. BULLIMORE: I will entertain friendly amendments on the topic.

DR. MC CULLEY: We never reached consensus.

DR. VAN METER: Is the agency happy with where we stand on
accountability?

DR. ROSENTHAL: I don\'t know that that is an appropriate question.

DR. MC CULLEY: I think we have a motion on the floor. It has been
seconded. It is under discussion.

Dr. Pulido?

DR. PULIDO: I would like to add an amendment to it, and that is
contingent upon some say 20 percent data from the remainder cohort that
can be obtained by phone showing similar patient satisfaction to those
in the PMA cohort.

DR. MC CULLEY: Do you accept that friendly amendment?

DR. BULLIMORE: I don\'t accept the friendly amendment and here is why.
Basically what we are criticizing the sponsor for and our criticisms may
be justified or not is less than adequate science in their
accountability of their subjects. I am worried that in setting any
conditions that we really be guilty of the same thing, and we would be
setting arbitrary targets, drawing lines in the sand that really we
don\'t have a sound basis, and they might be seen as just nothing more
than hoops that we want the sponsor to jump through. So, with due
respect, Dr. Pulido, I don\'t accept your amendment.

DR. MC CULLEY: If I am correct, what we do now is the Panel needs to
vote as to whether it wishes to include that amendment in the motion,
not whether you are voting on the motion but voting on the amendment.

All those in favor of the amendment raise your hand?

PARTICIPANT: What is the amendment?

DR. MC CULLEY: The amendment to have a 20 percent assessment of those
lost to follow-up. Dr. Bullimore has not accepted it as a friendly
amendment.

Does the Panel feel that, you need to vote yea or nay as to whether that
amendment should be added as I understand the proceedings.

All those in favor of that amendment raise your hand?

(There was a hand.)

DR. MC CULLEY: You are consistent.

All those opposed?

(There was a show of hands.)

DR. MC CULLEY: The amendment is defeated.

Further discussion on the motion on the floor?

DR. VAN METER: I would like to make an amendment that we ask for 90
percent accountability at 6 months.

DR. MC CULLEY: Is there further discussion on \-- do you accept that as
a friendly amendment?

DR. BULLIMORE: With due respect to Dr. Van Meter, I decline to accept
that.

DR. MC CULLEY: Is there further discussion on the proposed amendment?

Those in favor of the amendment raise your hand?

(There were six hands.)

DR. MC CULLEY: Those opposed?

(There were four hands.)

PARTICIPANT: Can you do it again?

DR. MC CULLEY: Let us do it again.

Raise your hand high, those in favor of \-- restate the amendment.

DR. VAN METER: I would like to ask for 90 percent accountability of
patients at 6 months.

DR. WANG: A point of clarification, is that 90 percent accountability of
the PMA cohort or of all eyes?

DR. VAN METER: We have 76.3 percent accountability of the PMA cohort at
6 months, and I would like 90 percent accountability of the PMA cohort.

DR. WANG: So, that would not include the remainder cohort?

DR. VAN METER: That would not include the remainder cohort.

DR. MC CULLEY: Further discussion on the amendment?

Okay, Dr. Wang?

DR. WANG: That would entail additional study because obviously with the
current data set that is not there.

DR. MC CULLEY: Further discussion?

Those in favor of the amendment \-- you had further discussion?

DR. BULLIMORE: I just think this is an unreasonable, unrealistic target
for the sponsor to fulfill. So, I will continue to vote against the
amendment.

DR. VAN METER: I would like some discussion on why it is unreasonable
and could you tell me why we are changing, why you are happy with less
than 90 percent data now when you have not been happy in the past?

DR. BULLIMORE: You put me on the spot, Woody. As identified by the Chair
at the beginning of this proceedings we are dealing with a procedure
here which has probably been performed on 100, 200, maybe 300 or more
thousand Americans and then performed by many people sitting around this
table. So, it is with that that I am sort of coloring my perspective on
this PMA.

I think my previous comments notwithstanding the fault I don\'t believe
is with the sponsor per se. There are one, actually two investigators
that really did them in.

DR. VAN METER: I agree.

DR. BULLIMORE: Who are responsible for 25 percent of the total cohort.
If you look beyond that to the PMA cohort you see pretty good
accountability at 3 months across the board. I would like to see it
higher at 6 months, but we may be presenting something to the agency
that they either have to go against or that the sponsor may not be able
to meet.

DR. MC CULLEY: Woody, I can tell you what gives me some degree of
comfort. There was 90 percent accountability at 3 months and stability
was reached at 3 months. My judgment of that gives me sufficient degree
of comfort, but I will only be voting to break a tie.

DR. VAN METER: I understand. The issue becomes that we don\'t have any
information on a certain subset of patients, and I would like to get
some information on those patients. Now, I realize the 6-month data is
not obtainable, but I think it is possible for some communication with
these patients to be attainable or some examination.

Now, the reason I voted against Jose\'s amendment was I think 20 percent
telephone is inadequate, but if you can make contact with 90 percent of
the patients then perhaps that would be adequate.

DR. MC CULLEY: So, clarify your request. It is not necessarily full data
at 6 months. It is some accountability with those \--

DR. VAN METER: I would like to have 90 percent accountability,
accountability of 90 percent of the patients after 6 months. Now,
6-month data is not possible now, and within what is possible can we get
some information on these patients that we don\'t have information on?

DR. BULLIMORE: Mr. Chairman, maybe a little clarification as to Dr. Van
Meter\'s intent; is this to assure the safety and efficacy of this
particular PMA or is this colored by the desire to have more complete
data in future PMAs?

DR. VAN METER: Both. My comments are colored by the fact that I am
concerned about patients that don\'t do well, and we had testimony this
morning about a few patients, a very few patients that have problems
with this procedure afterwards. One way to keep this from happening is
to have very adequate informed consent that people know what they are
getting into.

It appalls me that a heart medication which is necessary to preserve
life may have a few paragraphs of what is good about it and then two
pages of what is bad about it. Here is something that affects the visual
system, and somebody has to live with it. We are not talking about a
life-threatening disease.

In order to make patients aware of an informed consent I think we need
to have better data than we have and my concern is that some patients
are slipping through the cracks. It is a wonderful procedure. It is
widely advertised. I know people are going to do it no matter what we
say, but I would like to have some information on this particular set of
patients that all is well.

DR. MC CULLEY: Dr. Rosenthal?

DR. ROSENTHAL: I don\'t think anybody wants that more than the agency as
well. I think the issue is that the agency regulates the companies and
the companies must provide a balanced view of the issues. We do not
regulate doctors in their offices and we do not regulate what doctors
advertise. We regulate companies and the company\'s responsibility is to
put in their labeling all the issues related to all the things you were
talking about, and that accompanies, in this instance there is a laser,
and I don\'t know what is going to happen with the PMA, but there is a
laser and if that company ultimately adopt that PMA they will have to
put in the information that was obtained from the data that was
generated.

If you think that in fact that data is biased then you must request
additional information. If in fact, you want it for, I don\'t know,
consistency\'s sake, then you must request that information.

I think the issue is one of, and Rick said it more eloquently than I
did, one of public health. There is a procedure being done 400,000 times
a year in this country and there is no information, and I am not making
one side or the other. It is your decision to make, and I respect your
decision, but I would like you to weigh a device that is new to the
system in which there is no information in which there is no question
the highest standards must be obtained and a device or an indication for
a device which is being used widely throughout this country in which
there are no indications for use, no information that is being publicly
provided for by either a government agency or by an organization or
something like that. I just ask you to take that into consideration.

DR. VAN METER: I understand what you are saying, and Mr. Chairman, I
accept the accountability data.

DR. MC CULLEY: You withdraw your \--

DR. VAN METER: I withdraw.

DR. MC CULLEY: Your friendly amendment?

DR. VAN METER: I withdraw my friendly amendment.

DR. MC CULLEY: That, I believe is allowable by Robert\'s rules of order.

So, that friendly amendment is withdrawn.

Dr. Pulido?

DR. PULIDO: I would like to propose a separate amendment and that would
be that labeling would say, \"Accountability data after 6 months is
insufficient to determine long-term safety and efficacy.

DR. MC CULLEY: We had something about 6 months before. Does what we had
before, royal scribe, cover it? We need more?

DR. BULLIMORE: I accept that friendly amendment.

DR. MC CULLEY: Okay, is there further discussion on this amendment, and
then I will get to Marian.

Dr. Wang?

DR. WANG: Ming Wang. I just want to second Dr. Bullimore\'s. I think
even though there is a technical difference between 80 and 90 percent,
but this procedure has turned out to be by and large a reasonable,
efficacious and safe procedure. I understand Dr. Ferris\' concern about
possibility of unknown bad complications lurking out there, but I think
the possibility with LASIK based on clinical experience is probably
small for this particular PMA.

I don\'t think we need to worry about setting a precedent in terms of 80
percent. Each PMA is different as Dr. McCulley pointed out. So, I will
support no additional data is needed.

DR. MC CULLEY: Further discussion on the amendment?

DR. BULLIMORE: Could I read it back as I have it before we put it to
bed? The seventh labeling condition be a statement that approval and
data was based on 76 percent accountability at 6 months or beyond.

DR. MC CULLEY: Are there any further amendments, discussion?

MS. MORRIS: I am sorry to complicate this. I need to ask, Lynn Morris. I
need to ask a procedural question here. I have had some of the same
concerns that were mentioned earlier about informed consent and I have
held up talking about it because I wasn\'t sure whether it should be a
labeling issue. So, before you vote and close this issue off I want some
sort of direction from you on whether that issue will be discussed in
some other way or whether that needs to be discussed in the labeling
issue.

DR. MC CULLEY: Good point, and I am not sure how to answer.

Dr. Rosenthal?

DR. ROSENTHAL: I think I can answer. We do not regulate the practice of
medicine.

MS. MORRIS: Oh, I understand that.

DR. ROSENTHAL: We do not tell a doctor what he can put in his informed
consent, but if we have in a labeling that there are certain concerns
and there are certain issues, then it is up to the doctor to make the
decision how he wants to present it to his patient and how he doesn\'t
want to present it to his patient. That is all we can do.

MS. MORRIS: But is it our responsibility to recommend in practitioner
labeling or instructions something that we would want in the informed
consent?

DR. ROSENTHAL: Dr. Waxler just told me there will be a patient labeling
brochure in which information that the company will be required to \--

MS. MORRIS: I understand that.

DR. ROSENTHAL: \-- make sure the patient gets it. Whether the doctor
gives it to the patient or not \--

MS. MORRIS: What I am asking is not in the patient information book but
in the practitioner information.

DR. MC CULLEY: You mean the information provided to the physician?

MS. MORRIS: That is right. So, can we make, I mean is this the point in
the discussion where we should be making recommendations on how we want
a physician to use the informed consent document?

DR. MC CULLEY: My impression is that I think that is wonderful, but I
don\'t think that it is \--

MS. MORRIS: That is what I am asking you, procedurally can we do that or
not?

DR. ROSENTHAL: I am afraid it is not the purview of the agency.

MS. MORRIS: We cannot recommend things in practitioner information?

DR. ROSENTHAL: We cannot tell them how to write an informed consent. We
can tell them what the labeling issues are with respect to the device,
the adverse events, the complications, the potential hazards, and we can
embolden it in big bright blue letters, but if a doctor does not want to
tell it to the patient, we cannot tell him to do so.

DR. MC CULLEY: The check and balance in the system for that physician
who does not is our legal system.

DR. ROSENTHAL: I am afraid.

DR. MC CULLEY: Other discussion?

All right, we have a motion on the floor for approvable with the
conditions that have been read into the record, and it has been
seconded.

DR. VAN METER: We have not voted on Dr. Pulido\'s amendment.

DR. BULLIMORE: I accepted it as a friendly amendment.

All of those in favor of the motion, please raise your hand high?

(There was a show of hands.)

DR. MC CULLEY: Nine.

All those opposed, please raise your hand high?

(No response.)

DR. MC CULLEY: Two abstentions. There were none and so obviously by
simple math, two abstentions.

Now, each person will be asked to indicate why you voted as you voted or
I guess abstained as you abstained.

We will start with Dr. Wang.

Identify yourself each time.

DR. WANG: This is Ming Wang. I voted to approve with conditions as
outlined by Dr.Bullimore as I feel the sponsor has done an adequate
study in addressing some major concerns regarding safety and efficacy of
this procedure.

DR. MANNIS: Mark Mannis, likewise I vote in favor of the recommendation
based on the data provided us in the study which I felt was adequate for
safety and efficacy.

DR. MATOBA: Alice Matoba. I voted in favor of the motion and I, also,
feel that the study did show adequate safety and efficacy.

DR. BULLIMORE: Mark Bullimore. I voted yes. I do have a number of
residual concerns, most of which are covered within the labeling.

DR. SUGAR: I voted yes, as well. This is a real-world study and it was
done, I think in a relatively unique way with multiple surgeons funding
their own investigation. This provides us with an opportunity to set
standards and set the position of the bar for the future for this
technique, and I am in favor of it.

DR. PULIDO: I voted yes only after I was able to get some amendment
showing that accountability was poor because that was a real problem
with the study, and again I don\'t want to see this kind of study
brought forward in the future.

DR. HIGGINBOTHAM: I voted yes because the stated conditions do cover my
concerns including the accountability issue which has been covered, and
I applaud the physicians for their initiative in bringing this to the
Panel.

DR. JURKUS: Jan Jurkus. I voted yes because I believe this information
is very much needed regarding LASIK surgery for both the practitioners
and the public.

DR. MACSAI: Marian Macsai. I abstained because there is a body of
information out there that is in the scientific literature that has
undergone peer review regarding this subject which provides knowledge
regarding the procedure. However, I cannot recommend approval of this
PMA because I cannot assess that true safety and efficacy has been
established due to the lack of accountability.

DR. VAN METER: Woodford Van Meter. I voted approvable with conditions. I
am concerned about the accountability issue, but I realize that taking
the sponsors at their word this information likely is not obtainable,
and I don\'t wish to visit the sins of a few investigators on the
sponsor. I am, also, concerned about informed consent as patients view
this with the barrage of advertising that even though it is not under
the purview of this agency or this committee is outside the range of
this discussion, but it concerns me, nonetheless. I hope we don\'t have
a whole lot more patients with accounts like we heard this morning come
forward with LASIK.

DR. FERRIS: Rick Ferris. I abstained from the vote because it is my
belief that the data that were included in this PMA are not
scientifically adequate for approval. However, I note that while we have
been yammering about this probably hundreds of these procedures have
been done this morning, and that there are other people on this Panel
with personal experience and, also, knowledge from other individuals and
reports that I don\'t have as a poor retina person that make me not want
to vote against it because I don\'t have that information, and I
acknowledge that their knowledge is better than mine in this area.

DR. MC CULLEY: Thank you.

Ms. Thornton has a couple of messages.

MS. THORNTON: Three to be exact. This is for the Panel. Will you please
place the documents that pertain to this discussion this morning on PMA
990010 behind the Panel table, please, for collection.

I wold like to remind those in the audience to please sign in. Also, I
wanted to note there is a section in the restaurant reserved for FDA,
about 25 seats to the far right of the restaurant.

Have a good lunch.

DR. MC CULLEY: Remember my admonition prior to the break and we will, by
my watch, check yours relative to what it is, I have one-twenty-eight.
We will start at two-twenty-five.

(Thereupon, at 1:28 p.m., a recess was taken until 2:25 p.m., the same
day.)

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[S]{.underline} [I]{.underline} [O]{.underline} [N]{.underline} (2:35
p.m.)

DR. MC CULLEY: I\'ll call the panel to order again. We will begin
discussion on PMA P980051. I would like to welcome to the deliberations
Dr. Mike Grimmett, and I\'ll ask Mike to introduce himself.

DR. GRIMMETT: Dr. Michael Grimmett from Bascom Palmer Eye Institute in
Miami, Floor.

DR. MC CULLEY: I\'d like to turn the floor now to the sponsor, who has
60 minutes to present your data.

**Agenda Item: Sponsor Presentation of PMA P980051**

DR. KOCH: Thank you, Dr. McCulley, and good afternoon everyone. My name
is Doug Koch. It\'s a pleasure to be here with you to present the
initial portion of this PMA from Sunrise Technologies. I am a paid
consultant for Sunrise Technologies, but I am not a shareholder of the
company. The other presenter this afternoon will be Doyle Stulting, and
Dr. Till Anschuetz from Baden-Baden will be here to answer questions as
well.

Before I begin, I would like to make two additional points regarding
this PMA submission. The first one is that although I don\'t have a
financial interest, I have a long vested interest in this topic. I began
work on this 11 years ago personally. I started this work as a strong
skeptic, not really believing that this technology or any form of
thermal keratoplasty could work. With time, as we improved the
technology and began to gather data, I became a cautious optimist. I now
stand before you as an enthusiast for what I think is an important
technology.

Another point I would like to make is that all the data for this study
were compiled and analyzed independently by an independent statistical
firm.

And the third point that I\'d like to make is that we are going to show
you this afternoon data that I believe convincingly demonstrate the
safety, efficacy, predictability, and believe it or not for thermal
keratoplasty, stability that is acceptable, and certainly would justify
the approval of this PMA.

The goal of this technology is to develop a procedure to correct
hyperopia that is safe, effective, minimally invasive, provides high
quality vision, and does not preclude other surgical procedures. The
technology of thermal keratoplasty is now 101 years old, and multiple
approaches have been tried in the twentieth century, as many of us
already know. But basically all these non-laser approaches were
abandoned for one primary problem, and that was that they were
overheating corneas, resulting in scarring, epithelial problems,
regression, irregular astigmatism, and other sorts of similar problems.

Lasers that have been studied include the CO~2~ laser, hydrogen fluoride
holmium, and continuous wave diode lasers. The holmium yang lasers that
have been studied include the contact device that is available
originally from Summit, although they dropped their PMA, and one that is
investigated in Europe. That is the Technomed device. And the
non-contact technology in the holmium is of course the Sunrise PMA we
are presenting today.

Now the Summit contact hand held probe is a non-simultaneous delivery
where you basically march around the cornea with a probe, and it\'s
highly surgeon-dependent. That contact approach was abandoned due to
irregular astigmatism and regression. I\'m just bringing that up,
because I want to distinguish our technology and our approach from that
approach.

Some other specifics other than the fact that it\'s contact and
non-contact is the fact that there is simultaneous delivery with the
Sunrise, and the treatment parameters are very different. Summit uses 15
hertz. Sunrise uses 5 hertz. The number of pulses delivered in the
Summit approach were 25 as opposed to 7. So that the overall energy
delivered to the cornea was actually very high with the Summit approach,
as compared to a relatively modest amounts with the Sunrise approach.

In the preclinical and clinical evaluation of the Sunrise device, a
number of different ring parameters were evaluated. One, two, and three
rings were looked at. The inner ring diameter was evaluated, ranging
from 5.0 to 6.5 millimeters. And the orientations of various rings,
whether they were staggered, one relative to the other, or radially
aligned.

As a result of all these preclinical and clinical studies the optimal
ring parameter selected for this FDA trial were two rings at the 6.0 and
7.0 millimeter zones, radially aligned. And these were selected to
maximize outcomes, and also to maximize the size of the central
untreated zone of the cornea.

This is the appearance of a patient immediately after treatment, and
that just shows you the orientation of the spots in these two rings at
6.0 and 7.0 millimeters.

On your left you see a picture of the device. This is the actual laser
in this box here, connected to the slit lamp delivery system by a fiber
optic cable. Both the surgeon and the patient are seated at the slit
lamp delivery system. The patient fixates at a central target, and there
are eight tracer helium neon beams that represent each of the holmium
beams, and these are centered around the patient\'s entrance pupil. So
centration is very simple and very predictable.

The treatment technique involves eight spots simultaneously delivered at
6.0 millimeters, and then a second ring is delivered at 7.0 millimeters.
The spot size is about 600 microns. And we use seven pulses, and since
this device works at 5 hertz, it represents 1.4 seconds per ring.

This short video will demonstrate the procedure that is used in the FDA
trials. The additional equipment that is needed is obviously very
simple: some preparacaine(?), eye pads, a lip speculum, and a timer. A
drop of preparacaine is administered, and we then wait three minutes. A
second drop is administered, again waiting an additional three minutes
for it to absorb. Finally, a third drop is administered.

We wait five minutes, during which the fellow eye is patched to insure
that there is no cross fixation. A lid speculum is inserted to prevent
blinking during the procedure. And then the approach that we are going
to recommend for labeling is to allow the tear film to dry naturally for
three minutes. The laser energy is absorbed by the tear film, and we
would like to have it dry completely by the time of the treatment.

The final instructions are given to the patient with regard to fixation
of the target while the lid speculum is in place. The laser is then
prepared by setting the energy, as you see circled in yellow. The number
of pulses is set at seven. Then the remainder of the laser is arranged,
set a 6.0 millimeters. The orientation of the beams is established. One
can insure that all the beams are in fact fully activated.

The final instructions are given to the patient. The final review of all
laser parameters. The laser is activated. Then by stepping on the foot
pedal one delivers the first ring of treatment, as you will see in the
video in just a moment. You can see the helium neon tracer beams. I\'m
sorry those aren\'t real clear, but you will see them a little bit
better on the slit lamp view through the camera.

That was the first ring that was treated. It\'s just that fast. Then the
rings are adjusted from the 6.0 millimeter to the 7.0 millimeter
diameter, again staying along the same radial alignment. The second ring
is then treated. That concludes the treatment of the second ring.

The patient then sits back from the slit lamp. The lid speculum is
removed, antibiotic drops are administered, and instructions for
post-operative care are given.

This is a patient pre-operatively and immediately post-operatively. You
can see the whitening of the epithelium that takes place. In addition,
there is haze in the stroma that has a conical shape that extends to
approximately three-quarters depth. For the treatment parameters in this
study, this is the appearance at one month. The spots are fairly faint.
It varies from patient to patient obviously, but they are certainly
relatively subtle.

At six months, again you can just see them with a broad beam
illumination. Certainly you can readily see them with the other
sclerotic scatter or retinal illumination. They have never been noticed
by patients, or we have not had patient complaints relating to these,
and they certainly are not visible to the naked eye after the first day
or so.

This is an elevation map that tries to show the effect of the laser on
corneal curvature. This is pre-operatively. At some point
post-operatively you can see on a difference map that there is
peripheral depression that is created along with the central elevation.
If we then translate these elevation data into a corneal power map, in
other words reflecting corneal curvature data, again pre-operatively,
post-operatively you can see the nice large zone of correction that is
generated here, which we think is in contradistinct. You can see the
difference map, again, the large central zone of steepening that is
generated by the treatment.

On your left you see an anterior elevation map of laser thermal
keratoplasty. And you can see that there typically is a smaller zone in
patients that have undergone hyperopic LASIK. This study began with a
feasibility study conducted in 1992 on non-sighted eyes by Peter
McDonald. Then in 1993, the Phase IIA was begun of 28 eyes using
different treatment parameters than we used in the subsequent trials.
The expanded IIA was begun in April 1996, and we went into Phase III in
November of 1997.

As will be pointed out by Dr. Stulting in his talk, the first group of
patients in this expanded IIA study had a different drying technique
used. And we initially thought that they would have the same results,
but we subsequently began to see that these patients were
undercorrected. So from about this point hence, we went back actually to
the drying technique that was used in Phase IIA, and that\'s the drying
technique that we think has produced the best results.

In a meeting with FDA in June 1998, we talked with them about our
criteria for submitting the PMA. These criteria were generated. When
stability was achieved in the accordance with the October 1996 FDA
guidance, the PMA could be submitted. That guidance indicated that 95
percent of eyes had to have a chance in refraction of less than or equal
to 1 diopter, 2 visits, 3 months apart. We had to have at least 300
cases at that stability endpoint, which turned out to be 6 months.

It was felt that 300 cases were certainly sufficient to detect less than
a 1 percent incidence of complications, and more than sufficient for the
efficacy endpoints. They also wanted to see 100 cases at one year
following treatment.

If you look at what our data are, in December 1998 we submitted a PMA
with 345 eyes, and 123 in a year. But actually, we had a 90 day update
in March, and then in response to FDA questions in June, we now have at
six months, which we believe is our stability endpoint, 596 eyes, 436 at
12 months, and 144 at 18 months.

If we use the FDA definition of accountability as circulated in the
draft guidance document regarding accountability, we have excellent
accountability, as you will see. I hope that\'s not one thing we will be
discussing this afternoon also; 97 percent at one month, but basically
92 percent at six months, 86 percent at 12 months, and even 82 percent,
even in excess of 80 percent at 18 months.

The investigational sites included: myself, Drs. Alan Aker, Sandra
Belmont, David Brown, Dan Durrie, Paul Ernest, Howard Fine, David
Hardten, his partner Dick Lindstrom, Modest Trap, Peter McDonald, and
Robert Gale Martin. So you can see we had an excellent group of
investigators, who are highly respected ophthalmologists.

The indications for use in this study were unilateral or bilateral
hyperopia +0.75 to +2.50, with 3/4 of a diopter refractive cylinder or
less. Patient should be 40 years of age of older; 656 eyes were treated
under this algorithm in which basically the only variable was laser
energy, but the number of applications, spot placement, and pulse
frequency was not varied. Again, the only other variation, as I
mentioned, was that the first 46 eyes in that expanded Phase IIA had a
different drying technique, which as we will point out, led to early
undercorrections in these patient, and late undercorrections as well.

The pulse energy was varied based on the pretreatment manifest of
refractive spherical equivalent ranging from 228 to 256 mJs.

Let\'s look at the safety. According to the October 1996 guidance the
safety criteria include: loss of best spectacle corrected visual acuity
of greater than 2 lines must less than 5 percent; vision less than 20/40
must be less than 1 percent; induced manifest refractive astigmatism
greater than two diopters should be less than 5 percent; and adverse
events should be less than 1 percent per event.

If we looked at best spectacle corrected visual acuity, you can see a
smattering of eyes on the plus side, and we have a small number of eyes
on the minus side, and this is at six months. Specifically, we have 2.3
percent of eyes that lost two lines of vision. That represents 13 eyes,
and because we used EDTRS charts, 11 of those 13 eyes lost vision from
20 over 12.5 to 20/20. The other patient was 20/25, another one was
20/32. So basically, they all retained excellent vision, although within
the strict criteria of two lines, they certainly meet that criterion.

Of these patients, this represents two patients that lost more than two
lines, and let\'s look at those in closer detail. One was a 60 year old
patient that was 20/20 before treatment, but developed an age-related
cataract at six months after the treatment, and his vision dropped to
20/40.

The only patient that could be considered attributable to the actual
laser treatment is a patient who was 20/10 and at three months he was
20/13, but he dropped three lines to 20/20 at six months, but he was
back to 20/13 at 12 months. So we don\'t really feel that there were any
patients who had any laser-induced loss of vision in excess of two
lines. We believe that the preservation of best spectacle corrected
visual acuity is unparalleled compared to other refractive surgical
procedures, especially those for the treatment of hyperopia, or
including those.

Adverse events include one patient with unresolved differential
diagnosis of chronic retinoschisis, which is retinal detachment, whose
vision was 20/25 uncorrected at one year. A 71 year old who developed a
cataract at 12 months, and again the vision dropped in this patient to
20/50. It\'s hard to really relate any of these again to the laser
treatment itself.

The FDA medical officer\'s review stated that \"no laser related adverse
events were reported during this investigation.\" Obviously, we are well
below the 1 percent target per event.

If we look at other complications, you can again see these are really
negligible. Some small comments about foreign body sensation, 0.2
percent at three and six months. Pain at 0.3 percent at three months.
And again to quote the medical officer\'s review, \"The only
complications noted at six months or later post-treatment was mild
foreign body sensation in a small number of patients. This generally
consisted of mild itchy, scratchy feeling, requiring artificial tears,\"
not altogether surprising in a predioptic(?) population.

If we look at the incidence of induced manifest cylinder, and this is
one of the questions for panel discussion, I think question three, the
FDA criterion for this is cylinder greater than 2 diopters must be less
than 5 percent. At six months we had 0.8 percent, and at 12 months, 0.2
percent. So obviously it was way, way below the FDA target.

If we expand that a little bit and look at greater than equal to 2
diopters, we\'re still well below that 5 percent threshold. If we extend
that a little bit farther and look at greater than 1 or great than or
equal to 1 diopter, the only time that we remain above the 5 percent
threshold is just for the greater than or equal to 1 diopter.

But if we look here at 18 months, we have your four eyes that have more
than a diopter of induced cylinder at 18 months. Actually, every one of
these eyes had excellent correct acuity. There was no loss of best
corrected acuity, and three of these four eyes had 20/32 uncorrected
vision. So we don\'t think that induced cylinder is an issue. I think we
have demonstrated not only the safety, but preservation of excellent
vision.

I\'d like to make a few more comments about induced cylinder, because
the precision of measurement for this parameter has not really been
established. There are no reported data in the literature that we could
find for induced cylinder of greater than a diopter, or greater than or
equal to a diopter for other refractor procedures. Nor are there
criteria for cylinder change of these magnitudes in the FDA guidance
document, and it\'s not a criterion that has been used to judge previous
refractive devices.

If we think about the measurement issues here, for a manifest
refraction, the accepted standard deviation for measurement error is
around a half diopter, so that gives you about 95 percent plus or
minus 1. Cylinder measurement is generally assumed to have a higher
standard deviation.

Assuming a standard deviation, however, of a half diopter, remember we
are starting with patients that don\'t have cylinder. Up to 5 percent of
induced cylinder greater than a diopter could be attributable to
measurement error alone, which we think could be another compounding
factor in these patients at 12 and 18 months. However, bottom line, I
think we have met the FDA criteria. There is no loss of vision in these
patients with regard to this issue.

So reviewing again the safety criteria, loss of greater than two lines,
vision worse than 20/40, induced cylinder greater than 2 diopters. We
are way, way, way below the FDA criteria.

Another question for panel discussion related to double vision. We gave
patients a questionnaire, and they could check if they had double
vision. We decided to contact those patient that had checked that they
had double vision either at 6 months or 12 months after surgery, because
again this relates to topics that have already been discussed before the
panel today in the public session, and with regard to the LASIK
submission.

What we found is certainly the majority of patients had none. But those
that we contacted by phone, if we combine all these groups, 95 percent
of the patients either did not initially check that box, or those that
did, they said it wasn\'t worse than pre-op or it wasn\'t bothersome.

Now we were unable to contact 3 percent of the patients, but 2 percent
of the patients said yes, they still had double vision when contacted.
But if we looked at the data, none of them had loss of best spectacle
acuity, all of them had good uncorrected acuity, and all of them
indicated that they had good patient satisfaction. So we don\'t think
that that this is an issue of any sort that we need to worry about.

If we again look at another issue in question four, light sensitivity
and photophobia, often and always, if they checked that box, we did the
same thing. Those that checked the box, we called them, and we had an
independent person call both that group and this group. Again, we had 95
percent of the patients who either didn\'t check the box, or indicated
it wasn\'t worse than pre-op, or wasn\'t bothersome. Again,
interestingly there was a different group largely, but 3 percent
couldn\'t be contacted.

But of the 2 percent that said they still had light sensitivity and
photophobia, 1.8 percent said they were still satisfied with the
procedure. Interestingly, the only patient who said that she wasn\'t
satisfied, was upset because she lost the near vision that she had
gained early in the post-operative period, and then had lost that.

Now if look at safety and think about alternative procedures, I think we
are all aware of the potential complications of the microkeratome. These
are just a few. Some of these are mild. Some of these are obviously more
severe, corneal perforation, retinal hemorrhage, optic nerve injury.
There are a whole array of flap complications that can be induced with
hyperopic procedures involving a microkeratome. I think that we don\'t
really need to dwell on these, except to remember them in this
discussion.

If we look at post-operative complications, dry eye, lasekias(?),
epithelial defects, yes; epithelial ingrowth under the flap, yes;
irregular astigmatism, yes in LASIK. I\'m going to put minimal under
Sunrise, simply because if you define irregular astigmatism as loss of
best spectacle corrected acuity, or visually symptomatic problems, then
I would say we have none, but I think if you did topographic analysis,
you would certainly find some small amounts of it. But we think it\'s
well below the clinical threshold.

Loss of best spectacle corrected visual acuity, certainly with LASIK and
none with Sunrise. I say none, because the only patients we had were two
cataracts, and one patient that dropped transiently to 20/20 and went
back to 20/13.

Other LASIK problems, infection, interface inflammation, stromal melts,
vascular occlusions, macular hemorrhage, retinal hemorrhage, and it is
certainly worth pointing out that LASIK as a procedure involves cutting
through the visual axis, and the Sunrise procedure is obviously
conducted well outside it.

I would close on this issue of safety by posing the question, is there
any other refractive surgical procedure that has this outstanding safety
profile?

I\'m going to turn the podium over to Dr. Stulting, and thank you for
your attention.

DR. STULTING: Thank you, Dr. Koch. I\'m Doyle Stulting. I\'m professor
of ophthalmology at Emory University. I\'m a paid consultant for Sunrise
Technologies. My involvement with them began about a year ago when they
asked me to review this data and help them prepare it for submission. I
told them that I had not had any experience with this, and I am not one
of the investigators. I have, however, subsequently used the instrument
outside of the United States, and examined patients post-operatively. So
I do have some experience with the device.

My job today is to discuss with you efficacy, patient satisfaction, and
stability. This slide shows the FDA guidance criteria for effectiveness:
85 percent of eyes should have 20/40 or better uncorrected acuity; 75
percent should be within 1 diopter of the attempted correction; 50
percent within a half a diopter.

And the definition for stability is that 95 percent of eyes have a
manifest refraction spherical equivalent within 1 diopter measured on
two visits that are at least three months apart.

Dr. Koch emphasized that the drying technique that was used in this
investigation in fact changed during the study. During Phase IIA, which
did not contribute any of the data that are in the cohort submitted for
analysis today, a three minute drying time was utilized. This in fact
was the one that was seen in the video.

When the expanded Phase IIA was begun, that is, the investigation that
provided the data for you today, the investigators decided that it would
appropriate to change the drying time, and in fact the protocol was
changed so that a 30 second drying time was used, and this was followed
by a damp WeckCel sponge wipe of the cornea.

After the initial patients were treated, it became apparent to the
investigators that the outcomes were not as good as those that they were
used to seeing in Phase IIA. So they were analyzed at that time, and it
turns out that these patients indeed were being undercorrected. As a
result, the initial drying technique was reinstituted, and continued for
the remainder of this study.

When the data were originally submitted to the FDA, concerns were raised
about the poolability of this early treatment group. A preliminary
analysis was performed at that time with the available data, looking at
outcomes three and six months post-operatively. These appeared to be
poolable.

As you saw in the slides that Dr. Koch presented, a considerable amount
of data has become available since the initial submission. Now
additional analysis clearly demonstrate that these data are not poolable
with the remainder of cases. Moreover, the inclusion of these data
actually artificially skews the outcomes to make the outcomes look much
worse than they really are. This is particularly the case with late
outcomes.

The analysis of the earliest cases, that is those with the longest
follow-up show that there were fewer eyes that were overcorrected by a
diopter or more early on at one month. There were fewer within a half a
diopter of intended correction at 12 months. There were differences in
uncorrected visual acuities at 1 month and 12 months. And these eyes
were consistently more hyperopic, with statistical significance being
reached at one week, one month, three months, and 18 months. So there
was a statistically significant difference in at least nine separate
efficacy parameters shown in this slide.

The sponsors properly concluded that the early cases had been
undertreated, leading to less early overcorrection, better early
uncorrected visual acuity, but poorer late results when stability had
been reached. It is therefore, not statistically valid to pool the early
cases with the remainder of the cohort.

Let me show you just two slides to give you a good feeling for what\'s
going on with these early cases. This slide shows the percentage of
cases contributed to the original cohort at each time period. The blue
line shows the contribution of the first 50 cases, while the red line
shows the contribution of the cohort without the 50 cases included.

You can see here that early on in the consistent 12 month cohort, the
first 50 cases contributes about 10 percent of the outcome measures. At
18 and 24 months, however, the early cases in fact contribute an
increasing portion of the outcome measures. So that at 24 months, these
early case contribute the majority of the outcomes.

So that if you are having poorer outcomes in these 50 cases as a result
of a technique change, what you can expect is that the data will look
worse at these time points out here, than it did in the early time
points simply because these cases contributed a disproportionately
larger amount to the cohort.

Let\'s look for example at the percentage of eyes that achieved 20/20 or
better visual acuity. Here the green line presents the original cohort
submitted to the panel for review. You can see here that there is an
unquestionable fall off in the percentage of eyes that has 20/20 visual
acuity from 12 to 24 months.

Let\'s look at the eyes that were treated with the new drying technique,
the first 50 cases. What we see is that in fact at three months had a
higher proportion 20/20 or better outcomes. This is the case, because
they didn\'t get the overshoot that is necessary in order for optimal
outcomes to be produced. From 12 months on, as these eyes became a
larger and larger portion of the data pool, you can see that the
outcomes fall off.

The red line shows the outcomes of the cohort minus the first 50 cases.
Here the percentage of eyes that achieved 20/20 or better acuity is
essentially stable throughout the observation period, out to 24 months.
So all efficacy analyses that are presented here, will be presented
using the consistent 12 month cohort, without the first 50 cases in
here. It\'s 357, still exceeding the number that is felt to be necessary
for this analysis.

We think it\'s important to note that data presentations that include
the first 50 eyes simply do not reflect the results that are obtained
with the recommended drying technique that was used for the remainder of
cases, and that is intended to be used when the device was approved.

Let\'s look then at efficacy. This slide shows uncorrected visual acuity
at six months after treatment; 88 percent of eyes were 20/40 or better;
78 percent, 20/30 or better; 59 percent, 20/25 or better; and 40
percent, 20/20 or better.

This slide shows the percentage of eyes that are 20/20 or better as a
function of time after treatment. You can see that 85 percent of eyes
are 20/40 or better at 12 months, and 86 percent at 18 months. Thus, the
FDA target value of 85 percent is exceeded at each of these examination
points. Notice as well the 95 percent confidence interval here for the
last three measures. These confidence intervals overlap, indicating that
there is no significant change in the percent of eyes achieving 20/40 or
better with time beyond six months.

The average visual acuities obtained at 6 months, 12 months, and 18
months are another indicator of the stability of the outcome that is
obtained with the procedure. These numbers are 20/27, 20/27, and 20/28.
In fact, the disparity in uncorrected visual acuities between 6 and 18
months is 0.9 EDTRS letters. Clearly, within measurement error, and
clearly below the level of clinical significance.

This slide shows the percentage of eyes that are 20/20 or better with
time after surgery. There is no FDA guidance target for this number, but
we show it anyway. You can see that 40 percent of eyes are 20/20 or
better at 6 months; 38 percent of eyes are 20/20 or better at 12 months;
and 37 percent of eyes are 20/20 or better at 18 months. Once again, the
94 percent confidence intervals overlap at six months and beyond,
indicating that there is no statistically significant difference in
these outcomes.

So in summary, the distance uncorrected visual acuity is stable within
statistical limits between 6 and 18 months after surgery. Only a very
small, amounting to a 2-3 percent non-statistically significant change
is seen in the percent of cases seeing 20/20 and 20/40 or better at
these time points. At 6, 12, and 18 months post-treatment the percent of
cases that is 20/40 or better meets or exceeds the FDA guidance target
value of 85 percent.

Ninety percent of eyes six months post-operatively were within 1 diopter
of the target manifest refraction spherical equivalent. This exceeds the
FDA target value of 75 percent.

Looking at this number as a function of time, we see that 90 percent of
eyes were within 1 diopter of the intended correction at six months; 84
percent at 12 months; and 80 percent at 18 months. Notice the expanded
confidence interval here, and the fact that the confidence intervals
overlap. There is no statistical difference among these measurements.
Again, all of them exceed the FDA target value of 75 percent.

This slide shows predictability; the number of eyes within a half a
diopter of intended correction as a function of time after surgery.
Sixty-six percent of eyes were within a half diopter at six months; 58
percent at 12 months; and 48 percent at 18 months. The FDA target value
of 50 percent is met at all intervals except this one, where the eyes in
this study fall 2 percent below the target value. The confidence
interval is wider here, because there are fewer eyes to examine, but it
still incorporates the 50 percent value. So in summary, this device
meets FDA effectiveness criteria.

Let\'s talk for a moment about patient satisfaction. As you know, a
survey was sent to these patients initially. To clarify and understand
the answers, the sponsor called all patients who reported any
dissatisfaction with the procedure at 6 or 12 months after treatment
where the reason was not clearly delineated in their initial responses
to clarify the data as much as possible.

Here are the results: 87 percent of these patients were satisfied; 3
percent could not be contacted. Let\'s take a look at the 10 percent who
were identified as being dissatisfied. One of them was the patient that
Dr. Koch described with the cataract. One of them was dissatisfied
because of a slight overcorrection.

Three patients actually had good distance vision, and were pleased with
the good distance vision. Their dissatisfaction was based on the fact
that they liked the near vision that they got when they were initially
overcorrected immediately post-operatively. The bulk of the patients
were dissatisfied simply because of undercorrection. This protocol did
not permit retreatments, so these patients could not be treated.

International experience, however, at this point indicates that
retreatments are not only possible, but are effective. And Dr. Anschuetz
is here today to answer questions if you have any of him.

But remember that this PMA is being sent to you as a single treatment
modality. No enhancements were permitted, and yet the satisfaction rate
is still quite high. More importantly, no patient mentioned visual
symptoms such as glare, halos, difficulties driving at night, or
diplopia as a cause of dissatisfaction.

This point is especially pertinent because of the comments made in the
public session this morning, and because of the comments made in the
presentation earlier today. It is clear that this agency must look at
outcome measures other than Snellen visual acuity to assess the safety
and efficacy of devices.

And I say this again for emphasis, because it\'s very important. No
patient mentioned visual symptoms such as glare, halos, or difficulties
driving at night or diplopia as a cause of dissatisfaction.

An effort was also made to understand why fellow eyes were not treated.
The sponsor contacted all patients who did not wish treatment during the
study for their fellow eyes to determine the reason that they didn\'t
want treatment. Ninety-six percent of these patients fell into one of
the three categories indicated on the slide. Either when they were
contacted, they had actually already had the other eye treated, or they
desired to have the treatment, having originally postponed the treatment
for personal reasons, for scheduling reasons, or because the protocol
simply didn\'t allow treatment of their second eye.

The third group of patients answered no to this question for reasons
that were totally unrelated to negative outcomes of the primary LTK,
that is, they were not candidates. They had monovision, and like it. And
the one patient who had the cataract was also in this group. Therefore,
only 4 percent of patients in this study chose no fellow eye treatment
for any reason due to the first eye outcome.

Now the obvious reason to have refractive surgery is to get rid of
glasses and contact lenses. This was accomplished in 88 percent of eyes
in this study, and remember that additional repeated treatments were not
allowed.

Let\'s talk for a moment about stability, and I\'m going to dwell on
this, because there were concerns that were raised about this in the
early panel reviews. The first thing that I want to say is that the
criterion that has traditionally been applied to stability is that eyes
be within 1 diopter manifest refracted spherical equivalent from one
visit to a next, with those visits being at least three months apart.

The target value is that 95 percent of eyes fulfill this criteria. At
the agency\'s request, multiple analyses for stability were performed at
the time of the original submission. This bar represents the outcomes
from the 6 month consistent cohort, from the 12 month consistent cohort,
from the 18 month consistent cohort, and from the entire cohort. All of
these subgroups fulfill the FDA requirement for stability at 6 months.

Additional questions, however, were raised about the stability of this
procedure following six months. This slide shows the post-operative
spherical equivalent manifest refraction on the vertical axis as a
function of time after treatment on the horizonal axis going out to two
years. You can see that there is some change here with a tendency toward
a more hyperopic refraction. The rate of change is not the same on the
first part of this curve as it is at the last part of this curve.

This graph shows you the rate of change, so that the first point
represents the rate of change from one week to one month; the second one
from one month to three months, and so on. This graph shows pair-wise
data, so that every eye that has available data at one week and one
month is included in this measurement, and so on. So we\'re getting as
much data as we can, and as many analyses as we can.

It is apparent that there is a rapid phase here where the loss of
correction occurs at a fairly rapid rate, and then this is followed by a
slower change here. I emphasize now this is rate of change, not the
actual manifest spherical equivalent. So when this line reaches zero,
there is statistically and mathematically zero change. This is a much
more detailed and sophisticated analysis than has ever been presented
before to my knowledge.

Those points from four months onward bear a linear relationship to the
months after treatment. This is the rate of change in diopters. This is
the time after surgery. There is a tight linear regression fit as you
can see from the line, with an R squared value 0.98, and P value of
0.008.

If this line is extrapolated to the horizontal axis, the intercept is at
26.3 months. In fact, if you look at the eyes with the current drying
technique, the intercept is at 20.5 months. This is another mathematical
and statistical proof of long-term stability beyond the FDA criteria.

I call to your attention the absolute value shown on the horizontal
scale here. This is one-tenth of a diopter per month at the top of the
scale. This is one-hundred of a diopter per month at the bottom of the
scale. At the last time these eyes were examined the change rate was
0.02 diopters per month.

It is clearly incorrect to conclude that the spherical equivalent
continues to change with time, and to extrapolate the rate of change
from the last examination indefinitely. In fact, the data clearly show
that with the current drying technique there is 0 rate of change of by
the most statistically appropriate and stringent analysis that we can
perform at 20-21 months.

Step back from this a moment, however, and realize that these data meet
the FDA criterion at six months. The additional analyses that I have
shown you here are simply additional data that are provided because of
the original comments that were received.

The sponsor in fact met with FDA personnel during the development of the
PMA to determine what rate of change would be acceptable. The guidance
that were received at that time was that about 0.3 diopters per three
months would be appropriate and within the range of acceptability,
although a lower value would be nice to see. It was suggested that 0.3
diopter mean change would not by itself be a reason to disapprove a PMA,
although the change rate might be appropriately reflected in the
labeling.

The Sunrise LTK exceeds the 0.1 diopter per month criterion at all time
points. In fact, it drops from 0.09 diopters per month at 3-6 months, to
two-hundredths of a diopter per month between 12-18. This is the figure
that you need to remember.

During the preparation of this PMA, we were curious academically about
the refractor results of treatment for hyperopia. The data on this slide
are shown to you not for direct comparison to the LTK data, but because
we believe that the decisions that are made today should be made with
the full knowledge of existing treatments and existing publicly
available literature, which this represents.

What you can see here by simply eyeballing the slide is that for all of
these treatment modalities the post-treatment spherical equivalent
continues to drift toward hyperopia for all time points and for all
studies. These represent Excimer laser treatments.

The details of these publicly available treatments are shown in this
slide. As you can see there are five different laser manufacturers. It
includes seven studies for PRK and two for LASIK. It includes follow-up
intervals that vary from 6 months to 24 months. The drift rate per month
at the last available measurement interval varies from a low of 0.03
diopters per month, to a high of 0.36 diopters per month.

So looking at this data on hyperopic refractive procedures, it appears
that the magnitude of change is similar regardless of the manufacturer
or laser type. In fact, the similarity in drift rates between these
studies may in part be due to physiologic or measurement changes.

In conclusion, the PMA cohort results that have been presented today,
and that you have in your hands, surpass or meet all safety, stability,
and effectiveness criteria for refractive lasers. Given the
extraordinary safety profile, the efficacy and stability, this is a
technology that should be available to physicians and patients in the
United States, as an option for refractive surgery.

Thank you.

DR. MC CULLEY: Does that conclude the sponsor\'s presentation? Thank you
for a well done presentation.

I believe there is a request by FDA that we break now for set up for
your AV needs. So we will take a 10 minute break.

\[Brief recess.\]

DR. MC CULLEY: Before we begin, I just want to let everyone be aware
that we are following the new approach of having one of the primary
reviewers serve as scribe to list all the areas of concern and questions
so that there is someone other than me trying to keep up with the
listing of issues. Dr. Michael Grimmett has been asked to do that for
this PMA.

Prior to resuming with the PMA, Dr. Rosenthal, you had an announcement?

DR. ROSENTHAL: May I make two comments before Dr. Eydelman starts her
presentation? The first comment has to do with the guidance document to
which all sponsors are referring. That guidance document, which was
dated October 1996, is for low to moderate myopia up to -7 diopters.
There is no guidance document yet that has been established by the
agency, and in fact when we discussed the issues with the panel, I think
they did not advise any levels for other indications. They suggested we
keep that document in place. But it is still the document for low myopia
to -7.

The second issue has to do with comparison data which the current
sponsors have presented. Dr. Stulting prefaced his remarks by saying
that the data is presented for general knowledge only. You are not
allowed to use it as comparative data.

I think the other issue I must point out is that it is not data that has
been vetted by the agency. So whether or not it is accurate, I just
don\'t know, and the agency doesn\'t know. It is not a study that the
agency has overseen. And certainly the publications are not publications
that the agency has condoned. So I want you to be aware of that.
Although it is correct for him to present it as background or
informational knowledge to the panel to help make the decision, you
cannot make a direct comparison. The PMA must stand on its own.

DR. MC CULLEY: Dr. Pulido?

DR. PULIDO: Your, honor, a point of order. I believe that the sponsors
\-- we should be able to question the sponsors before the FDA gives
their presentation about it.

DR. MC CULLEY: That\'s correct. We\'ll bring them back. But if you think
there are issues now that we should query them about before FDA is given
the floor, we can do that. The sponsor will be back for the opportunity
query.

MS. THORNTON: Is Nancy Puhouski(?) here? She needs to address this.

DR. MC CULLEY: Shuffle time guys. Sorry. I\'m going to ask the FDA to
depart the table, and the sponsor to return for us to query. That\'s my
second big mistake for today. That\'s your first one.

Does panel have questions for the sponsor? You better \-- Dr. Pulido.

DR. PULIDO: Just one quick question. In volume number five you showed a
beautiful regression analysis, figure three, and you had shown it up
there as well. I actually preferred the one that you showed now, because
it first showed one steeper curve, and then a less steep subsequent
curve.

If you do the integral of that curve, or basically just take the area
underneath that curve, that will be your total dioptric change over that
time period. Did you do that analysis?

DR. KOCH: No, we did not. It\'s a good idea. We didn\'t do it.

DR. PULIDO: I think it\'s very important and very telling. Maybe later
on we\'ll talk about that.

DR. MC CULLEY: Are there any other questions? Dr. Sugar?

DR. SUGAR: Do you have any data on the rate of change or rate of
regression with age? That is for a population that was treated at age 40
versus a population treated at age 50, was the rate of change different?

DR. KOCH: No, we don\'t have those data. We could look at that. We
didn\'t, as I remember, find that age is much of a factor in terms of
outcomes, either in terms of amount of correction given endpoints or
uncorrected acuities. But we did not do specifically a regression rate
in accordance with age.

DR. GRIMMETT: On the regression line that was presented in Dr.
Stulting\'s slides, as well as just was referenced in volume 5, page 8,
figure 3, to the best of my knowledge those data arrive from a not
continuous cohort of patients. I think it is derived from volume 3,
table 41a. Is that correct? Are those not a continuous cohort of
patients?

DR. STULTING: Those are pair-wise analyses of the follow-up for the
entire cohort. So that if a patient had data available on two adjacent
examinations, the data from that patient were included, even if we
didn\'t have data available for another. Because what we were interested
in looking at here was the change from one examination to another, not
the overall change from the beginning of the study to the end. So it
would be appropriate to include patients who have adjacent examinations,
even if that\'s all the data that are available on that patient.

DR. GRIMMETT: And those data did not then exclude the first 50, is that
correct?

DR. STULTING: The original graph that I showed you, and this one include
even the first 50 eyes, because we didn\'t know \-- the hypothesis is
that those eyes are basically undercorrected. But once they are treated,
whatever effect that they get is going to follow more or less the same
course as the other eye. So to be complete, this includes all of the
eyes, even the first 50. If you examine the cohort without the first 50,
the X intercept occurs even earlier than it does with this cohort at
about 20 months instead of 27.

DR. MACSAI: According to the protocol, the sponsors performed
cycloplegic refractions pre-operatively, at 6, 12, and 18 and 24 months.
Have you provided that data?

DR. KOCH: Yes, we have. They actually show \-- presumably because this
is a pre-hyperopic population, that there is no more than 0.09
difference throughout a mean between the manifest and the cycloplegic.

DR. MACSAI: But have you done regression analysis, refractive drift
analysis on that data?

DR. KOCH: No, we have not. We don\'t think it\'s a concern because of
the similarity of the numbers.

DR. STULTING: Dr. McCulley, I\'ve done a little math, and I think I can
answer Dr. Pulido\'s question. Your question was what\'s the area under
this curve in figure 3. You can compute that pretty quickly, because the
horizontal number is 27 months, the vertical number is about one-tenth,
so it\'s 2.7 diopters. You have to divide that in two, because it\'s a
triangle. So the entire dioptric change represented by this graph is
1.35 diopters.

DR. PULIDO: Correct, so that\'s what I had gotten from that one. But if
you add the other steeper curve, it is closer to 1.5. So over the time
period, I calculate there is about on average 1.5 dioptric change in
these patients. So I think that\'s important, and your data should have
been analyzed to look at that, because it\'s there from the data and
important data considering what the average was that we first started
with, number one.

Number two, I would like to say on the other hand, you have wonderful
accountability, and I think that is very important.

DR. KOCH: Thank you.

DR. MC CULLEY: Other questions for the sponsor?

DR. MATOBA: I\'d like you to clarify this information. This is table 3
from the medical officer\'s review regarding demographics. In the subset
of 260 patients who mastered a questionnaire, 16.9 percent did not wear
glasses or contact lenses pre-op. I was wondering how those patients
entered into this study, and what their expectations were, and what the
criteria would be for satisfaction?

DR. KOCH: That was full-time spectacle wear.

DR. MATOBA: No, didn\'t wear glasses or contact lenses.

DR. KOCH: The question worded to the patient was full-time, as in the
actual questionnaire. That\'s a good question. We were permitted to
enter patients whose uncorrected acuities were actually better than
20/40, because it\'s hard to recruit patients who are +3/4 and +1, whose
uncorrected acuity sometimes are worse than 20/40. So that\'s how we
were able to fill in some of those low numbers in terms of the level of
hyperopia. And some of those patients do many thing without glasses.

DR. GRIMMETT: Dr. Stulting presented a slide that showed statistical
analyses between the earliest cases treated and the later cases treated.
Some of those, I believe are in volume 2, amendment 6, but I don\'t
think all of them are. Were some of those data new on your slide versus
what was in the materials?

DR. STULTING: You\'re asking for the slide that had the nine P values on
it?

DR. GRIMMETT: Yes. I believe the data on the earliest cases, at least
that I\'m aware of by reviewing the materials show I believe two
statistical analyses in amendment 6, volume 2. And a lot of those data,
do they appear in the materials we received?

DR. STULTING: You had analyses early on for the original data that
showed poolability. You should have received this information that was
presented today. Perhaps not?

DR. GRIMMETT: I\'m not aware of it. On the earliest cases treated that
you presented the slides on, at least in amendment 6, volume 2, they
were comparing for example, the first 77 eyes versus the remaining 521.
Were any of those data that you presented specific to the first 50? Were
the first 50 looked at compared to the rest? Or it should be the first
46, because that\'s where the drying changes. I assumed you rounded it
off, is how you came up with 50.

DR. STULTING: Yes, that\'s right.

DR. GRIMMETT: Were they referable to the first 50?

DR. STULTING: The data actually that were on that slide were obtained by
analyzing the people who had late follow-up. So I think you are correct
in what you are saying. Yes, those were the people that contributed to
the late follow-up.

DR. SANDERS: Donald Sanders, a consultant for Sunrise. I\'m not sure
that you have seen the information, but the mean spherical equivalent
between the two groups at one week, one month, I believe three months,
and 18 months are significantly different from them with the later data.
I have to look, but I\'m not that that\'s in the submission you have
seen. There was the 50.

DR. MC CULLEY: Does the FDA have that data? I think this is a procedural
point, is it not, Dr. Rosenthal? We need to know if the FDA has received
that data for evaluation. If they have not, my understanding is that
it\'s not submissible.

DR. KOCH: I believe we have some of the comparisons there, but I believe
that we don\'t have all of the ones, as Dr. Grimmett pointed out.

DR. MC CULLEY: But there is a procedural point with this that I think we
are bound to go by. And that is that you cannot submit data for
consideration that has not been submitted to the FDA for their
evaluation prior to meeting.

DR. STULTING: Okay, I\'ll respond to that. On page 4 and page 5 of the
amendment 6, you will see accuracy of manifest refraction at 1 month and
spherical equivalents at 12 months, spherical equivalent at 1 month, and
20/25 or better at 1 month, and low hyperopia group. That is on page 6;
20/20 or better at 12 months, and the low hyperopia group. That\'s on
page 6. Then 20/20 or better at 1 month, in the moderate hyperopia
group. That\'s on page 7. So that\'s the bulk of the data.

It\'s actually kind of unusual. Ordinarily, the sponsor is fighting for
poolability. Here we are admitting non-poolability, and saying that
these eyes were treated with a different technique, and we don\'t think
that your decision ought to based on that.

DR. MC CULLEY: This is a procedural point.

DR. STULTING: The answer to your question is that they are found on
those pages that I just cited.

DR. MC CULLEY: Dr. Grimmett, does that satisfy your question?

DR. GRIMMETT: Yes, I need to look at your slide again, but yes, that
satisfies my question. Thank you.

DR. MC CULLEY: Other questions of panel members for our sponsor? Dr.
Macsai?

DR. MACSAI: If you could just save me a little time. Can you tell me
what page I would look on for the cycloplegic refraction outcomes data
on the group -50? Which of these volumes and which page?

DR. SANDERS: That was a very recent request by the FDA to provide a
table on cycloplegic refraction. We\'re trying to pull it right now.

DR. MC CULLEY: Has the FDA received that?

MS. THORNTON: Yes, it\'s in your handout. It\'s probably the next to the
last page in your notebook under the PMA number.

DR. ROSENTHAL: Mr. Chairman, may I also comment that the information
that Dr. Grimmett was questioning was submitted.

DR. MC CULLEY: So we\'re still looking for the cycloplegic \-- have you
found it? Dr. Pulido?

DR. PULIDO: While they are looking for the cycloplegic, maybe you could
help me, because this is going to come up later. If the mean pre-op was
1.69 diopters hyperopia, and if the area to that curve is around
somewhere between 1.35 and 1.5 diopters, then at 26 months the patient
is back to +1.5 diopters, the average patient.

DR. KOCH: That\'s very important, and that sort of came out in our
presentation. We looked for an early overcorrection. In other words, we
looked for initial correction of -1, -1 1/4 because of the fact that
these patients do drift back, and we do need that area under the curve
hopefully to occur below the level of ametropia. So that is intended,
and that\'s an understood part of the procedure. And I think you heard
that actually some of our patient dissatisfaction data occurred with
patients that lost that initial near acuity.

So there is an initial overcorrection that we seek in order for the
patient to drift back to what we will be ametropia plus a quarter or
whatever, in that range. That\'s how the procedure is intended to work.

Did that answer your question?

DR. PULIDO: No, because you have lost 1.5 diopters by the end. So if you
are starting at 1.69, if you lost that 1.5, you are back to \--

DR. KOCH: But that curve starts at four months.

DR. STULTING: You\'re not getting the whole curve. And it doesn\'t make
sense to me to do the analysis you are talking about. The curve that I
showed you is the first derivative of the refraction with time. That is
based on the original raw data. If you all want to know is what the
total change is in the population, you ought to go back to the original
raw data, instead of reintegrating a curve that doesn\'t include all of
the post-operative points.

DR. PULIDO: Well, you are the ones that submitted the curve.

DR. STULTING: Yes, but it wasn\'t for the purpose that you are using it
for. It was for the purpose of analyzing the rate of change, and how the
rate of change relates to time after surgery. It wasn\'t designed to
determine what the total change was, or the residual fraction was.

DR. MC CULLEY: Other questions for our sponsor? Have you found what you
are looking for, Marian?

DR. MACSAI: He let me look at those. It was not in my packet.

DR. MC CULLEY: You have it? You found it?

DR. MACSAI: Dr. Waxler(?), what you showed me was a single page like
this. It just compares the pre-op mean, manifest refractive spherical
equivalent and cycloplegic refractive spherical equivalent at 6 months
and 12 months. It doesn\'t tell me anything about the data on that.

DR. MC CULLEY: Do you still have a question then?

DR. MACSAI: I\'ll address it in my review.

DR. MC CULLEY: Okay. Any other questions for sponsor?

DR. MATOBA: Did you check intraocular pressure immediate after the
procedure? It seems to me that if there is uniform energy to shrink
collagen there, you might have an increase in IOP short-term.

DR. KOCH: We did not. We checked them early post-operatively, and we\'ve
done that in earlier studies, checked them as early as a day, but not
immediately. We actually in some patients found lower pressure, almost
as if it was pulling on the trabecular mesh work.

DR. MC CULLEY: At what time point?

DR. KOCH: In the first few weeks, but it went ahead.

DR. MC CULLEY: So you don\'t know what the shrinkage, whether you
crowded and shot the pressure up?

DR. KOCH: No, we don\'t. That inconceivable to me that that would
happen.

DR. HIGGINBOTHAM: Well, since the door was open, I\'ll walk in. Did you
do baseline gonioscopy and follow-up gonioscopy considering these people
are hyperopic and older than 40?

DR. KOCH: No, we did not, although I don\'t think any of us would have
enrolled patients that have clinically narrow looking angles, just on
clinical judgment.

DR. HIGGINBOTHAM: The gonioscopy was done?

DR. KOCH: Was not done.

DR. SANDERS: Can I address that issue of glaucoma? As you recall, we had
those elevation maps that actually quantitate the amount of elevation
and depression of the cornea. And we\'re dealing on the order of
possibly a depression, which would be a tightening, of approximately
20-25 microns. That\'s on the anterior surface of the cornea. When you
look at the posterior surface, there is virtually no movement of the
posterior surface.

So given that, it\'s highly unlikely that \-- and these have been done
fairly acutely, within hours of the procedure \-- so it\'s highly
unlikely that those would have an effect on intraocular pressure.

DR. MC CULLEY: Any other questions? We\'ll excuse the sponsor now. Now
the FDA is invited back to the table.

**Agenda Item: FDA Presentation of PMA P980051**

DR. WAXLER: Well, good afternoon. I have the pleasure of introducing Dr.
Everette Beers, who will be giving a brief description of the PMA. I\'m
still chief of the Diagnostic and Devices Branch.

DR. BEERS: Thanks, Morris. Good afternoon. My name is Everette Beers.
I\'m the team leader for the Sunrise Technologies P980051. This is a
holmium YAG laser for laser thermal keratoplasty. The application was
filed December 14, 1998. The sponsor is requesting approval for a laser
thermal keratoplasty for the correction of hyperopia between 0.75 and
2.5 diopters.

The primary panel reviewers for this application are Dr. Michael
Grimmett and Dr. Marian Macsai. I wanted to thank, or at least recognize
the FDA team that has been evaluating this PMA, and also to recognize
Marsha Nicholas, who was the team leader for the clinical study portion
of this. Engineering and physics were Dr. Bruce Drum, Capt. Robert
Faaland, and Dr. Woody Ediger; for statistics, Ms. Phyllis Silverman;
from GMPs, Ms. Mary-Lou David; for patient information labeling, Ms.
Paula Silberger, and Ms. Carol Clayton; and for bioresearch monitoring,
Ms. Pam Reynolds; and for software review, Mr. Joseph Jorgens.

At this time I would like to introduce the clinical reviewer for this
application, Dr. Malvina Eydelman.

DR. EYDELMAN: Good afternoon. I would like to preface my talk today with
the fact that I have not seen a final copy of slides of the panel
presentation slides today. Therefore, please forgive any redundancies
that might be contained in my presentation.

The Hyperion LTK System, as you heard, is a non-contact holmium YAG
laser that delivers laser energy to cornea via a procedure known as
laser thermal keratoplasty, or LTK. This device is the first non-Excimer
refractive laser to be presented for panel consideration. Currently, we
do not have a guidance specific to this technology.

The Hyperion LTK system is intended for patients with unilateral or
bilateral hyperopia in the range of 0.75 to 2.5 diopter spherical
equivalent, with less than or equal 0.75 diopters of pre-existing
cylinder. It is intended for patients who are 40 years of age or older.

PMA cohorts analyzed in the submission have undergone several revisions.
I would like, therefore, to define all the cohorts at the beginning of
this presentation for clarification purposes. PMA cohort analyzed in
amendment 2 incorporated all qualified eyes treated as 3/12/99. Analysis
of this cohort was the basis of my written review and primary panel mail
out. The sponsor subsequently began to refer to this cohort as
\"original.\" For the sake of clarity, I will adopt this terminology.

Subsequent to the primary mail out, in an attempt to answer questions
raised in my review, as well as questions from the primary panel
reviewers, the sponsor submitted three additional amendments. In my
presentation today I have incorporated data in all the amendments
received by FDA as of today.

In order to provide the agency and the panel with the most up-to-date
information, the sponsor has updated the PMA data set, and submitted
some of the analysis to FDA on June 28. This cohort is being referred to
as the \"updated\" cohort. The sponsor has also submitted some analysis
on the updated cohort following removal of the first 50 cases. This
cohort is referred to as the \"updated minus 50.\"

Two types of pretreatment drying techniques, as you heard, were utilized
during this study. The first 46 eyes enrolled were prepared for
treatment by placing the lip speculum, allowing the eye to air dry for
60-90 seconds, and then wiping the cornea with a moist WeckCel sponge.
The remaining eyes enrolled were prepared for treatment using modified
drying technique. The lid speculum was put in place, and the eye was
allowed to air dry for three minutes, and the WeckCel sponge was not
used.

As of amendment 2, sponsor believe that the first 46 eyes could be
poolable with the rest of the cohort. Sponsor states that following a
further update of the database, however, substantial differences were
found, and that currently they believe that these eyes should not be
poolable. The FDA statistician agrees that the first 46 eyes can be
analyzed separately.

The sponsor has settled on excluding the first 50 eyes, because \"this
is a round number, and most of them received the old drying technique.\"
Sponsor believes that inclusion of the first four cases with the current
drying technique did not change the outcome. Most likely sponsor is
correct in this assumption. We have not yet, however, received data to
validate this conclusion.

I would like to point out the magnitude of the increase in the eyes
analyzed in the updated versus original cohort. While the number of eyes
at 6 months essentially remained the same, the numbers analyzed at 12,
18, and 24 months almost doubled. Updated cohort had also significantly
better accountability at 18 and 24 months intervals as compared to the
original.

In order to determine the appropriate point of refractive stability
after treatment with this new device, sponsor was asked to present data
for all available eyes, i.e., pair-wise sequential visits, and 6, 12,
and 18 months consistent cohorts. That is, eyes that were examined at
each exam.

Analysis of the stability of the original 12 month consistent cohort is
presented in this slide. This analysis of the original cohort eyes that
had data for 1 week, 1, 3, 6, and 12 months exams. While between 3 and 6
months, 95 percent of all eyes had a chance of MRSE less than or equal
to 1 diopter. And this number remained at 94 percent between 6 and 12
months.

Looking at the mean rate of change per months, it is decreasing from 1
diopter per month between 3 and 6 months, and 0.06 diopters between 6
and 12 months.

If we look at the comparable analysis for the 18 months cohort, we can
see that between 12 and 18 months the mean rate of change is 0.05
diopters. These two slides mean that between 3 and 6 months the mean
rate of change would be equivalent to 1.2 diopters per year, decreasing
to 0.72 diopters per year between 6 and 12 months, and 0.6 diopters
between 12 and 18 months. But certainly as Dr. Stulting pointed out, it
is not a constant change.

In the latest amendments sponsor provided stability analysis utilizing
pair-wise sequential visits only for the updated cohort. I have compared
it to the equivalent analysis of the original cohort in these slides. As
one can see, there is a slight decrease in the mean rate of change per
month beyond the six months interval. Of most interest, however, is the
outcome for 18 to 24 months time frame.

Due to low N, stability analysis was not assessed between 18 and 24
months in the original cohort. As one can see in the updated cohort,
90.7 percent of eyes experienced change in the MRSE less than or equal
to 1 diopter in this time frame, while the mean rate of change per month
was calculated to be 0.02 diopters.

Data in the PMA was also asked to be stratified according to the degree
of preoperative hyperopia. A low hyperopia was defined from 0.75
diopters up to 2, and the moderate hyperopia was defined as 2-2.5
diopters. Stability analysis stratified by diopter group show a trend
for moderate hyperopes to have slightly lower percentage of eyes, with
less than or equal to 1 diopter between consecutive visits, and higher
mean rate of change per month. The panel will be asked to incorporate
all this data in their determination of the appropriate stability time
point.

Analysis of the predictability of the manifest refraction in the
original cohort shows the decrease in accuracy with time. The sponsor
has recalculated the predictability for all three cohorts, as you can
see in these slides. As you can see, the accuracy within 0.5 diopters
decreases from 65 percent at 6 months to 11 percent at 24 months in the
original cohort.

While 6 and 12 month outcomes are almost the same for all three cohorts,
the outcomes at 18 and 24 months are improved significantly in updated
and updated minus 50 cohorts. Accuracy within 1 diopter shows a similar
reduction with time, and once again this reduction is less in the
updated and updated minus 50 cohorts.

Data in these slides point to regression as the probable cause of
decrease in predictability of MRSE with time. In the original cohort,
percentage of eyes undercorrected by greater than +1 diopter increased
from 10 percent at 6 months, to 56 percent at 24 months. Updated cohort
data is rather similar, with an increase from 10.3 percent at 6 months,
to 45.8 percent at 24 months. Similarly, undercorrection by greater than
+2 diopters shows an increase with time in all cohorts.

Once again, the sponsor was asked to stratify the predictability of
manifest refraction by the level of hyperopia. A similar analysis was
carried out for the updated minus 50 cohort, but only for the subcohort
of the eyes seen at all exams through month 12, i.e., 12 months
consistent cohort. Even though this analysis shows continued decrease in
percentage of predictability within 0.5 diopters with time, the decrease
appears to be smaller than in the original cohort.

Predictability within one diopter showed a decrease, mostly of 18 and 24
months in the original cohort. As you can see once more, the decrease is
less in the updated minus 50 cohort. One more time just to point out,
this analysis also carried out only for the 12 months consistent cohort.

We can see that decrease in predictability in stratified analysis once
again points to regressions as the cause. Undercorrection is smaller,
but still present in the updated minus 50 cohort.

Moderate hyperopia predictability analysis of the original cohort showed
a rather dramatic decrease in accuracy, within 0.5 diopter with time.
Even though once again the updated minus 50 cohorts analysis is somewhat
better, please note that at 18 months only 25 percent of moderate
hyperopes achieved accuracy within plus or minus 0.5 diopter. Also,
please note that due to the very low number of eyes available at 24
months, we do not really know the outcomes at this time point.

Accuracy of manifest refraction within 1 diopter decreases to 36 percent
for moderate hyperopes in the original cohort at 18 months. Fifty-eight
point one percent of the updated minus 50 consistent 12 months cohort
achieved accuracy of refraction within one diopter at 18 months.

As you can see, the increase in undercorrection greater than 1 diopter
with time in moderate hyperopes is rather large. The updated minus 50
cohort once again shows somewhat less of a change. Note, however, that
even in this cohort the percentage of eyes undercorrected by greater
than 1 diopter more than doubles between 6 and 18 months.

It is of special interest to analyze the percentage of eyes that end up
undercorrected by greater than 2 diopters among those that started with
preoperative refraction between +2 and +2.5 diopters. At 18 months, 6.5
percent of the updated minus 50, 12 months consistent cohort were
undercorrected by greater than +2 diopters.

Panel members are being asked to incorporate all these outcomes in their
recommendations this device\'s predictability of correction of
refractive error.

While only 0.2 percent of eyes had UCVA of 20 or 25 or better
preoperatively in this study, 38.3 percent of the original cohort was
able to see 20/20 or better at 6 months, obviously, quite a good
improvement. The percentage of eyes that maintained that level of UCVA,
however, seems to have decreased with time. Here I have plotted the
outcomes of UCVA of 20/20 or better for all three cohorts.

In white you can see the curve for the original cohort, yellow plots the
outcome of the updated cohort, and green, the updated minus 50 cohort.
In your interpretation of the 24 months outcomes, please consider the
fact that there were only 13 eyes available for analysis in the updated
minus 50 cohort; 18 for the original; and 48 for the updated cohorts.

While UCVA of 20/40 or better appeared to decrease with time in the
original cohort, updated and updated minus 50 cohorts have almost
insignificant changes through the 18 months. Once again, the 24 months
data had difficulty to give too much weight to due to a rather small N.

UCVA data on our request was also stratified by degree of preoperative
hyperopia. The sponsor has provided an updated, stratified analysis of
UCVA only for updated minus 50, 12 months consistent cohort. There
appears to be an insignificant drop with time in this cohort. For
moderate hyperopes, however, there seems to be definite decrease in UCVA
with time in both cohorts.

The 24 months data for UCVA for moderate hyperopia is based on total N
of 2 for the updated minus 50 cohort, and an N of 5 for the original.
Thus, once again, accuracy is quite a question.

UCVA of 20/40 or better for low hyperopes showed a minimum decrease with
time. For moderate hyperopes, however, there is a definite drop in the
percentage of eyes achieving 20/40 or better with time. Panel members
will be asked to comment on the acceptability of UCVA outcomes at all
time points for this device.

Another issue that I would address today is the cylinder induction
associated with this device. At 6 months there appears to be a
significant percentage of eyes with magnitude greater than or equal 1
diopter. Please observe quite a significant reduction in this percentage
between 6 and 12 months in the original and updated cohorts. The
percentage of eyes with cylinder greater than 1 diopter is significantly
smaller than that seen for increase greater than or equal to 1 diopter.
However, one can still see it in 9 percent of those original and updated
cohorts.

Only about 2 percent of eyes experience an increase in cylinder
magnitude of greater than or equal to 2 diopters, and less than 1
percent experienced greater than 2 diopter cylinder increase at any time
point.

Vector analysis was performed to evaluate the axis orientation at 6
months post-treatment for the cases among the original cohort that had
greater than 1 diopter of cylinder induction; 65.4 percent of these
cases exhibited surgically induced cylinder in against the rule
direction, and 32.7 percent had oblique induced cylinder.

Those cases who had an increase in post-treatment astigmatism of greater
or equal to 1 diopter has significantly more pre-treatment hyperopia by
an average of 0.12 diopters than those that did not. And also as
expected, post-treatment UCVA was significantly worse in the increased
astigmatism group.

Panel members will be asked to comment on their interpretation of the
significant of the induced cylinder with this device.

According to the protocol, a patient questionnaire was administered in
this study pre-operatively, and at 1, 6, 12, and 24 months
post-operatively. Photophobia and double vision appeared to be the
visual symptoms with the greatest change in the study. While
pre-operative 0.7 percent of patients had mild, moderate, or marked
photophobia, 6.9 percent experienced this level at 6 months, and 8.2
percent at 12 months. Double vision experienced often or always
increased from 3.4 percent pre-op to 14 percent at 6 month and 12
months.

In order to better understand the significance of the visual symptoms
found to be of concern in the study, the sponsor attempted to contact by
phone all patients who reported significant photophobia or double
vision. At the time of the telephone questionnaire only 2 percent of
patients continued to have bothersome photophobia, and 2 percent had
bothersome light sensitivity. Unfortunately, from the sponsor\'s
telephone questionnaire data, the post-operative time frame for
resolution of symptoms is unclear.

Even though the sponsor did a lot of work to investigate the current
status of patients\' with special symptoms, they have not yet submitted
updated patient questionnaire analysis. In light of almost doubling the
number of eyes examined at 12 months in the updated cohort, and
availability of 48 eyes at 24 months, an updated analysis of the patient
questionnaire might reveal additional important information.

Panel members will be asked as to their recommendation of the necessity
for the analysis of this data prior to an approvability decision.

Spherical equivalent at the 180 day post-treatment exam was analyzed as
a continuous variable as the function of various baseline factors.
Increased corneal curvature was found to be directly correlated with the
amount of reduction in hyperopia with each diopter that associated with
0.05 diopter increased refractive change.

Thus, with all other variables being equal a patient with a corneal
curvature of 46 diopters would expect to have 0.2 diopters more effect
than a patient with a 42 diopter corneal curvature given the same
treatment.

Increased age was also directly correlated with increased effect, with
all the patients having 0.018 diopter reduction in hyperopia per year of
increasing age. Thus with all other variables being equal, a 60 year old
patient could expect to have a 0.36 diopter more effect than a 40 year
old given the same treatment.

Caucasian patients had 0.262 diopter less refractive change compared to
non-Caucasian patients. Thus, with all other variables being equal,
Caucasian patients would expect about a quarter diopter less than the
non-Caucasians.

Each unit of baseline spherical equivalent was associated with an
increase in the 180 day spherical equivalent by 0.64 diopters. This
correlates well the observation that slight undercorrection occurred at
the higher ranges of treatment.

I bring all of these to your attention since all of these associations
will be reflected in the final decision of the patient.

I do want to highlight some of the other safety factors associated with
this device. As you heard, analysis of the original cohort did reveal
low loss of BSCVA. There no laser-related adverse events, and minimal
complications. Furthermore, the endothelial cell analysis performed in
this study did not show any significant changes.

Taking all of these factors into consideration, I would like to go ahead
and pose the questions.

1\. Which cohort \-- original, updated, or updated minus 50 \-- do you
believe to be the most appropriate for assessment of safety and efficacy
of this device?

2a. Has adequate refractive stability been demonstrated with this device
by six months?

2b. Based on the refractive stability presented in this PMA, is the
current follow-up of eyes treated sufficiently to provide reasonable
assurance of safety and effectiveness of this device?

3\. The predictability of manifest refraction and the uncorrected visual
acuity results decrease between 6 and 18 months. Does this raise
concerns about treatment efficacy?

4\. At 6 months post-treatment, 18 percent of all eyes examined had
greater than or equal 1 diopter increase in cylinder. Most induced
cylinder axes were in against-the-rule and oblique directions. Does this
raise any concerns?

5a. Visual symptoms data reveal photophobia and double vision to be the
symptoms with greatest change from pre-operative levels. Do increases in
these visual symptoms constitute a safety concern?

5b. Is analysis of the updated patient questionnaire necessary prior to
making a recommendation regarding approvability of this device?

6\. Do the safety and effectiveness outcomes stratified by diopter of
preoperative hyperopia +0.75 to +1.99 diopter and +2.00 to +2.50 diopter
support approval for the full range of hyperopia of +.075 to +2.50
diopters of spherical equivalent?

7\. What are your recommendations for labeling regarding:

a\. potential regression;

b\. cylinder induction, and

c\. visual symptoms?

Do you have any additional labeling recommendations?

This completes my presentation. Thank you for your attention.

DR. MC CULLEY: Thank you. Are there questions for the FDA from the panel
members at this point?

DR. HIGGINBOTHAM: Malvina, I was struck by the differences between the
original group versus the updated group in terms of the drying
technique. Recognizing again that this is an over 40 age group, I wonder
if there was any difference in gender considering the prevalence of
dryness in women post-menopausal versus men. Did you see any evidence of
that in the data?

DR. EYDELMAN: I did not see any analysis to that.

DR. MC CULLEY: You didn\'t see any analysis to that, so you can\'t
answer the question?

DR. EYDELMAN: Correct.

DR. WANG: I\'ve been trying to think about difference between the
original and the updated, the minus the 50. If it\'s a mere drying
effect, it should add a constant amount to the correction , just
parallel shift perhaps in time by a constant amount. I don\'t know
whether anybody performed that analysis, you or the sponsor, by taking
into account that the two groups still coincide pretty well if the
matter of not drying is just a constant amount on the correction.

DR. EYDELMAN: I agree from the slide that Dr. Stulting showed there was
a different rate of regression of effect.

DR. WANG: Then you should find the amount of correction by a constant
amount. The two curves should coincide, because if hydration only
results in the undercorrection, that should be just a parallel shift. It
should not change the nature of stability of this procedure whether or
not this 50 is included or not.

DR. EYDELMAN: Perhaps you can ask this of the sponsors when they come
back to the podium.

DR. MC CULLEY: Any other questions for FDA? Dr. Pulido?

DR. PULIDO: I just would like to commend Dr. Eydelman for a wonderful
presentation.

DR. MC CULLEY: I think we all share in that.

DR. FERRIS: Malvina, I still don\'t understand why is it 46 or 50. Were
there 46 people that didn\'t have drying, or were there 50?

DR. EYDELMAN: There were 46 that had the original drying technique. And
in the original analysis these 46 were compared to the rest of the
cohort and found to be poolable. Later on in the latest amendments
received within the last two weeks or so, the updated cohort analysis
was once again compared against the 50.

Now as I said, sponsor claims that the 46 to 50 was just a rounding
effect, and that these four eyes shouldn\'t make any difference, but we
have not really seen any data to that effect. That was a bit confusing,
and that\'s why I had those slides. Perhaps you want me to go back.

DR. FERRIS: No, I\'m still confused. I\'ll just remain confused. Maybe
later the sponsor will unconfuse me.

DR. ROSENTHAL: May I suggest you ask that of the sponsor?

DR. MC CULLEY: Dr. Grimmett, you had a question for FDA?

DR. GRIMMETT: She clarified it, thank you.

DR. MC CULLEY: Any other questions, points of clarification for the FDA?
Seeing none, we will go to the primary reviews. The first primary review
would be by Dr. Marian Macsai.

**Agenda Item: Primary Panel Review of PMA P980051 - Dr. Marian Macsai**

DR. MACSAI: Before proceeding with my review of PMA 980051, I would like
to commend Dr. Eydelman on her outstanding review, and commiserate with
her for the need for rapid turnover in analysis of complicated data
provided by the sponsor in rapid sequence. The sponsors presented to us
tremendous data in voluminous quantities, and they also should be
commended for the organization of that data and presentation.

Before proceeding with the details of my review, I would like to define
some relevant terms for panel members and the audience. First slide.
Hyperopia exists when the resting, non-accommodating power of the eye is
too weak.

Next slide. Accommodation is the ability to increase the refractive
power of the eye beyond its static resting power. Accommodation is
measured in diopters. At age 40 the average person has 6 diopters of
accommodation. These numbers are removed from the book, \"Optics for
Clinicians,\" by Mel Rubin, the most recent edition. At age 44, the
average person has 4.5 diopters of accommodation, and at 48 years of age
the average person has 3 diopters of accommodation. By 52 years of age,
the average person has 2.5 diopters of accommodation. As we age, our
accommodation decreases.

Third slide. Cycloplegia is the temporary paralysis of accommodation or
paralysis of the surrounding muscle activity, and can be temporary when
done pharmacologically.

Next slide. By definition, absolute hyperopia cannot be overcome by
accommodation. And the total hyperopia of a patient can only be elicited
by cycloplegia. Latent hyperopia can only be uncovered by cycloplegia.
For the ophthalmologists in the audience and on the panel, of course
this is the undercorrected hyperope, the patient that drives many
physicians a little bit crazy by their astronomic complaints, which are
vague, and frequently related to their undercorrected hyperopia, and
with age, their inability to accommodate, to overcome it.

Next slide. Manifest hyperopia is the portion of total hyperopia
accepted by the patient without cycloplegia. That includes the
facultative hyperopia or portion of total hyperopia which a patient can
overcome with accommodation. We know that accommodation plays a
significant role in hyperopia, and that accommodation decreases with
age. Therefore, the manifest hyperopia, the facultative hyperopia, and
the latent hyperopia in the patient will all change with age.

These changes are continuing in patients 40 years of age or older.
Therefore, studies in hyperopia must compare the total hyperopia in a
patient pre-operatively with the total hyperopia post-operatively to
determine what effect a refractive procedure has in a hyperopic patient
if that patient is going to measured on two time points between which
they age.

Next slide. Efficacy can only be established by comparison of the total
hyperopia at two separate post-operative time points. The sponsor has
measured the cycloplegic refraction (total hyperopia) and treated
patients at the pre-operative and the post-operative visits 6, 12, 18,
and 24 months, according to their protocol. Within our handouts there is
one page that addresses cycloplegic refraction. In it, it shows at 6
months the mean cycloplegic refraction spherical equivalent is 0.27,
however, at 12 months this increases to 0.57.

Next slide, please. Refractive stability is critical in analysis of this
PMA. We are talking about the treatment of patients from +0.75 diopters
to +2.50 diopters hyperopia pre-op such that analysis based on
measurements of 2 diopters would be significant adverse events. So we
must look at the data on a much different scale when we are talking
about treating such a small amount of refractive error.

If we are talking about refractive stability, the sponsors have
calculated refractive stability of LTK, and demonstrated a progressive
decrease in the mean rate of manifest refractive spherical equivalent
changes, with the change of 1.09 diopters per year between 3 and 6
months, 0.7 diopters per year between 6 and 12 months, 0.5 diopters per
year between 12 and 18 months, and 0.5 diopters per year between 18 and
24 months.

In volume four, the sponsor suggests the refractive change may not be
related to changes in corneal topography, but perhaps secondary to
articular changes or changes in accommodative amplitude. If the original
measurements used to treat patients with LTK were based on cycloplegic
refractions, and accommodative amplitude had been measured
pre-operatively, then this hypothesis would not be speculation.

In fact, the pre-operative measurement of accommodative amplitude in the
hyperopic patient population over 40 years of age would be critical in
interpreting post-operative results and stability, as would the
pre-operative and post-operative cycloplegic refraction. In this way,
the sponsor will be able to demonstrate the true effect of the
procedure, and whether or not the natural changes in accommodative
amplitude experienced in the over 40 population play a role.

The sponsor has provided a comparison of the results of three data sets
as alluded to and clearly demonstrated by Dr. Eydelman. The original PMA
cohort, the recent updated data, and then the updated data without the
first 50 cases. The reason for exclusion of the first 50 cases was a
difference in drying technique on the first 46 patients, which had a
significant effect on data when analyzed by the primary reviewers and
FDA medical officer.

Table 1, as you see, demonstrates the percentage of eyes undercorrected
by greater than 1 diopters, combining primary and fellow eyes.
Percentage of eyes undercorrected by greater than 1 diopter at 6 months
in all three groups is 10 percent. This increases to between 31 and 56
percent by 24 months in each of the groups.

Next slide. When you look at the patients examined through the 12 month
visit, again, segregating the patients based on the grouping of
original, updated, updated minus 50, again the same trend is seen of an
increase in undercorrection with time.

Next slide. This same trend to an increase in undercorrection over time
is seen in the patients with a 18 month follow-up, however, it\'s not as
rapid a drop off between 18 and 24 months, but the number of patients is
very low at the 24 month visit.

Here we have the data from volume five, in which the sponsors have
segregated patients treated for low and moderate hyperopia to see what
is the percentage of patients undercorrected by greater than +1
diopters. Again, in the low hyperopic group at 6 months this is 3
percent, however, it increases dramatically to 22 percent by 24 months.
In the moderate hyperopes, 19 percent are undercorrected by greater than
+1 diopters at 6 months, and this increases to 50 percent by 24 months,
however, the numbers at 24 months are probably too small.

Next slide. If you look at the hyperopes and try and see how close they
are to where they were supposed to be, or in other words, the plus or
minus 1 diopter manifest spherical equivalent. In the low hyperopes the
data looks okay out to 18 months, but again, it falls off at 24 months,
which may be attributable to the small numbers. In the moderate
hyperopes there is significant fall off between the 6 and 24 month time
period.

In this slide the percentage of patients in the three groups that have a
visual acuity of greater than 20/40 is seen. At 6 months, approximately
87 percent of all eyes treated had a visual acuity of 20/40. By 24
months, this number decreases to between 61 and 70 percent, depending on
how you segregate out patients with the drying technique or without.

Next slide. The same trend is seen in patients with 12 months follow-up,
with a significant fall off at 24 months, but note that the Ns are
rather small. In the all eyes, minus the first 50, the N is 11.

Next slide. And this trend is seen again, but not as clearly with all
eyes who are followed-up to 18 months.

Next slide. Now we are looking at the uncorrected visual acuity of
greater than 20/20, all eyes available. Now these measurements again are
made by allowing the patients to accommodate to the best of their
ability. With these measurements it appears that between 38 and 39
percent of patients in each group have an uncorrected visual acuity of
20/20 at 6 months. But by 24 months this percentage has dropped to
somewhere between 11 to 31 percent. Thirty-one percent in the bottom
right-hand square is 4 out of 13 patients. At 6 months there were 548
patients, and at 24 months we have data on 15.

All nine tables that I have just shown you demonstrate a refractive
drift with an increase in the percentage of patients that are
undercorrected by greater than +1 diopters from 6 to 24 months. A
decrease in percentage of patients with uncorrected visual acuities of
greater than or equal to 20/40 between 6 and 24 months, and a decrease
in the percentage of patients with an uncorrected visual acuity of
greater than 20/20 from 6 to 24 months.

Regarding the induction of cylinder of greater than 1 diopter of
astigmatism, in my opinion this issue remains one of safety. The
sponsors quoted the guidance document from 1996 intended for low to
moderate myopia, stating the safety guideline of patients with greater
than 2 diopters of induced astigmatism should be less than 5 percent of
subjects.

However, if a device is treating patients with between +0.75 and +2.50
diopters of hyperopia, then it is reasonable to look at induction of
greater than +1 diopters of astigmatism as a safety variable. The data
quoted by the sponsor demonstrates greater than +1 diopter of
astigmatism induced in 8 percent of patients at 12 months, 10 percent of
patients 18 months, and 11 percent of patients at 24 months.

It is disconcerting that this induced astigmatism appears to be
increasing in time. Yet the sponsor states the astigmatism tends to
resolve with time. Now this irregular or induced astigmatism could very
easily be the cause of patients\' complaints.

The sponsors made an excellent effort to contact by telephone all the
patients who complained of double vision. When asked again by telephone,
less patients complained of diplopia. However, corneal topography,
refractions to detect astigmatism and/or hard contact lens over
refractions to determine irregular astigmatism, were not included in
this addendum.

Lastly, I\'d like to address retreatments. In volume four the sponsor
stated that retreatment questionnaires were sent to eight centers
demonstrating greater than 3,000 primary LTKs performed with between
9-30 percent requiring retreatment, and 7-20 percent retreated with LTK,
with 50-70 percent success rate with retreatment. The data is given only
on 27 eyes from one center, and 11 from another.

In summary, to determine the safety and efficacy of the treatment of
hyperopia with LTK, follow-up of the total hyperopia in patients to the
24 month visit will clearly supply data to establish whether or not
there is a refractive drift, and whether or not there is a safety issue
with induced astigmatism. Further analysis of this data at 24 months is
recommended.

DR. MC CULLEY: Thank you, Dr. Macsai. Dr. Grimmett.

**Agenda Item: Primary Panel Review of PMA P980051 - Dr. Michael
Grimmett**

DR. GRIMMETT: My detailed safety and efficacy comments can be found in
the written documents I have previously supplied, dated 24 July. This
presentation will summarize some of the highlights, but it\'s not
intended as a comprehensive substitute.

I apologize for being redundant. I had not seen some of the
presentations prior to this panel.

We have talked about the three cohorts. The manufacturer over the last
month has presented data on three separate cohorts requiring three
separate data analyses. The original cohort has a large drop off in eyes
after the six month interval, shown in the blue, which drops off
markedly in the later time intervals.

I agree with the manufacturer in volume one, page 198 when they state,
\"The decreasing number of eyes available for follow-up on beyond six
months precludes any conclusion from being reached beyond this time
point. Data at these outer post-treatment visits represents the
initialized treated and the learning curve issue for a small number of
eyes available, and may not be representative of the overall study
cohort or subsets.\"

The updated cohort provided shows a doubling of numbers at the 12, 18,
and 24 months interval. We have approximately two-thirds of eyes in at
12 months. We have already seen the accountability data. At 18 months
there is 80 percent of eyes missing, and at 24 months there is 92
percent of eyes missing.

For the updated minus 50, there is a serious data limitation. At 24
months there are only 13 eyes available in the updated minus 50 data
set. Overall for these longer time intervals we can look for a trend,
but we cannot generate firm conclusions based on these data.

Regarding the exclusion of the first 50 cases, we discussed the drying
technique changed after case 46. I just found out today why it was
rounded to 50. In volume one, appendix G, the first 46 weren\'t
considered doable because there was no statistically significant
difference on several outcome variables to include distance and near
uncorrected visual acuity, best spectacle corrected visual acuity, as
well as those remaining plus or minus 1 diopter from intended.

I have learned today that there was statistical analysis regarding the
first 50 to the rest of the updated data, however, these data have not
been supplied to me for analysis, so I cannot make comment whether it is
appropriate to exclude or include these 50.

The data down at the bottom regarding that there are less
overcorrections in the earlier treated eyes is seen in amendment 6,
volume 2, under tab 4. That is one feature I believe that was on Dr.
Stulting\'s slide.

I\'ll talk very briefly about a few safety issues. Regarding best
spectacle corrected visual acuity of loss greater than 2 lines, it
approximates 3 percent after month 6. The higher rate of best spectacle
corrected visual acuity loss one month suggests early post-operative
irregular astigmatism subsequently improves with time. All eyes were
20/40 or better in six months, as previously noted. While not
insignificant, a 3 percent rate likely meets the standard of reasonable
safety.

There was approximately a five fold increase in frequency of diplopia at
6 months, suggesting induced regular astigmatism, irregular astigmatism
and/or other higher order visual aberrations. By phone survey the
sponsor has now presented data showing a decrease in these symptoms of
diplopia.

Photophobia increased approximately 10 fold, considering mild, moderate,
or severe photophobia at 6 and 12 months. The updated data by phone
survey additionally showed a decrease.

Comparing treated versus untreated eyes, there was approximately a four
fold increase in sensitivity to light between the eyes show in blue; a
two and a half fold increase in night difficulty between the eyes, shown
in pink; and approximately a three fold increase in glare between the
eyes. Regarding all these symptoms concerning photophobia and night
vision problems, diplopia and glare, I would simply recommend that the
labeling should reflect the potential for increased visual symptoms
consonant with the most updated data that we have.

The major limitation of this study to my mind is regarding the stability
of the refractive effect. The major study limitation that is a
confounding factor for the entire study, as Dr. Macsai has already
alluded to, is that there is no cycloplegic data that is available for
my review. The table that was discussed today was not provided to me. I
did not have the opportunity to review any cycloplegic data on this
cohort.

If the patients are hyperopic, residual accommodative reserve can be
expected to skew the results. Hence, for all uncorrected visual acuity
tables, expect skewing of the uncorrected visual acuity data toward
better visual outcomes. Additionally, the refraction accuracy may also
be altered.

Looking at astigmatism magnitude greater than a diopter of approximately
1 in 5 had astigmatism induction greater than or equal to a diopter at 6
months. Fortunately, this does decrease with time and direction to
light. By 12 months it drops to 8 percent, and gradually climbs to 11
percent in the original cohort. In the updated cohort, in the pink, it
decreases with time.

We like that it decreased, however, the mere fact the astigmatism
induction is shifting points to refractive instability of the procedure.
I would rather see it stable at some level, whatever level that might
be.

Seventeen eyes were evaluated for astigmatism axes. For ten eyes
against-the-rule, 6 months later and at the 12 month interval, there
were only 4 eyes against the rule. At the 6 months interval for eyes
with oblique astigmatism, of six eyes there was only one remaining
oblique. One eye remained at the 6 and 12 month intervals with visible
astigmatism.

Hence, the astigmatism may shift against the rule to oblique or vice
versa. The mere fact that there is an astigmatism directional shifts
with time, granted it\'s a small subset, it does suggest refractive
instability. I was unable to locate updated data in this regard.

Looking at the uncorrected visual acuity for the moderate hyperopes \--
and I apologize that this is redundance \-- some of the tables that have
been presented reflect these data. Looking at those greater than 20/40
in the original cohort, we see it decreases over time. We realize the
limitations over longer time intervals. Those of greater than 20/32
decrease in time. Those greater than 20/20 decrease over time.

Showing the updated minus 50 cohort for completeness, although as I
stated, I have not seen the statistical analysis that warrants the
appropriateness of doing this technique. Those remaining with 20/32 or
better decrease over time. Those remaining with 20/20 or better decrease
in time, with an isolated data point at 18 months, and those remaining
greater than 20/40 did not decrease, however, taken together the
progressive declines in uncorrected visual acuity suggests regression of
the refractory effects.

Looking at predictability, those remaining plus or minus a half or plus
or minus 1 diopter from intended in the original cohort, we see
decreases in those remaining plus or minus 1, decreases in those
remaining plus or minus a half. The updated minus 50 again for
completeness, with a weak data point out here in the 24 months, we do
see a small decrease in those remaining plus or minus 1, and a similar
trend in those remaining plus or minus a half. Taken together the
declining predictability with time also suggests refractive instability.

Looking at the moderate hyperopes with regard to predictability, those
remaining plus or minus a half or plus or minus 1 diopter from intended,
generally decreased with time in the original cohort. The updated minus
50 also shows a trend, although not as marked. We also see decreases for
plus or minus a half. For moderate hyperopes the declining
predictability also suggests refractive instability.

For all eyes looking at predictability plus or minus a half diopter from
intended, all three cohorts showed declining predictability over time.
No matter how you slice it, they all go down. The updated minus 50 does
not decline as dramatically however, and realize the weakness again of
the later time intervals. These declining predictability with time
suggest refractive instability.

Looking at the low hyperopes as a percentage of undercorrections, we see
both for the original and the updated minus 50 cohort increasing
undercorrections with time suggesting regression from refractive effect.

Similarly, for the moderate hyperopes we see increasing undercorrection
with time to a whopping greater than 50 percent down here at the later
time intervals, suggesting regression with refractive effect. Lumping
all eyes together, no matter how you slice it, all three data sets show
increasing undercorrections with time as a trend going upward. These
also suggest regression from refractive effect.

This is not a consistent cohort of eyes. From the original cohort, the
mean refraction changes from month 1 to month 18. It changes by
approximately 1.5 diopters in the hyperopic correction. Interestingly,
the change in the refraction almost agrees with the area of the curve
that Dr. Pulido pointed out earlier of 1.35. The increasing mean
refractional time suggests refractive instability. The updated data
mimics this curve, showing increasing refraction over time.

There is also a large continuous refractor shift between time intervals.
This is the original cohort for a consistent cohort of 72 eyes at 18
months from table 50, volume 1, page 38. Between the 3 to 6 month
intervals, 0.92 diopter per year shift, between 6 and 12 months it\'s a
0.76 diopter shift, from 12 to 18 months there\'s a 0.56 diopter per
year shift.

I was unable to locate a consistent cohort in the updated data set from
the material that was provided to me. You have already seen the
pair-wise data presented. This continuous refractive shift over time
suggests a large percentage of the refraction in fact is temporary, and
I interpret this as poor efficacy.

In summary, regarding refractive instability, the following features
suggest: (1) refractive instability in this PMA of astigmatism magnitude
shifts; (2) astigmatism axis shifts; (3) progressive declines in
uncorrected visual acuity; (4) progressive declines in the proportion
remaining plus or minus a half or plus or minus 1 diopter from intended;
(5) progressive increase in uncorrections; (6) progressive increase in
the mean manifest refraction spherical equivalent; and (7) a continuous
refractory shift between time intervals.

Taken together, since it can be reasonably construed that the average
patient will want more than a temporary refractive effect, it is my firm
opinion the PMA is not approvable since reasonable assurance has not
been given that the device is effective under the conditions for use
described, recommended, or suggested for the proposed labeling.

My recommendations would be to complete the data collection for longer
time intervals; prepare a revised analyses for all of the outcome
variables;, and resubmit a revised PMA to the FDA at a future date for
review. Perhaps if the refractive instability shift can be better nailed
down at the later time intervals, appropriate labeling can properly
advise patients as to what to expect regarding the seemingly temporary
nature of this procedure.

Thank you all for your attention.

DR. MC CULLEY: Thank you, Dr. Grimmett.

In terms of procedure now, the panel will begin its deliberation. But I
have heard a sentiment, and then we will call FDA back and the sponsor
back for closing comments. I heard a sentiment for a break. Is there a
sentiment for a break? Okay, there is enough of a sentiment for a break.

\[Brief recess.\]

DR. MC CULLEY: The panel will now begin its deliberation and discussion
among ourselves of this PMA. We will then have the 30 minute open public
hearing session, and then five minutes of FDA closing remarks, and then
five minutes of sponsor closing comments.

So would the panel like to have open discussion at this point, or would
you like to conduct the discussion using the mechanism of placing the
questions that the FDA has up and answering them?

DR. SUGAR: I think some of this needs open discussion. This is different
from the things we looked at before, at least in full panel. I think
there have been some homework assignments on hyperopia, but not full
panel reviews of hyperopia. We are starting with a population that has a
mean refractive error of plus 1.69 diopters. So the criteria of
stability being 1 diopter of change over any time interval, 1-3 months,
3-6 months, 6-12 months and so on, is not applicable. That is, that\'s
too easy or too broad a criterion if you are starting out with 1.69
diopters and you stable can get 0.99 regression, that\'s not stable.

Likewise, predictability or accuracy plus or minus 1 diopter in 75
percent is not sufficient. So that everything we do with looking at this
I think is sort of without precedent in terms of our previous activity.
I think that there was a suggestion from the primary reviewer that they
become appropriate, even though they would not have been appropriate for
other modalities for other indications. That is hyperopia is different
from myopia.

DR. PULIDO: Just a question for the panel. The one I had asked the
sponsors, there was this change back towards pre-operative levels. They
said this was normal hyperopic drift. I would like know if that truly is
the natural history of hyperopes that they become more hyperopic over
time.

DR. BULLIMORE: There is excellent published cross-sectional data on this
from the Beaver Dam study and the Baltimore eye study. Both suggest that
there is indeed a hyperopic shift that goes in the forties and the
fifties population. In the sort of population that we are looking at
here, I would guess that the change for the decade was somewhere on the
order of 3/4 of a diopter per decade, so less than 0.1 per year, and
less than 0.01 diopter per month.

We actually presented some data on this a couple of years ago, which is
why I know the data. We had longitudinal data, retrospective, and found
similar results. About a half a diopter shift for the decade in the
hyperopic direction. So again, 0.05 per year, and way less than 0.01
diopters per month.

Personally, I don\'t believe that it\'s physiological.

DR. PULIDO: So the 1.35 diopters hyperopic shift over time, over 24
months would not \--

DR. BULLIMORE: Over the course of the study I would imagine that less
than 0.1, or at most 0.15 diopters was \"physiological,\" maybe 10
percent of the total change.

DR. MC CULLEY: In your studies that have been done in your analysis of
the others, how much of these is development of absolute hyperopia, and
how much of it is our inability to compensate for refractive hyperopia?

DR. BULLIMORE: Data in these studies is largely collected in the same
way as it was collected in this study.

DR. MC CULLEY: So there wasn\'t cycloplegic? So you really can\'t tell?

DR. BULLIMORE: We didn\'t have cycloplegic data. But one thing that is
evident from the sponsor\'s data that they present, is that there is no
systematic change over the study period between discrepancy cycloplegic
and non-cycloplegic. I think there is a danger that we overstate the
cycloplegic issue.

DR. MC CULLEY: I heard concerns about the absence of cycloplegic data.
Did I mis-hear, Dr. Grimmett?

DR. GRIMMETT: That was correct. I did not see any cycloplegic data
materials provided to me, and I would have like to have seen them.

DR. WANG: I have actually two comments. One is in addition to the
question with respect to guidance criteria for this type of correction,
in addition to the lower magnitude of correction, I think the cornea,
for some reason, is very reluctant to become more steepened. It doesn\'t
mind to be flattened. That\'s the way a cornea likes to behave.

So I think in addition to the low magnitude correction, that we need
more stringent criteria in stability follow-up. Also, the natural
tendency, so to speak, that the cornea doesn\'t like to be steepened is
also a reason to have more stringent criterion follow-up.

My second comment has to do with discussion of Dr. Pulido and Dr.
Stulting. I did a calculation of the two graphs that they were
mentioning. One is figure 3 and one is figure 4 of this blue, which 1 in
5. The figure 3 is the rate of change over time. Figure 4 is the
hyperopic refraction over time.

You can integrate figure 3, and it is consistent with the results in
figure 4. It is consistent in each figure, that there is about 1 diopter
over 18 to 24 months hyperopic shift.

DR. ROSENTHAL: I just want to comment that the panel has in fact
considered a hyperopic PMA for Excimer laser.

DR. PULIDO: I would like to say at that time we accepted the theory of
hyperopic shift as physiological.

DR. MC CULLEY: Which Dr. Bullimore has stated as real. What was your
assessment of the hyperopic shift in this relative to physiologic shift?

DR. BULLIMORE: It\'s not physiological. This is a genuine change, a
genuine regression. And were I free to discuss other studies, I would
say that was genuine regression as well. This is not a physiological
effect.

DR. MC CULLEY: But we\'re sticking with this PMA.

DR. BULLIMORE: I think this is perhaps a little off point, but the main
issue on the table as far as this PMA as far as I can see is, is it
effective? Dr. Grimmett, is sort of, basically in his slide presentation
proposed that it\'s not. And looking at the data presented by the
sponsor, I have difficulty convincing myself that I would recommend this
to a patient.

We have a cohort that starts off with an average of 1.68 diopters.
Twelve months later they are 0.49 diopters on average. And reading the
numbers off the graphs, because I couldn\'t find them off the table, it
looks like at 24 months they are on average around about 0.8. So it\'s
only 50 percent effective two years out from the procedure. That\'s
really where I think the rubber hits the road on this one.

DR. MC CULLEY: Other comments before we start to answer the FDA
questions.

DR. HIGGINBOTHAM: Just to be fair, I think the numbers are small, as has
been indicated several times. I would just qualify that last statement.

DR. BULLIMORE: Duly qualified.

DR. MANNIS: I don\'t know if it\'s been clarified by the sponsor as to
why cycloplegia wasn\'t used as the baseline in this study
pre-operatively?

DR. MACSAI: According to their protocols, it was performed
pre-operatively at 6, 12, 18, and 24 months. So it\'s in the volume one
or two.

DR. MC CULLEY: That was asked for before \-- sponsors now have had time.
When they come back, hopefully they can include that in the closing
remarks.

DR. PULIDO: And point of clarification, I agree with Dr. Higginbotham,
the cycloplegic refractive spherical equivalents has been given to us in
the white volume.

DR. MACSAI: I wanted the cycloplegic refractions comparing pre- to post-
over time by low and moderate hyperopes, demonstrating refractive
stability, out to 24 months, because that should tell us if it\'s
stable.

DR. FERRIS: Just a general comment. I\'d a big advocate of doing visual
acuity examinations, as most of you know. But I also think you have to
remember that there is a large subjective component to a visual acuity
exam. It becomes important here, because there is no control group. It
is somewhat surprising to me that there is only a tenth of a diopter
difference between the cycloplege and the uncycloplege refractions. It
may turn out to be that that\'s just the way it is. These people don\'t
accommodate, even though they could see better if they did accommodate.

I assume the visual acuities are done one eye at a time. In theory at
least, they could accommodate and see better. So I think it\'s important
to also have the cycloplegic refractive data or some other hard
endpoints to try to get a better assessment or more objective
assessment. In many ways, the subject of assessment is the most
important thing in these patients. They have a disability.

They want to get better, and they either are or they aren\'t. But it
would be nice to have some other data as well. I think we have to
remember that there is a big, subjective component. I don\'t know
whether there is a placebo effect to this treatment, but I wouldn\'t be
surprised if there is.

DR. MC CULLEY: Other questions, comments at this point before we start
the questions from the FDA?

DR. WANG: I\'d like to just make two very brief comments for the panel.
One is in addition to what Dr. Grimmett mentioned, the suitability from
the statistical analysis of excluding the first 50, also, I cannot
understand from the physics standpoint if you have the first 50, let\'s
say overhydrated, and you just have a 0.5 diopter undercorrection for
that group, why wouldn\'t that group result in the drop of stability
long term?

Because all you\'re going to do is just parallelly, treating less 0.5
diopter. While on figure 2 in book 5, there is quite a difference, as
Dr. Stulting pointed out that if you include the 50, it is not stable.
If you exclude 50, it is stable at 18 to 24 months on this scale of the
graph. So I have a conceptual problem of why a constant shift in the
amount of correction would affect stability over time.

My last comment is I would like to know what is the reason for
against-the-rule astigmatism as the predominant post-op astigmatism,
knowing that the treatment is symmetric? The reason I ask that is again,
our focus is stability of treatment. Could it be such a specific type of
astigmatism, which you know for example corneal disease endpoint occurs?
But could that suggest in terms of having a predominant astigmatism
post-op, any suggestion or cornea weakness or threatening instability?
I\'m just puzzled why symmetric treatment will give you asymmetry
post-op.

DR. MC CULLEY: Thank you for your comments. Any other questions or
comments now before we start to answer the FDA\'s questions?

DR. FERRIS: A quick comment. I think you have to be awfully careful
looking at that flat part of cohort minus 50 at 18 and 24 months,
because if you put some confident intervals around those points, maybe
there is drift, maybe there\'s not drift. I just think we don\'t know
yet.

DR. MC CULLEY: Because the numbers are so small?

DR. FERRIS: Yes.

DR. MC CULLEY: Malvina, would you like to put your questions up, please?
I\'ll let you read them.

DR. EYDELMAN: Question 1, which cohort (original, updated or updated
minus 50) do you believe to be the most appropriate for assessment of
safety and efficacy of this device?

DR. GRIMMETT: I think ideally I\'d like to see updated minus 46. And I
would like to see statistical analysis comparing the new updated numbers
in a similar fashion to volume one, appendix G. Rerun with numbers with
46.

DR. MC CULLEY: Dr. Macsai, would you like to add to that?

DR. MACSAI: I\'d like to see the same analysis, but I guess I need to
see the analysis before I say which one I think we should use.

DR. VAN METER: This question is a little unfair, because we have longer
follow-up for the original 46. We have the current technique that
supposedly works better with the updated minus 50, but we don\'t have
the time for those. So what we would like to do is have the time for the
original 46, and the technique for the updated minus 50, and we don\'t
have either one.

DR. EYDELMAN: This question was based on trying to make an assessment
today with the data that is currently available.

DR. MC CULLEY: Would you like to respond to that?

DR. VAN METER: Well, I don\'t think either one of them are appropriate
for assessment of safety and efficacy.

DR. MC CULLEY: Any other comments? Dr. Grimmett?

DR. GRIMMETT: Without seeing the statistical analysis of the 46 versus
the rest, the poolability analysis, I believe we\'re left with looking
at the updated cohort if we are going to make the decision today.

DR. FERRIS: I\'d like to add to that it seems to me that if what we
would come out with is a recommendation for a procedure, and those first
46 are a different procedure that the sponsor themselves said is not the
procedure we want to use, I don\'t see how we can have those 46 or 50
useful. I still am looking forward to finding out the difference.

DR. MC CULLEY: So you would say updated minus 50?

DR. FERRIS: Yes, the other just seems useless.

DR. MC CULLEY: So updated minus 50 would be \-- to answer your question
the way you ask it, updated minus 50. Is that correct?

DR. FERRIS: Or 46.

DR. MC CULLEY: Well, we don\'t have minus 46, do we?

DR. FERRIS: Oh, well, I take that point.

DR. EYDELMAN: Question 2, has adequate refractive stability been
demonstrated with this device by 6 months?

DR. MACSAI: No.

DR. MC CULLEY: Would you like to elaborate on that? That\'s enough?

DR. MACSAI: I just gave a presentation on it.

DR. MC CULLEY: Dr. Grimmett. I don\'t want you to give it again.

DR. GRIMMETT: As indicated in my slide presentation, the answer is no
from my standpoint.

DR. MC CULLEY: Does anyone else have any comment they would like to add?

DR. BULLIMORE: No.

DR. MC CULLEY: That didn\'t add.

DR. BULLIMORE: Definitely no.

DR. MC CULLEY: That\'s better. All right, 2b?

DR. EYDELMAN: Based on the refractive stability presented in this PMA,
is the current follow-up of eyes treated sufficient to provide
reasonable assurance of safety and effectiveness of this device?

DR. MC CULLEY: Dr. Grimmett?

DR. GRIMMETT: I would recommend additional follow-up to the 24 month
interval, as previously indicated. So my answer is no, primarily with
regard to effectiveness.

DR. MC CULLEY: Is there agreement on that? Dr. Macsai?

DR. MACSAI: I would agree with Dr. Grimmett and recommend 90 percent
accountability at the 24 month mark.

DR. MC CULLEY: Is there agreement on that?

DR. BULLIMORE: I could go with a little less than 90 percent. At 24
months I think 80 percent is a little more reasonable.

DR. MC CULLEY: Shoot for 90, accept 80?

DR. FERRIS: Why do we accept 80 percent? It is not an impossible task to
get 90 percent follow-up. It seems to me that at the very least you
ought shoot for 90 percent. I don\'t know whether there might be some
circumstances where I would take 80, but I\'m unhappy if we have 95
percent.

DR. MC CULLEY: I think that what we would say, we would want to shoot
for 100 percent. Then the closer to it, the happier we have. We have in
previous other guidance documents that have some parallels, set that
mark at 90 percent.

DR. YAROSS: I would just like to point out the 90 percent standard I
think was initially put in place with the idea that 10 percent loss to
follow-up in one year was reasonable. So I think if you are talking
about two years, it may be more appropriate to allow 10 percent per year
as a realistic, real world situation.

DR. MC CULLEY: Yes, we make based adjustments based on reality. As it
relates to requested numbers and the guidance, I think we can still be
flexible as time goes on.

DR. MACSAI: I agree, Dr. McCulley. I also think this is a new laser, and
therefore the more data we can get to establish safety and efficacy, the
better.

DR. MC CULLEY: No, question. I think that would affect our flexibility.

DR. WANG: I just wanted to make a comment. I second your opinions. I
think in fairness to the sponsors that in a continuing improvement of
hyperopic treatment given the low range of correction, I think that the
cornea are willing to speak, to become steepened. Probably we should
strive in addition to looking at this particular PMA, devise these
documents so they have something to shoot for in terms of continuing
proof, in terms of different parameters in the guidance document for
hyperopic treatment.

DR. MC CULLEY: Dr. Rosenthal, you\'re sitting there close. Can you
restate that?

DR. WANG: I think in fairness to the sponsor and trying to improve
devices for hyperopic treatment strategy, given the uniqueness of
hyperopic treatment, low range of correction, and the difficulty in
steepening the cornea, perhaps at some point we should spend some time
seriously in coming down with some real numbers.

DR. MC CULLEY: A hyperopic guidance document in the future. I
understand. Good suggestion.

DR. ROSENTHAL: That would really require probably another panel meeting.
I think to be fair to the agency, we asked you all to do that back
there, not about this device, but about the Excimer, and there was no
consensus. But I appreciate the suggestion.

DR. MC CULLEY: The sentiment is that we need, in fairness to everyone, a
guidance document for hyperopia that we do not have. That\'s a very good
point, and it would be nice to have.

I think we have answered that question. Do you want further
clarification?

DR. EYDELMAN: Yes, please. For the purposes of the record, I want a
clarification as to whether you are referring to 80 percent
accountability, or 80 percent of the eyes entered into the study seen at
24 months? Because when we calculate accountability, we take into
account eyes not yet reaching that time period, and therefore you can
have theoretically an 80 percent accountability with 50 or 60 eyes.

DR. MC CULLEY: I guess it would depend on the number to a degree that a
certain number needs to reach the 24 months.

DR. EYDELMAN: That\'s the clarification I\'m trying to obtain.

DR. MC CULLEY: And you\'re asking what that minimum number reaching 24
months would be with 90 percent accountability? Stay with number that we
have used. We can adjust.

DR. ROSENTHAL: I don\'t think it\'s fair for us to change our definition
of accountability. Everyone is now used to using it. Those that don\'t
reach that time period are subtracted from the denominator. I think what
Malvina is asking, is there a specific number? We know if there are 12
eyes out of 300, it\'s not adequate. Do you have a sense of the number
of eyes that reach 12 months?

DR. MC CULLEY: It\'s 24 months. What is you are asking is how big or
small a denominator would we accept.

DR. MATOBA: I think if you previously agreed that you would allow 2
percent loss per year, then at the end of 12 months it should be \-- no,
that\'s not true?

DR. MC CULLEY: No. We wanted 90 percent accountability.

DR. MATOBA: No matter how long the study goes.

DR. MC CULLEY: I don\'t think we qualified it.

DR. FERRIS: Did we have a minimum sample size in the other guidance,
which I thought was 300?

DR. MC CULLEY: I think so.

DR. FERRIS: So I didn\'t see any reason that you would hold hyperopia to
a higher standard than myopia. So there have to be at least 300 that
reach the 2 year visit, if people are happy with 2 years.

DR. MACSAI: Well, it\'s either 90 percent of the PMA cohort enrolled in
Phase III clinical trials, or it\'s a number that provides you with an
acceptable confidence interval, be it 300 or 400 or whatever, or 200. We
have done it before, and I know that the FDA has provided us with this
information to extract that number.

DR. EYDELMAN: I now understand the sense of the panel. We can move on.
Question 3, the predictability of manifest refraction and the
uncorrected visual acuity results decrease between 6 and 18 months. Does
this raise concerns about treatment efficacy.

DR. MC CULLEY: I think we have answered that, did we not?

DR. ROSENTHAL: Could you answer it again?

DR. MC CULLEY: It does. That was the sentiment of the panel, I believe.
For the record, yes.

DR. EYDELMAN: At six months post-treatment, 18 percent of all eyes
examined had greater or equal to 1 diopter increase in cylinder. Most
induced cylinder axes were in against-in-rule and oblique directions.
Does this raise any concerns?

DR. GRIMMETT: Yes, I believe it raises a concern. The follow-up data did
demonstrate a decrease in the astigmatism of direction that we all like
it to go. I think for that issue, if the astigmatism is shifting,
perhaps because of decreases, perhaps that could be reflected in the
labeling. But it is a concern for these low level hyperopes that are
having 1 diopter of astigmatism induction.

DR. VAN METER: The improvement in astigmatism probably reflects the same
stabilizing force on the cornea, i.e., as Dr. Wang said, the cornea
doesn\'t want to be steepened. If you look at the initial change,
certainly there is some refractive instability, as Dr. Grimmett showed.
Part of that refractive instability is manifest with an increase in
cylinders.

As you lose the cylinder, you also lose some of the refractive effect I
think as the cornea heals its wounds. So these sort of go hand-in-hand.
But I think the concerns of refractive instability are manifest by both
regression of effect, and decrease in the increased cylinder.

DR. MC CULLEY: If we get what the panel has already asked for, which is
300 eyes at 24 months, then it may take care of itself.

Any other comments?

DR. WANG: I think my answer is yes. In particular, the treatment is
circular. The fact we are going to use 65 percent against-the-rule, I\'m
just wondering if that is suggesting in any way a weakening of the
cornea. Again, the context of examining refractive stability. So the
answer is yes.

DR. MC CULLEY: Next question.

DR. EYDELMAN: Question 5, visual symptoms data reveal photophobia and
double vision to be the symptoms with the greatest change from
pre-operative levels. Do increases in these visual symptoms constitute a
safety concern?

DR. MACSAI: Well, it seems the sponsor has tried to address this by
questioning these patients with a phone questionnaire. But it\'s my
understanding that this data wasn\'t submitted for FDA review, the
tabulations. Were they, of the phone questionnaire, or weren\'t they?

DR. EYDELMAN: The summary of this was submitted.

DR. MACSAI: Sorry. Got it.

DR. EYDELMAN: What was not submitted was the information on the updated
cohort. But the phone questionnaire, the original was submitted.

DR. MACSAI: The original, but not the updated.

DR. MC CULLEY: Again, if we\'re going the route that we\'re going, which
is requesting more, it\'s a moot point; 5b.

DR. EYDELMAN: Is the analysis of the updated patient questionnaire
necessary prior to making a recommendation regarding approvability of
this device?

DR. MACSAI: Yes.

DR. GRIMMETT: It seems to redundant to me to the last question. Didn\'t
we just agree that we would like the updated questionnaire information?
So certainly we would like that information on the review.

DR. MC CULLEY: Next question.

DR. EYDELMAN: Do the safety and effectiveness outcomes stratified by
diopter of pre-operative hyperopia +0.75 to +1.99 diopter and +2.00 to
+2.50 diopter support approval for the full range of hyperopia of +0.75
to +2.50 diopters of spherical equivalent?

DR. MACSAI: Not yet.

DR. MC CULLEY: Dr. Grimmett, would you like to add to that?

DR. GRIMMETT: I agree. As soon as we have the updated data, we will be
in a better position to reanalyze the safety and effectiveness data. I
believe it should be stratified in the updated data as well.

DR. MC CULLEY: Other comments? Number 7?

DR. EYDELMAN: What are your recommendations for labeling regarding
potential regression, cylinder induction, and visual symptoms? Do you
have any additional labeling recommendations?

DR. MC CULLEY: Dr. Pulido, would you like to respond to that question?

DR. PULIDO: I would say that right now this is a moot point.

DR. MC CULLEY: Do you have any other questions for us?

DR. EYDELMAN: No, thank you.

DR. MC CULLEY: Does the panel have any other issues to add at this
point?

DR. HIGGINBOTHAM: I guess in addition to the additional follow-up, I
would like to see some analysis of whether or not there might be gender
influence here. You have that? Okay, thank you.

DR. JURKUS: I am also wondering if a more detailed analysis about
near-front acuity would be available.

DR. MACSAI: I would like to expand on Dr. Higginbotham\'s request for
gender analysis in that this is the patient population at high risk for
dry eyes and keratoconjunctivitis and that may have an influence on the
efficacy of the laser. So if they could make an analysis of that as a
barrier.

DR. PULIDO: I\'d like to thank again the sponsor for supplying, one,
good accountability, and number two a good data set from which we could
see the strengths and weaknesses.

DR. FERRIS: I\'d like to follow-up on something Dr. Wang said. That is
although I know we are not going to rewrite the guidance document, I\'m
concerned if the data at two years is showing a decrease, whether at
least with the other laser system we have asked about documenting
stability, and so I worry that we may or may not find two years to be
the endpoint.

At some point you need to go until you document stability, or at least
it would seem to me that I would I might know about stability, because
my patients would probably want to know more than a two year effect. Is
it going to level off or is it not. If hasn\'t leveled off, I think
there may be concern bringing it back here.

DR. MC CULLEY: So what one would say if we were writing the guidance
document would be minimum of two years for a new device, assuming that
stability is demonstrated at two years?

DR. PULIDO: And stability being what?

DR. MC CULLEY: It would have to be redefined for this group, as has been
pointed out. That would be to be determined in the guidance. We don\'t
have that.

DR. PULIDO: Shouldn\'t we tell the sponsor what we would like for
stability, since we were asking for long-term results now? We need to be
able to help them in that regard. What will we be happy with?

DR. MC CULLEY: Dr. Grimmett or Dr. Bullimore, either one.

DR. BULLIMORE: Primarily, I would like to see a little more data. I mean
it\'s very difficult to make decisions on stability with so little data
at the 24 months. I reiterate my impression that at two years the
technique appears to be on the order of 50 percent effective. I base
that both on the cross-sectional data that has been presented \-- I\'m
sorry, the longitudinal data that has been presented, but also the
pair-wise comparison, looking at the change in the elegant integration
of that data that was done in various people\'s heads. I think that will
remain my primary concern.

DR. WANG: I just want to make a comment. I would like to echo Dr.
Pulido\'s comment to the sponsor in this well conducted study. I think
the gist of the problem is the sponsor looked at the myopic guidance
document and it seems to fit. However, I think there is definitely the
need if FDA examines further hyperopic treatment devices, a clear
guidance document.

**Agenda Item: Open Public Hearing Session**

DR. MC CULLEY: Any other comments? At this point that will conclude the
panel discussion. We now have a 30 minute potential open hearing
session. We will recognize individuals in the audience who wish to come
to the podium to make comments. Each individual will be limited to five
minutes.

Is there anyone in the audience that would like to come forward and
speak? Ms. Thornton has one mail in that it had been prior agreed would
be read.

MS. THORNTON: Dr. Edward Yavitz(?), and ophthalmologist from Rockville,
Illinois has requested that the following remarks be read into the
record, since he was unable to present them himself. Dr. Yavitz is an
investigator Laser Sight.

\"The amount of hyperopia treated in this study should be broken down
into 0.5 diopter increments by age of patient and sex. If the degree of
pre-operative hyperopia is skewed for higher amounts in the oldest
patients, and lower amounts in the youngest patients with better immune
systems, and is also lumped into only two groups by degree of hyperopia
by age or sex, then regression could be mapped.\"

\"It is necessary to provide the refraction results in cycloplegic terms
and not manifest. Manifest refractions are meaningless especially on
those having less than 1.25 diopters of pre-operative hyperopia. Once
could have total regression while refracting such a patient, and still
categorize it as stable success if using the term less than 1 diopter.\"

Thank you.

DR. MC CULLEY: See no other requests for individual to speak in the open
public hearing, that session is now closed.

We now have five minutes allotted to the FDA for closing comments, and
then the sponsor. You each will have five minutes. Does FDA have
additional closing comments?

**Agenda Item: FDA Closing Comments**

DR. ROSENTHAL: No.

DR. MC CULLEY: Thank you. We now have the opportunity for the sponsor to
have five minutes for closing comments.

**Agenda Item: Sponsor Closing Comments**

DR. KOCH: I just want to re-emphasize that we had good follow-up. We
have over 90 at 18 months. In the low hyperopic group we have 20/40 or
better that is consistent from 6 months to 18 months, and the 20/20
group is also consistent. So even though we need a lot of patients at 24
months, we had great acuities that maintained themselves.

If you look at the uncorrected acuities, you saw them for the groups as
whole, the uncorrected acuities in these patients are 20/26, 20/24, and
20/25. And I think those are extraordinarily good data, and demonstrate
good efficacy.

The moderate hyperopes are lower, and was pointed out, I think that\'s
the 20/40 or better, 20/20 or better. But if you look at their mean
uncorrected acuity, it is 20/30, 20/34, and 20/34. So these patients are
still satisfied. They have confidence intervals that incorporate the FDA
criteria, even though it is for myopia, and these are happy patients.

You have sen the regression curves. You have seen that with the original
cohort they go to 26.3 months. With the new data we have shown that with
the drier technique the stability endpoint is reached with no regression
at 20.5 months. So we think that these data demonstrate in fact that it
is adequate for approval.

Certainly, again I would challenge you that with regard to any safety
data, I think we have already shown in the astigmatic data and the other
data that this is not a safety issue, and that the efficacy data in fact
at 18 months are outstanding.

DR. MC CULLEY: You still have three minutes. Are there any other
comments? I see Dr. Stulting.

DR. STULTING: Over the years the FDA and the Ophthalmic Devices Panel
have viewed a number of refractive surgical devices. It is common
knowledge that approved refractive technologies in the United States are
years behind those available outside this country. US ophthalmologists
and patients must still leave this country in order to access
technologies that we know to be better on the basis of public scientific
data, common sense, and personal experience.

Indeed, the international users of this device are unable to understand
why it would not receive FDA approval on the basis of the clinical data
presented today. You have before you an application for a device that
effectively treats low hyperopia with a low level of risk that is unique
among refractive procedures.

Uncorrected and best corrected acuity is excellent and remains so
through 18 months, as you just saw. There is a small amount of
post-operative refractive change, but the procedure is stable by the
FDA\'s own definition at six months. Moreover, it shows a more favorable
regression profile than any published refractive laser study.

It is important that the same standards be used to judge this PMA as
have been used to judge similar applications that have recently come
before you. This clearly does not appear to be occurring today. As your
colleague and a potential user of this device, I strongly urge you to
recommend approval of this PMA. We need to reverse the current trends so
that new, safe, and effective technologies that are available outside of
the United States are made available to patients and surgeons in this
country in a timely manner.

DR. MC CULLEY: Does the sponsor have any other comments? The indication
is no. Ms. Thornton will now read the voting options.

MS. THORNTON: Just to refresh you memory, the panel\'s recommendation
options for the vote are as follows: approval, there are no conditions
attached; approvable with conditions.

The panel may recommend that the PMA be found approval subject to
specified conditions such as physician or patient education, labeling
changes or further analysis of existing data. Prior to voting, all the
conditions are discussed by the panel, and listed by the panel chair.

Number three, 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.

DR. MC CULLEY: Dr. Grimmett, you have been collecting the data as we
have been going along and scribing for us. Would you like to make a
recommendation?

DR. GRIMMETT: The consensus I believe, and I will add some comments
regarding additional data that people have asked for is that the current
PMA in its current form is not approvable because reasonable assurance
has not been given that the device is effective under the conditions
prescribed, recommended, or suggested in the proposed labeling.

Issues regarding future submission will include cycloplegic data for all
time intervals. Statistical analysis is requested specific to the first
46 cases. The data should be presented as the updated cohort minus 46.
We would like the updated questionnaire regarding visual symptoms. And
Drs. Higginbothmas and Jurkus were talking about requiring or asking for
gender analysis, and I believe near-point acuity.

DR. MC CULLEY: That\'s the motion with added information. Is there a
second to the motion?

DR. GRIMMETT: I didn\'t mention the number of patient required. Was the
consensus 90 percent accountability, with minimum of 300? I wasn\'t
clear.

DR. MC CULLEY: I believe so, at 24 months.

DR. GRIMMETT: We will add that as an amendment.

DR. MACSAI: Second.

DR. MC CULLEY: The motion has been made and seconded. Is there further
discussion of the motion on the floor? Seeing none, all in favor of the
motion signify by raising your hand high. It\'s unanimous.

\[Whereupon, the motion was unanimously approved.\]

DR. MC CULLEY: Dr. Grimmett summarized, but we do need to have each
panel member indicate why they voted as they did. We\'ll start at the
other side over here.

DR. FERRIS: Well, as others mentioned, I commend the presenters, the
sponsor for the data they have collected thus far. But for the reasons
that were outlined by Dr. Grimmett and Dr. Macsai, I think additional
data is necessary before we have a good sense of both the safety and
efficacy. It\'s apparent this does something, but a little bit more data
is needed.

DR. VAN METER: I voted not approvable. I believe the device is
reasonably safe. I think the sponsors have shown that to my
satisfaction. I have questions about the efficacy because the
instability of the refraction and the regression.

The last table that was shown showed seemingly stability had percent of
patients in the Y axis. And it would be more helpful to have the actual
refraction data, ideally a cycloplegic refraction data, and show that to
be stable, rather than have a percentage of patients that is 20/20.

DR. MACSAI: I voted not approvable. This is a new refractive laser.
Despite the fact that the sponsor has done a great job in providing data
in an organized, reviewable manner, it is just too soon to tell. The
data reviewed to date demonstrates refractive drift and decreased
efficacy over time. There is an increase in astigmatism with a
progressive axis shift. Analysis of the total hyperopia as measured by
cycloplegic refraction will determine the true efficacy of this
procedure, and with further follow-up we will be able to better
determine the safety and efficacy.

DR. JURKUS: I voted not approvable for the same reasons that have been
indicated.

DR. HIGGINBOTHAM: I voted not approvable considering I think the need
for additional follow-up as evidenced by the increasing symptoms that
patients are complaining about, as well as the lack of refractive
stability long-term. I think we really do need to see what happens with
these patients over time.

DR. PULIDO: I voted not approvable, again because I think not so much
the safety data, but the effectiveness data. We need to have longer-term
results to make sure we\'re not putting out to the American public, a
new technique that is not stable over the long run.

DR. SUGAR: I voted not approvable. I believe the procedure is safe. I
believe that the effectiveness is disappointing and further data will
either confirm or refute that. I disagree with the 90 percent
requirement. I don\'t think that that is realistic, but otherwise I
agree with the vote.

DR. BULLIMORE: I voted not approvable. While I will accept that the
device is reasonably safe, the efficacy data is somewhat disappointing.
I believe that both sponsor and reviewers and indeed FDA have been
hampered by the lack of a guidance document, but nonetheless one can
apply some common sense to this data and look at the degree of change
that has been attempted, and place the actual achieved change at
different time intervals in the context of what is being attempted.
Based on that, I don\'t think that the sponsor has to date demonstrated
efficacy.

DR. GRIMMETT: The average consumer will likely want more than a
temporary refractive effect. Since there is a paucity of reliable,
long-term data that cannot reasonably substantiate critical stability
issues, I voted that the PMA is not approvable primarily due to
effectiveness issues. I do believe the PMA shows that the procedure is
reasonably safe.

DR. MATOBA: I voted that this procedure is not approvable for reasons
elucidated by Dr. Grimmett and Dr. Macsai. I also agree with Dr.
Sugar\'s comments regarding the accountability.

DR. MANNIS: I voted not approval primarily based on lack of
demonstration of efficacy.

DR. WANG: I voted for not approvable. I do want to share the sentiment.
As a refractive surgeon there is a need of the American public to have
refractive surgical procedures offered to them in a timely manner, with
good conscious consideration of all parameters. This study is well
conducted. It does fit the myopic guidance document, however, it\'s not
approvable based on our discussion. This heightens further the need of
FDA to come up with specific guidance document for the correction of
hyperopia, since it is a different animal.

DR. MC CULLEY: Ms. Thornton, do you have closing remarks or a comment?

MS. THORNTON: I just wanted to in closing, first of all thank the panel
for a lot of hard time reviewing, as well as deliberating today. I want
to ask them please to take \-- anything that is pertaining to this
document should be put back behind the panel table, as you did with the
first document this morning for pick up. Anything left on the table will
be destroyed as well. So please take your notebooks with you or whatever
out of the packs that you want to keep with you for tomorrow\'s
deliberations.

Again, I want to thank you. It\'s been a long day, and we appreciation
your hard work and attention to our needs.

DR. MC CULLEY: I would like to thank everyone for what has been I think
a job well done. There were very professional presentations and panel
discussions both this morning and this afternoon. With that, we will
adjourn.

\[Whereupon, the meeting was recessed at 6:10 p.m., to reconvene the
following day, Friday, July 23, 1999, at 8:00 a.m.\]