UNITED STATES OF AMERICA

\+ + + + +

FOOD AND DRUG ADMINISTRATION

MEDICAL DEVICES ADVISORY COMMITTEE

\+ + + + +

OPHTHALMIC DEVICES ADVISORY PANEL

106^TH^ MEETING

\+ + + + +

FRIDAY,

OCTOBER 3, 2003

The panel met at 8:30 a.m. in the Gaithersburg Marriott Washingtonian
Center, 9751 Washingtonian Boulevard, Gaithersburg, Maryland, Dr. Jayne
S. Weiss, Chair, presiding.

[PRESENT:]{.underline}

JAYNE S. WEISS, MD., Chair

ARTHUR BRADLEY, Ph.D., Member

MICHAEL R. GRIMMETT, M.D., Member

ALICE Y. MATOBA, M.D., Member

TIMOTHY T. McMAHON, O.D., Member

ALLEN C. HO, M.D., Member

ANNE L. COLEMAN, M.D., Ph.D, Member

KAREN BANDEEN-ROCHE, Ph.D, Consultant,

deputized to vote

WILLIAM D. MATHERS, M.D., Consultant,

deputized to vote

JOEL SUGAR, M.D., Consultant, deputized to vote

MARIAN S. MACSAI-KAPLAN, M.D., Consultant,

deputized to vote

JAMES P. McCULLEY, M.D., Consultant

OLIVER D. SCHEIN, M.D., Consultant,

deputized to vote

GLENDA V. SUCH, M.Ed., Consumer Representative

R. MICHAEL CROMPTON, J.D., M.P.H., R.A.C.

Acting Industry Representative

[SPONSOR\'S PRESENTERS]{.underline}:

HENRY F. EDELHAUSER, Ph.D

HELENE LAMIELLE, M.D.

DONALD R. SANDERS, M.D., Ph.D.

STEVEN G. SLADE, M.D.

JOHN A. VUKICH, M.D.

[FDA PARTICIPANTS:]{.underline}

A. RALPH ROSENTHAL, M..D.

GERRY W. GRAY, Ph.D.

DONNA R. LOCHNER

MALVINA B. EYDELMAN, M.D.

SARA THORNTON

[OPEN PUBLIC HEARING SPEAKER]{.underline}:

CAPT. STEVEN C. SCHALLHORN, M.D.

C-O-N-T-E-N-T-S

Call to order 5

Introductory Remarks 5

FDA Presentation 13

Open Public Hearing 15

Open Committee Session 26

Division Update 26

Branch Updates 31

PMA P030016

[Sponsor Presentation]{.underline}

Helene Lamielle, M.D. 32

Steven Slade, M.D. 34

John Vukich, M.D. 44

Henry Edelhauser, Ph.D. 55

Panel Questions for Sponsor 69

[FDA Presentation]{.underline}

Donna Lochner 120

Malvina Eydelman, M.D. 128

Gerry Gray, Ph.D. 138

Panel Questions for FDA 154

Additional Comments from the Sponsor 169

Committee Deliberations

[Primary Panel Reviewers]{.underline}

Dr. Marian S. Macsai‑Kaplan 174

Dr. Joel Sugar 187

Dr. Michael R. Grimmett 192

Panel Discussion of PMA P030016 219

to Include FDA Questions to the Panel

C-O-N-T-E-N-T-S

FDA ‑ Closing Comments 374

SPONSOR ‑ Closing Comments 374

Voting Options Read 384

Panel Recommendation Takes by Vote 422

Polling of Panel Votes 426

Meeting Adjourned 432

P-R-O-C-E-E-D-I-N-G-S

(8:34 a.m.)

DR. WEISS: Would everyone please take their seats? We will be beginning
in a moment. I would like to call this meeting of the Ophthalmic Devices
Panel to order. We will have introductory remarks by Sally Thornton and
for the record, I would like to note that there is a quorum present.

MS. THORNTON: Good morning. I\'d like to introduce myself. I am Sara
Thornton, and I am the Executive Secretary of the Ophthalmic Devices
Panel. On behalf of the FDA, I would like to welcome you to the 106th
meeting of the Ophthalmic Devices Panel. Before we proceed with today\'s
agenda, I have a few short announcements to make. I\'d like to remind
everyone to please sign in our at the registration table. There are
sheets there for you to fill out, just your name and whether you\'re
from industry or the panel or FDA or the public. Please, we do like to
have that filled out.

All public handouts for today\'s meeting are available at the
registration table. There are two new additions to our usual group of
handouts. We\'ve put out there information on public participation in
open public hearings and copies of a guidance document for FDA and
industry on quality system information for certain pre-market
application reviews.

Messages for panel members and FDA participants, information or special
needs should be directed through Ms. AnnMarie Williams, who is available
at the registration table. The phone number to call for the meeting area
is 301-590-0044. In consideration of the panel, the sponsor and the
Agency we ask that those of you with cell phones and pagers either turn
them off or put them on vibration mode while in this room and to make
your calls outside the meeting area, please.

Lastly, will all meeting participants please speak into the microphone
and give your name clearly so the transcriber will have an accurate
recording of your comments? Now, at this time, I\'d like to extend a
special welcome and introduce to the public the panel and the FDA staff
a new panel consultant who is with us at the table for the first time
today, Dr. Oliver Schein, to my left, who comes to us from Johns Hopkins
University where he holds a joint appointment as the Grossman Professor
of Opthamology in the School of Medicine and as a Professor of
Epidemiology in the School of Public Health and Hygiene.

His clinical expertise is in the medical and surgical management of
patients with corneal disease and problems involving the interior
segment of the eye. I\'d also like to welcome our acting industry rep,
Mr. Michael Crompton, Vice President for Regulatory and Clinical Affairs
and Quality Assurance for Carl Zeiss Meditec, Inc. Mr. Crompton is
sitting in for Mr. Ronald McCarley, who will not participate in today\'s
proceedings at the request of the PMA sponsor.

Will the remaining panel members please introduce themselves beginning
with Glenda?

MS. SUCH: Glenda Such, Consumer Representative.

DR. SUGAR: Joel Sugar, University of Illinois at Chicago.

DR. BANDEEN-ROCHE: Karen Bandeen-Rhodes, Johns Hopkins University.

DR. McMAHON: Tim McMahon, Department of Ophthalmology, University of
Illinois at Chicago.

DR. MATOBA: Alice Matoba, Cullen Eye Institute, Baylor College of
Medicine.

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

DR. WEISS: Jayne Weiss, Kresge Eye Institute, Wayne State University,
School of Medicine.

DR. MATHERS: Bill Mathers, Oregon Health Sciences University.

DR. HO: Allen Ho, Wills Eye Hospital, Philadelphia.

DR. GRIMMETT: Michael Grimmett, West Palm Beach Florida.

DR. MACSAI: Marian Macsai, Northwestern University, Chicago.

DR. McCULLEY: Jim McCulley, University of Texas, Southwestern Medical
School, Dallas.

DR. COLEMAN: Anne Coleman, UCLA.

DR. ROSENTHAL: Ralph Rosenthal, FDA.

MS. THORNTON: Thank you, panel. I\'d like to read now the conflict of
interest statement for this meeting of October 3rd, 2003. The following
announcement addresses conflict of interest issues associated with this
meeting and is made part of the record to preclude even the appearance
of an impropriety. To determine if any conflict existed, the Agency
reviewed the submitted data for this meeting and all financial interest
reported by the committee participants. The conflict of interest
statutes prohibit special government employees from participating in
matters that could effect their or their employer\'s financial interest.

The Agency has determined, however, that the participation of certain
members and consultants, the need for whose services outweigh the
potential conflict of interest involved is in the best interest of the
government. Therefore, a waiver has been granted for Dr. Oliver Schein
for his interest in firms that could potentially be effected by the
panel\'s recommendations. The waiver which allows him to participate
fully in today\'s deliberations involves a pending consulting
relationship on a competitor\'s unrelated product for which he has not
received any compensation and also consulting with a competitor on
unrelated matters for which he receives between \$10,001.00 and
\$50,000.00 yearly.

Dr. James McCulley has been granted a limited waiver which allows him to
participate in the review and discussion but excludes him from voting on
the application. Dr. McCulley\'s waiver involves three consulting
arrangements with competing firms. For these consulting services he
received greater than \$50,000.00 within the past year. Copies of these
waivers may be obtained from the Agency\'s Freedom of Information
Office, Room 12A-15 of the Park Loan Building.

We would like to note for the record that the Agency took into
consideration other matters regarding Drs. Bradley, Schein and Coleman,
Michael Grimmett, Allen Ho and Jayne Weiss. Each of these panelists
reported past or current interest involving firms at issue but in
matters that are not related to today\'s agenda. The Agency has
determined, therefore, that the panelists may participate fully in the
deliberations with the exception of Dr. McCulley, as noted previously.

We would also like to note that the Acting Industry Representative for
this meeting, Mr. Michael Crompton, reported that his employer has
numerous business relationships with firms at issue. In the event that
the discussions involve any other products or firms not already on the
agenda for which an FDA participant has a financial interest, the
participant should excuse him or herself from such involvement and the
exclusion will be noted for the record.

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

I\'d like to read not at this time the appointment to temporary voting
status for this meeting. Pursuant to the authority granted under the
Medical Devices Advisory Committee Charter dated October 27th, 1990, and
as amended August 18th, 1999, I appoint the following individuals as
voting members of the Ophthalmic Devices Panel for this meeting on
October 3rd, 2003. Drs. William Mathers, Karen Bandeen-Roche, Joel
Sugar, Marian Macsai-Kaplan and Oliver Schein. For the record, these
individuals are special government employees and consultants to this
panel or other panels under the Medical Devices Advisory Committee.

They have undergone the customary conflict of interest review and have
reviewed the materials to be considered at this meeting. Signed, David
W. Feigal, Jr. MD, MPH, Director of the Center for Devices and
Radiological Health dated September 26th. Thank you. Dr. Weiss.

DR. WEISS: Thank you, Sally. We will now begin the open public hearing.
Captain Steven Schallhorn \-- I\'m sorry, I\'m just going to have him
approach the podium and then I have a statement. But, I\'m sorry, you
have a presentation to make to Dr. Matoba. I apologize.

DR. ROSENTHAL: I do thank you very much.

DR. WEISS: That\'s very important.

DR. ROSENTHAL: I will come over and stand next to her.

MS. THORNTON: Give him a microphone. This is important.

DR. ROSENTHAL: Hi. I get two kisses this time. I\'d like to give this
presentation to Alice Matoba and read the Associate Commissioner for
External Relations\' comments. \"Dear Dr. Matoba, I would like to
express my deepest appreciation for your efforts and guidance during
your term member \-- your term as a member of the Ophthalmic Devices
Panel of the Medical Devices Advisory Committee. The success of this
committee\'s work reinforces our conviction that responsible regulation
of consumer products depends greatly on the experience, knowledge and
various backgrounds and viewpoints that are represented on the
committee.

In recognition of your distinguished service to the Food and Drug
Administration, I am pleased to present you with the enclosed plaque\".
And I am pleased to express my thanks. Alice and I go back a long time.

(Applause)

DR. MATOBA: Well, thank you, Dr. Rosenthal. It was a great honor for me
to be asked to serve as a member of the FDA Ophthalmic Devices Panel and
it\'s been such a great pleasure for me to work with the excellent FDA
staff and fellow panel members and with you and especially with Sally
Thornton, who has done such a great job.

I have been so impressed with the thoroughness and the very high
standard of scrutiny that you give to all of the protocols that we have
seen and I look forward to continuing to work with you as a consultant
in the future. Thank you.

DR. WEISS: Thank you, Alice. Thank you, Dr. Rosenthal. We will now begin
the Open Public Hearing but first, I wanted to read a statement that was
requested by the FDA. \"Both the Food and Drug Administration and the
public believe in a transparent process for information gathering and
decision making. To insure such transparency of the open public hearing
session of the Advisory Committee, FDA believes that it is important to
understand the context of an individual\'s presentation. For this
reason, FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral statement, to advise the committee of
any financial relationship that you may have with the sponsor, its
product and if known, its direct competitors.

For example, this financial information may include the sponsor\'s
payment of your travel, lodging or other expenses in connection with
your attendance at the meeting. Likewise, FDA encourages you at the
beginning of your statement to advise the committee if you do not have
such financial relationships. If you choose not to address this issue of
financial relationships at the beginning of your statement, it will not
preclude you from speaking.

Dr. Schallhorn, we have your presentation, we have up to a half hour for
the open public hearing, but you have 10 minutes at this point.

DR. SCHALLHORN: Well, good morning, and thank you for allowing me to
address the panel. My name is Steve Schallhorn. I\'m an opthamologist,
the Director of Cornea and Refractive Surgery at the Navy Medical
Center, San Diego. I have no financial interest in STAAR. I\'m not a
paid consultant. I\'ve self-funded my travel to come here to address the
panel. I am a clinical investigator in the Toric ICL Study, which is
ongoing but treatments at our center have not begun.

I\'d like to also add that I\'m an active duty U.S. Navy Ophthalmologist
but the views that I express are not necessarily those of the U.S. Navy.

The reason I\'m here is just to address an important issue, I believe
and that is that we need options. We need surgical options, surgical
options beyond what we can do with keratorefractive surgery in
particular, excimer laser ablative procedures, especially to correct
high myopia. There are many issues here and they deal with issues such
as thin corneas. There are patients who are not good candidates for
refractive surgery because of high refractive errors.

Patients with high refractive errors may not be good candidates anyway
because current technology induces a number of aberrations on the cornea
which can result in visual symptoms. And there are patients or subject
that we want to treat that have critical visual demands, especially
those again with high refractive error.

Now, my area of expertise and what we\'ve studied to a great extent,
deals with the quality of vision after refractive surgery and that\'s
really what I\'d like to spend the rest of the time talking about. The
\-- what I\'d like to talk about is a study that we\'ve conducted
looking at a 105 consecutive LASIK subjects that we had visual acuities
measurement on, questionnaires and a special test, a night-driving
simulator. I\'ll talk more about that.

This was LASIK performed with multiple laser platforms with a six and a
half millimeter optical zone size with a transition zone, so it\'s the
latest technology for high myopia. This was also conventional and not
customer wavefront-guided. The average preop refraction was relatively
high, it was minus six, a little over minus six diopters and it ranged
up to minus 11. At six months the results were good and the uncorrected
visual acuity results were satisfactory with about three-quarters of the
patients achieving 20/20 uncorrected.

The night-driving simulator that we used was a derivative of the
simulator that Dr. Ginsberg developed that I believe was required in
some earlier investigational studies conducted for intraocular lenses.
This test, and it\'s shown here, you can see the \-- it doesn\'t show up
very well, but on the right side, it\'s looking over the shoulder of a
subject in best corrected trial frames right here, looking at a rural
night driving scene at 55 mile per hour. It\'s done in best corrected
vision. Each eye is tested independently. There were numerous conditions
at that the subject were tested on; that was business signs, traffic
signs, pedestrian hazards, et cetera.

Six thresholds were made for each one of those conditions for both
detection and identifying what that was and it was conducted with and
without a glare source simulating driving which led to 144 measurements
that were made, threshold measurements, per patient and so in these 105
subjects that we tested each eye independently, with this unique test,
the data represents thousands and thousands of man-hours because it\'s
extremely labor intensive. They\'re very, very specialized tests, but
nonetheless, it\'s a performance-based task and that\'s what I\'m going
to start with.

It is a performance-based task, whereas, other tests, I should say of
visual acuity such as contrast sensitivity, you can ask yourself, I
certainly pondered this, you know, what does it mean if somebody has a
subtle loss of contrast? What does that really mean and that\'s a very
good question? What does that really mean and we\'re trying to get an
answer to that, what does that really mean, but a performance based task
built in has some of those answers addressed. This is a task that we are
now looking at.

We look at that. Under all conditions, in this population of 105
subjects, we find a decrement in night driving performance. How much of
a decrement? A little bit. This is the data shown another way and this
shows the seconds improvement or the seconds decreased in the detection
or identification distance, preop to post-op, so it\'s a paired analysis
and zero represents no change post-op compared to preop and you can see
most patients had no change. But the trend and the significant \-- and
it is significant that there was a loss. About 40 percent of patients
had one second or longer increase in their detection distance.

Now, you could ask also, what does one second mean? Is that significant?
We\'ve worked with the National Traffic Safety Administration on the
meaning of this and they\'ve conducted studies which have shown that one
second is a significant decrement in night driving performance at 55
miles per hour under similar but different circumstances. So it\'s a \--
we\'re seeing a significant loss in a significant portion of patients
treated with LASIK for relatively high levels of myopia.

Now, let\'s look at the vision. This is best corrected and five percent
contrast acuity shown on the same chart. In orange, it\'s best corrected
and this is lines gained or lost and you can see most patients had no
change but the curve has shifted to the right meaning more patients had
improvement than a decrement, consistent with what we see and that\'s,
perhaps, partly due to reduction in minification from the act of putting
that correction on the cornea.

In contrast to what we see with high contrast acuity, we see a shift to
the left or worse with five percent contrast acuity, five percent low
contrast acuity. It\'s an ETDRS eye chart, that five percent level and
it\'s backlit. We see a loss, in fact, 25 percent of patients having
measurable loss of contrast acuity with this. How about the
symptomatology, most patients have no change in their symptomatology,
preop to post-op. However, the curve is shifted slighted toward worse.
Again, this is a paired analysis. We\'re looking at all patients and the
difference between post-op and preop. It\'s slightly shifted worse,
meaning patients have symptoms. In fact, a subset of patients can have
relatively significant symptoms after the surgery.

Now, we tried to find out, okay, what are the factors that now are
related to their driving performance decrement, what are those factors
and we\'ve done correlation analysis. And we find surprisingly that
pupil size placed no factor whatsoever and I\'ll talk more about the
briefly. Pupil size placed no factor in their night driving performance.
Where we see a significant decrement pupil size has no effect. One of
the strongest effects we see, though, is the level of preop myopia. The
higher level of preop myopia, the worse the night driving symptoms.
I\'ll talk, again, more about that.

We also get correlations with symptomatology in night driving
performance. We get correlations with the contrast. People who have
worse contrast, don\'t do as well in night driving. That all makes
sense. Here\'s, just quickly, shows the low-light pupil diameter and you
can see we had patients that were eight millimeters or larger. We had a
wide range of pupils. We did not exclude patients who had large pupils
in this study. Just to repeat, we did not exclude patients who had large
pupils from the study. We had a broad distribution of pupil size. We
found no correlation with pupil size.

And all of the analysis that we\'ve done, other types of analysis with
many, many other data sets have shown no correlation with pupil size.
However, we do find a significant correlation again, as I mentioned,
with preop myopia. Patients who have high levels of preop myopia had a
significant decrease in the night-driving performance. You can see on a
scatter plot of all the data that there is significant spread. However,
there is a significant relationship also.

Now, what are the causes of this, what are the causes of these problems
after LASIK and the answer is, I think, has to do with higher order
aberrations, the induction of higher order aberrations. This is looking
at preop, a distribution of the higher order RMS preop and looking at it
post-op in yellow and we see a significant increase in the higher order
aberrations.

We do correlation analysis with those higher order aberrations and we
find that the level of preop myopia is significantly correlated to
induced or an increase in spherical aberration. And again, a lot of
scatter, but a significant relationship. Likewise, we find that increase
in higher order aberrations, higher order RMS, change in higher order
RMS vertically versus change in five-percent contrast horizontally that
there also a significant relationship. Patients who have increase in
higher order aberrations have an increase or a decrease in their
contrast acuity.

Anyway, in conclusion, conventional LASIK works well. Most patients have
no symptoms, but in some patients, it can induce visual symptoms, it can
reduce low contrast acuity, it can increase higher order aberrations and
it can decrease night driving visual performance. Preop myopia is the
strongest risk factor. Patients who are especially above six diopters
have the greatest risk and, of course, that\'s also the range where
improved algorithms, improved ways to do LASIK, such as wavefront-guided
surgery, is not yet \-- is not available.

And lastly, we need these kind of surgical options. Surgical options are
needed especially to correct higher orders of myopia. Thank you.

DR. WEISS: Thank you, Dr. Schallhorn.

(Applause)

DR. WEISS: We don\'t usually have questions at this point, but if anyone
had any pressing questions for Dr. Schallhorn, we could limit them to a
few, otherwise, we\'ll \-- Dr. Bradley does, Dr. Schallhorn.

DR. BRADLEY: Thanks for the presentation, Dr. Schallhorn. One question,
you made an emphatic statement that pupil size was not critical. You
then inferred from your data that these driving problems were related to
higher order aberrations. Well, the one thing we know for use is that as
pupil size gets bigger, aberrations get worse. So how can there be a
correlation with higher order aberrations but not with pupil size?

DR. SCHALLHORN: Well, aberrations can increase as the pupil size
increases. But its effect on visual performance is what I\'m saying we
don\'t see that effect on visual performance. For instance, there may be
\-- I think there are things we really don\'t understand about the
visual system and this comes to the heart of several of them. You can
have a very aberrated eye that might have aberrations at seven or eight
millimeters but it may not effect visual performance. You can measure it
on an aberrometer, but if it doesn\'t effect visual performance, I\'m
not sure.

You know, I think the central four, five, six maybe larger than that,
millimeters, of the visual system is critical for high quality vision
but it may not be that the eye has to be that perfect beyond that range,
even though we can measure aberrations in that range.

DR. WEISS: Thank you very much. We are going to move onto the open
committee session with the Division update by Dr. Rosenthal, followed by
a Branch update by Donna Lochner.

DR. ROSENTHAL: Thank you, Dr. Weiss. This year we are pleased to
announce the addition of several members to the staff of our Division
and I\'d like to introduce them to you. There are actually two from the
Ear, Nose and Throat Branch but I will not introduce them. They\'re not
here and probably will not be playing much of a role, though I will
comment on them at the end on their \-- who they are.

First, I\'d like to introduce Lori Austin-Hanberry, who has joined our
Division in the position of Project Manager. Amongst her duties will be
insuring that the Division meets MDUFA (ph) product review goals. She\'s
a Lieutenant Commander in the Public Health Service, has over 14 years
experience as a registered nurse with clinical, instructional and
management background. Prior to joining FDA she managed various clinical
and administrative operations for the Montgomery County Department of
Health and Human Services, most recently managing the Childhood Lead
Poisoning and Prevention Program.

She was also a Captain in the Air Force Reserves for 11 years. She
obtained her nursing degree from Howard University and her Masters
Degree in Health Care Administration from Central Michigan University.
Lori?

Dr. Joseph Blustein is a shared hire with the Office of Surveillance and
Biometrics and will be working on post-market issues relating to
ophthalmic and ENT devices. He is a Board certified ophthalmologist and
former Medical Director of the Wisconsin Peer Review Organization. He
has two Masters degrees, one in epidemiology and one in food science. He
serves on the Wisconsin Public Health Advisory Committee and we welcome
Dr. Blustein.

Clay Buttemere went to Virginia Tech to pursue his engineering studies.
In 2000 he received his BS in engineering science and mechanic from
Virginia Tech. He and his wife, after living in Macedonia, moved to
Nashville, Tennessee where he enrolled in graduate studies in the
Biomedical Engineering Department at Vanderbilt University. His research
in the biomedical optics lab at Vanderbilt involved using optical
spectroscopy to assess tissue thermal damage in vivo. In May of 2003, he
received an MS degree in Biomedical Engineering from Vanderbilt and in
August of this year he joined the FDA as a Biomedical Engineer.

Brad Cunningham is also a Biomedical Engineer, who was hired to work in
Donna Lochner\'s Intraocular and Corneal Implants Branch. He received
his undergraduate degree from the University of Maryland in
Bioengineering focusing on biomedical instrumentation. After graduation,
he is employed full time at Walter Reed Army Institute of Research in
the Department of Neuropharmacology in the Division of Neuroscience.
Whilst there, he co-authored three papers, two recently published
articles focusing on studying the therapeutic intervention window
following transient cerebral ischemia and the delayed gene response and
he\'s also in the Public Health Service as you can tell from his
uniform.

I\'d like to announce that the Office of Science and Technology has
brought Dr. Ethan Cohen to work as a staff fellow in the
Electrophysiology Branch of the Division of Physical Sciences. This is
also a shared hire with OST. He will be working in our Division as well.
Dr. Cohen\'s area of expertise is electrophysiology of the retina and
Dr. Saviola usurped me. His position is a shared high with the Office of
Device Evaluation.

Dr. Cohn comes to CDRH from Harvard University where he was a visiting
professor in the Department of Molecular and Cell Biology. Prior to
working at Harvard, Ethan was an assistant professor in the Department
of Ophthalmology and Visual Sciences at Yale Medical School. His PhD is
in anatomy from the University of Pennsylvania Medical School. As an OST
staff fellow, he will continue to research synaptic interactions of
retinal cells. His review work with ODE will be in the area of retinal
prosthetic devices that are reviewed in the Vitreoretinal and
Extraocular Devices Branch of DOED. Dr. Cohen.

And the final two are from ENT. The first is Dr. Nandkumar, who is an
electrical engineer with an MS in EE from Tulane University receiving
his PhD from Duke in Electrical Engineering. He is an authority on
acoustical issues and will be working in the ENT Branch and the final
individual is Dr. Antonio Periera, who is a Board certified
otolaryngologist, head and neck surgeon who was trained at the
University of Puerto Rico and subsequently came to work in private
practice in Washington, D.C.

He has been in the Center for Biologics since 1995 and where he had
assisted in formulating regulations for the human tissue program and we
pinched him from them and I must say we\'re delighted to have him join
our staff, although there may not \-- they probably will not be working
on ophthalmic issues, they might be if we have issues that relate to
their expertise.

So we welcome all seven new people and I hope you will all get a chance
to work with them and enjoy their company. Thank you.

DR. WEISS: Thank you. Donna?

MS. LOCHNER: In the spirit of keeping the panel apprised of PMAs that
have come before the panel previously, I\'d like to discuss two such
PMAs. First, P010059 is a PMA for the Morcher endocapsular tension ring
used for capsular bag stabilization in patients with pseudo exfoliation
syndrome or other situations of compromised zonulas.

This PMA was reviewed by the panel in January of 2002. The panel
recommended that the PMA was approvable with requests for essentially a
complete reanalysis of the clinical data to resolve discrepancies in the
PMA and to clarify information that was presented at the panel meeting.
We are in the final stages of review and we expect a decision in the
near future.

The second PMA is P030002 for the C&C Vision CrystalLens Accommodating
Intraocular Lens. This PMA was reviewed by the panel in May of 2003. The
panel recommended that the PMA was approvable with requests that the
patient satisfaction data be stratified by pupil size and that certain
labeling revisions be made. The panel recommended that the lens provides
accommodative amplitude of about one diopter. Again, we are in the final
stages of review and expect a decision in the near future. Thank you.

DR. WEISS: Thank you, Donna. I will ask the sponsor to come to the
podium. We are going to begin the presentation of PMA P030016. The
sponsor has one hour for their presentation. I would request that each
presenter speak into the microphone, initially identify yourself and
your relationship with the sponsor and any potential financial
conflicts.

DR. LAMIELLE: Good morning. My name is Helene Lamielle and I\'m Chief
Scientific Officer for STAAR Surgical. We are pleased to present you
today PMA P030016 for the Collamer Implantable Contact Lens for the
correction of myopia. Presenting on behalf of STAAR Surgical today will
be Dr. Steven Slade, from Houston, Texas, Dr. John Vukich, a medical
monitor from Madison, Wisconsin and Dr. Henry Edelhauser, Director of
Ophthalmic Research at Emory University an Director of Specular
Microscopy Reading Center.

Dr. Vukich has a financial interest in STAAR Surgical while Dr. Slade
and Edelhauser are paid consultants with no financial interest other
than compensation for their time. Dr. Donald Sanders will participate in
the discussions that follow our presentation. Dr. Sanders has a
financial interest in STAAR Surgical.

The STAAR Myopic Implantable Contact Lens is the subject of today\'s
panel meeting, is indicated for the correction of moderate to high
myopia between minus three to minus 20 diopters and is intended for
placement behind the iris in the posterior chamber of the phakic eye.
The design of the ICL is very similar to that of standard plate haptic
intraocular lenses used for cataract surgery. However, the ICL has been
designed with forward vault to minimize contact with the central
anterior capsule of the crystalline lens. The lens material is a
hydrophilic biocompatible polymer known as Collamer and has a history of
safe use in approved standard posterior chamber intraocular lenses.

Here is a photograph of the ICL in the vault of the crystalline lens.
The footplates are approximately 100 microns thick and are intended to
rest in the sulcus. At this time, I would like to introduce Dr. Steven
Slade, who will present the surgical procedure, study method for the PMA
clinical trial and effectiveness outcome.

DR. SLADE: Okay, thank you, Helene. Good morning. My name is Steven
Slade and I certainly appreciate the opportunity to present for you
today. I\'d like to begin my presentation by describing the procedure
used to implant the STAAR ICL. The ICL is shipped to the surgeon in a
sterile glass vial and hydrated in saline solution. The lens is removed
from the vial with forceps. The lens is then loaded by the surgeon into
a sterile disposal injector cartridge for insertion into the eye and
this injection system is just like the ones we commonly use for small
incision cataract surgery.

The injector is specifically designed to minimize surgical manipulation
associated with the ICL insertion. Iridotomies are performed up to two
weeks before the ICL surgery. The pupil is dilated and the entire
surgery is performed under topical anesthesia. Viscoelastic is placed in
the anterior chamber. The lens is injected through a spornia (ph)
cataract-style incision.

Now, the surgery is completed then by positioning the lens haptics
beneath the iris and rinsing out the Viscoelastic. The lens centers
extremely well and no sutures were necessary in virtually all cases. The
STAAR ICL is specifically designed to vault over the anterior capsule of
the human crystalline lens. This vault should be approximately 500
microns or one corneal thickness. This shine through (ph) photograph
demonstrates an average vault with the STAAR ICL.

The clinical study of the STAAR ICL described in this PMA was a
prospective multi-center clinical trial designed to evaluate the safety
and effectiveness of this lens for the correction of moderate to high
myopia. Patients with myopia of minus three to minus 20 were enrolled
and followed for three years. The study was originally planned for a
two-year follow-up under the IDE which was approved in 1995.

During the study, follow up was extended to three years at the FDA\'s
recommendation to be consistent with more recent guidance for studies of
phakic refractive intraocular lenses. Our patients were required to be
between 21 and 45 years of age and of note, their best corrected vision
pre-optively could be as poor as 2100, and they were allowed to enroll
with as much as two and a half diopters of refractive cylinder, since
moderate to high myopia is associated with lower levels of best
corrected visual acuity, and higher amounts of cylinder. Our effective
parameters included a decrease in refractive myopia, improvement in
uncorrected visual acuity, predictability of the refractive outcomes,
refractive stability and patient satisfaction.

Safety parameters included a preservation of best corrected visual
acuity. Slit lamp findings, intraocular pressure, contrast sensitivity
with and without glare, reports of complications in adverse events.
Specular microscopy was also performed and we\'ll present the results in
detail of those studies. Accountability; 539 eyes of 305 patients were
implanted with the ICL. Thirteen eyes of 11 subjects did not meet the
entry criteria and were excluded from the safety and effectiveness
cohort.

This accountability was well within FDA guidance of no more than 10
percent loss per year of follow up. Even though the study was originally
planned for only two years of follow up, accountability at three years
was 77.2 percent, exceeding the target of 70 percent identified in the
FDA\'s draft guidance for refractive implants. Again, even though the
FDA guidance requires a minimum of 80 percent accountability at two
years, we had follow up on 91 percent of our cohort and at three years,
we were well above the minimum follow up of 70 percent of patients.

The demographics of the study population were fairly unremarkable but it
is worth noting that the average mean myopia preoperatively in this
population was over 10 diopters, minus 10.1 diopters. Now, I\'d like to
show you uncorrected visual acuity for the entire study cohort and then
uncorrected visual acuity for the eyes that had the potential
preoptively to achieve 20/20 uncorrected vision as well as then the eyes
that had the potential and were actually able to be targeted to
emmetropia or 20/20.

Because we enroll patients with up to 20 diopters of myopia, not all
eyes had the potential for 20/20 nor were all eyes able to be targeted
to emmetropia. In part, this was the result of limits on the range of
lens powers available during this study. If we look at the entire cohort
of study patients, the uncorrected visual acuity over time 20/40 or
better, excellent uncorrected distance visual was achieved rapidly, 80
percent at one week, 20/40 or better and had excellent stability, 81
percent 20/40 or better uncorrected at the three-year visit.

Again, looking at the entire study cohort, but at the 20/20 level, we
see again, a rapid improvement in uncorrected acuity and excellent
stability. It should be noted that the total cohort of eyes, this slide,
includes those eyes that were not able to be targeted for emmetropia,
eyes with preoperative best spectacle corrected visual acuity worse than
20/20 and eyes that had up two and a half diopters of refractive
cylinder.

Here\'s the breakout for uncorrected visual acuity for the entire study
cohort at three years showing the 20/20, 20/25, 20/30 and 20/40 levels.
Now, if you take that same format, I\'d like to show you the results for
eyes that had the potential for 20/20 uncorrected vision. In this group,
89 percent, of 250, 89 percent reached 20/40 or better at the three-year
visit and 52 percent were 20/20 or better, the eyes that had the
potential preoperatively to reach 20/20, and the results get even better
if we look at the patients who had both the potential to achieve 20/20
and were able to be targeted to emmetropia. In this population, good
visual potential, 59 percent were 20/20 or better at the three-year
visit and 95 percent were 20/40 or better uncorrected at their
three-year visit. If we take the population and stratify it by
preoperative myopia as in this slide, with less than 7, 7 to 10, 10 to
15 and over 15, it\'s apparent that the uncorrected visual acuity of
20/40 or better and of 20/20 or better was achieved by a lower portion
of the eyes with preoperative myopia greater than minus 15.

It\'s not unexpected given that the majority of these eyes could not be
targeted for emmetropia and the lens powers were not available to allow
for full correction of all eyes in this group. Further, in this group of
the highest myopes, only four eyes had best corrected visual acuity of
20/20 or better preoperatively. In fact, if we look at the patients
again stratified by myopia, who had the potential for 20/20 and were
targets of emmetropia, we see excellent results at both the 20/40 and
the 20/20 levels of uncorrected vision.

But indeed, none of the patients who were in the over 15 group actually
even had the potential for 20/20 at the same time they were able to be
targeted to emmetropia. We\'ll have more to say about this group of
higher myopes, over 15, later in the presentation since it certainly is
a unique population.

From a patient\'s perspective, this efficacy ratio slide comparing the
post-operative uncorrected visual acuity to the preoperative best
corrected visual acuity may be the most important data in this part of
our presentation, since this is what patients are seeking, uncorrected
vision, better than or equal to what they were able to see before
surgery with their best spectacle correction. The efficacy ratio for the
ICL was excellent with upwards of 60 percent of patients seeing as well
or better after surgery with nothing, no correction, than they were able
to see before surgery with their very best spectacle correction.

We examined the standard metrics of predictability of refractive outcome
as well as refractive stability. As indicated on this slide, our
achieved levels of plus or minus a half and plus or minus one attempted
versus achieved, were excellent and did exceed FDA targets for both
phakic IOLs and refractive lasers were greater than minus seven diopters
of myopia. Accuracy of the attempted refractive change was excellent in
eyes of pre-operative myopia looking at the cohort stratified by myopia
up to minus 15 and then did, indeed, decrease for the myopes with a
baseline myopia greater than 15 as you can see in this slide, again,
three years looked at the entire cohort stratified by myopia.

This slide pretty much speaks for itself. This is our stability slide.
The achieved refractive change was again, both rapid, one week, and
sustainable throughout the follow up minus a half, minus a half at 36
months. These outcomes do exceed FDA guidance for stability of manifest
spherical equivalent refraction.

A patient survey was administered to all study subjects and I will share
the three-year results of that survey with you. Ninety-nine percent of
our patients reported very extremely or moderately satisfied. When asked
to rate their quality of vision, 77 percent reported very good or
excellent quality of vision as compared to 55 percent of patients before
the surgery. Indeed, 97 percent of the study patients expressed a
willingness to have the ICL surgery again. The unwilling included eyes
with refractive errors, hyperopia (ph), myopia, vomiting right after
surgery, and one patient who questioned why repeat the surgery when they
had already had the surgery and were doing fine.

To summarize, our uncorrected distance visual acuity at three years all
eyes in the yellow was excellent. Eighty-one percent of the entire
cohort achieved 20/40 or better and 95 percent of the entire cohort
stratified now for those people that had the potential to see 20/20 and
were able to be targeted for 20/20, 95 \-- that group, 95 percent of
those patients achieved 20/40 or better uncorrected visual acuity.

Predictability of refractive outcome was also excellent, exceeding FDA
targets with a significantly \-- a very small amount of patients winding
up over-corrected or under-corrected, particularly in view of the very
broad range of high to moderate myopia treated and this does, again,
exceed FDA targets.

And now I would like to introduce Dr. John Vukich, who was the medical
monitor for the ICL clinical trial. Dr. Vukich will present safety
outcomes and he\'ll be followed by Dr. Henry Edelhauser who will discuss
the specular microscopy outcomes for the ICL study. Thank you.

DR. VUKICH: Good morning. My name is Dr. John Vukich and I am the
medical monitor of the STAAR Surgical Implantable Contact Lens Clinical
Trials. I have a financial interest in STARR Surgical. I will be
presenting the safety outcomes for the study cohort.

Key safety parameters that were analyzed and will be presented include
preservation of best spectacle corrected acuity, complications and
adverse events, lens opacities, inflammation, patient symptoms, contrast
sensitivity and endothelial cell analysis. There was a rapid and
sustained return of best spectacle corrected visual acuity in the study
population beginning at one week and continuing through every follow up
interval through the three-year period. At every follow up visit the
proportion of eyes with 20/40 best corrected acuity was improved over
the baseline preoperative level of 97 percent. When we break out the
best spectacle corrected acuity at three years, the improvement
experienced by the study population is even more notable particularly
with regard to the improvement in spectacle correction of 20/20 and
20/25.

Thus, these patients have the potential to benefit not only with regards
to uncorrected acuity, but also in terms of best spectacle corrected
acuity. This study population is quite different from other populations
that have undergone refractive surgery evaluations in that only 69
percent of the preop cohort could be corrected to 20/20 or better. We
believe this is a unique feature of this cohort and reflects the high
level of myopia and the unique challenges these patients face.

When we stratify postoperative best corrected acuity by baseline myopia,
at every level of myopia, the ICL cohort experienced an improvement in
best corrected acuity at 20/20 or better as compared to baseline. The
highest myopes, those with preoperative myopia greater than 15 diopters,
also experienced a substantial improvement at the 20/40 level. The most
dramatic increase was observed in those patients with the highest level
of myopia. While we acknowledge the contribution of magnification in
this group of very highly myopic patients, the visual results are real
and are enjoyed by the patients.

When we look at the changes in lines of best spectacle corrected acuity,
49 percent of eyes gained one or more lines of acuity at three years.
This contrasts with only eight percent of eyes that lost one or more
lines of best corrected acuity. Complications and adverse events are an
important aspect of the evaluation of the ICL and we examined this from
several perspectives. Perioperative complications were reported for 17
eyes, the most common of which was removal and reinsertion on the day of
surgery.

A small number of other perioperative complications was also reported
and these included reformation of the anterior chamber, a peripheral
iridectomy and repair of iris prolapse. Postoperative complications
other than intraocular pressure rises, lens opacities or secondary
surgical procedures were reported in five of the 526 eyes in the study
cohort for an incidence of less than one percent. Since there were so
few of these cases in this category, I think it is useful to describe
each of these individually.

One eye experienced a macular hemorrhage at one week and this result
without sequelae. An asymptomatic subretinal hemorrhage was observed as
an incidental finding at the three-month visit and best corrected visual
acuity remained unchanged from baseline in this eye. Three retinal
detachments were reported during the three years of follow up in this
ICL clinical trial. One eye had a retinal detachment with a macula off.
This required repair with silicon oil and a subsequent nuclear
pacification was noted with loss of best corrected acuity to count
fingers. This patient represents the only case in the study cohort with
irreversible loss of acuity to worse than 20/40. This patient had 16
diopters of myopia preoperatively.

Two other retinal detachments were reported during the course of the
clinical trial. Both cases were successfully repaired such that the
final best corrected visual acuity remained within one line of the
preoperative spectacle correction. Based on published reports, and
incidents of retinal detachment of .68 percent per year might have been
anticipated and we might have anticipated as many as nine retinal
detachments in this study cohort that is following 526 eyes over three
years. That fact that we had only three retinal detachments in this
study suggests that the ICL had limited or no impact on the incidents of
this adverse event.

Intraocular pressure rises occurred in 20 eyes or 3.8 percent of the
study cohort. The majority of the acture pressure rises occurred during
the first one to two days after surgery. Preoperative iridotomies were
performed on all study eyes as a routine part of the ICL surgery.
Seventeen eyes required additional YAG iridotomy or enlargement of an
existing iridotomy for control of intraocular pressure. Irrigation of
the anterior chamber for removal of retain viscoelastic was performed in
three eyes. Late intraocular pressure rises occurred in five eyes or
less than one percent of the cohort. This was defined as a single
reading intraocular pressure of 25 millimeters or greater or an increase
over baseline of 10 millimeters of mercury at three months or later.

In three of these eyes the intraocular pressures are being monitored
without intervention and the most recent pressures are shown on this
slide. Two eyes are currently being treated with a topical beta blocker.
The most recent intraocular pressure for these patients are 20
millimeters of mercury or less. Secondary surgical procedures were
performed in three percent of the study cohort. The most common
procedure was removal and replacement as a result of sizing issues.

Repositioning was performed in four study eyes. One ICL was replaced for
a power miscalculation. In the entire study cohort only three eyes
underwent ICL removal and cataract extraction representing .6 percent of
the entire study population. This summary slide shows all of the
secondary ICL surgeries. I\'d like to point out that only a single eye
lost best corrected acuity and this loss was only one line occurring in
one eye that underwent and ICL repositioning. It is particularly
noteworthy that those patients who underwent cataract extraction
maintained their best spectacle corrected acuity relative to their
preoperative level prior to insertion of the ICL.

Assessment of the crystalline lens was an area of significant concern
and this was monitored carefully throughout the course of the study.
Nuclear opacities were observed in five eyes of three patients. In a
patient who was previously described, a nuclear opacification occurred
following retinal detachment which was repaired with silicon oil. Both
eyes of two patients developed simultaneous bilateral nuclear opacities
between two and three years postoperatively and one of these four eyes
required cataract extraction. Once again, it should be noted that all of
these eyes were very highly myopic ranging from minus 14 to minus 17
diopters.

Lens clarity was graded at all patient visits using the LOCS 3 Scale.
This scale ranges from zero to 5.9 and under this system a Grade 1 was
best described as a trace opacity. Given here is the photographic
standard for Grade 1. I\'d like you to keep this photograph in mind
since over half of the anterior subcapsular opacities we are going to
describe were no greater than this clinical standard. In fact only one
eye in the study had an anterior subcapsular change at Grade 2 or
higher.

Anterior subcapsular opacities were observed in 14 eyes of 13 patients.
It is important to note that 12 of these 14 cases were asymptomatic and
visually insignificant at the most recent follow up visit. We believe
that many of these cases were surgically related and this is supported
by the fact that 11 of these cases occurred within the first six months
of surgery.

Clinically significant anterior subcapsular opacities were observed in
only two eyes. These were defined as LOCS score of less than \-- greater
than .5 with a loss of two or more lines of best spectacle corrected
acuity or an increase in glare or a opacity requiring ICL removal with
cataract extraction. One of these cases was a surgical mishap in which a
preservative containing topical miotic was inadvertently injected into
the anterior chamber.

The second case was an eye in which an opacity was observed six months
postoperatively. Cataract surgery was performed and post-cataract best
corrected acuity was unchanged from the pre-ICL baseline. To summarize
our findings on lens opacities, only three cataract extractions were
performed in the study population of 526 eyes.

One was related to the inadvertent injection of a topical preserve
miotic into the eye. One was a nuclear cataract and the third case was
an anterior subcapsular opacity that did progress to the level of
clinical significance. Best corrected visual acuity was unchanged or
improved following cataract extraction in all three eyes compared to
pre-UCL treatment. Safety may be best summarized in eye \-- by examining
the eyes with persistent loss of best corrected acuity of two or more
lines. There are only five of these eyes and you have seen all of these
cases previously in our presentation on safety.

Here is the retinal detachment repaired with silicone oil and the eye
irrigated intracamerally with preserve miotic agent. Additionally, three
of the nuclear opacities had a persistent loss of two or more lines of
best corrected acuity. One of these we\'ve just described had cataract
extraction. In the entire clinical trial, these are the only eyes that
had a persistent loss of two lines or more of best corrected acuity.

Next I would like to present our findings related to inflammation. Slit
lamp examination was performed in all study eyes at all visits and a
laser cell-flare meter was used to evaluate information in a sub-study
of patients. No inflammatory response was observed after the first week
postoperatively either clinically or by the more sensitive laser
cell-flare meter. Laser flare measurements following ICL implantation
were within the normal range for the first post-operative week, and
remained normal throughout the course of the entire clinical trial.

A subjective questionnaire was administered to all study patients
preoperatively and at follow up examinations. Patients were asked to
rate each of the symptoms listed on this slide as either absent, mild,
moderate, marked or severe. When comparing preoperative responses to
those attained at three years, there were no significant changes in
symptoms rated as absent or mild.

Equally importantly is the fact that there were no significant changes
from baseline to three years in symptoms rated as moderate, marked or
severe. Contrast sensitivity and glare were evaluated in a sub-group
study. Well established techniques were used in our contrast sensitivity
testing. After 10 minutes of dark adaptation, measurements were made
both with and without a glare source. There was no loss of contrast
sensitivity at any spacial frequency when compared to baseline to
postoperative results. In fact, at two frequencies there was a
significant increase in log units of contrast sensitivity. When contrast
sensitivity was repeated in the presence of a glare source, there was a
significant improvement at all four spacial frequencies starting at
three cycles per degree up to 18 cycles per degree.

I would now like to introduce Dr. Henry Edelhauser who will be
presenting the Specular Microscopy Substudy.

DR. EDELHAUSER: Thank you, John. Good morning. I\'m Dr. Henry
Edelhauser, Director of ophthalmic research at Emory University. I have
no financial interest in STAAR Surgical. I serve as Director of the
Specular Microscopy Reading Center for the ICL clinical trial and will
be presenting the results of a sub-study conducted by STAAR Surgical to
evaluate the effects of the ICL implantation on the corneal endothelium.
I would like to emphasize the importance of the methods used at the
Specular Microscopy Reading Center. Images were received from 12
investigators at nine clinical sites and a signal masked reader analyzed
all the images. The images were then scanned and analyzed with the Konan
KSS-300 Software. Approximately 1300 images were analyzed in this study
and the mean number of cells per image that was counted was 93. This
slide shows how the images were handled and that the images were taken
with a Konan. They were then sent to us in the reading center as hard
copy. We then scanned them. We then resized them and formatted the
images. We then calibrated and analyzed, put it in a spreadsheet and
then sent the data back for statistical analysis at STARR.

I think it\'s important when we talk about specular microscopy to review
what a good image is because not all specular microscope and reading
centers and photographers are able to take good images and this is the
real challenge in undertaking specular microscopy. One, it\'s important
to have distinct cells as illustrated on the right. In the specular
micrograph one can identify 100 cells and even more in that\'s
essentially what we do at the reading center is to identify as many
cells as possible because when you analyze this, it\'s done by putting a
dot in each one of the cells and then the analysis software is the
nearest neighbor analysis. So cells in the periphery that don\'t have a
nearest neighbor are not counted.

Cells need to be grouped into form in a contiguous area and then after
you have dotted all the cells, it\'s extremely important that the
evaluator or the reader check to see that the cells haven\'t been
double-dotted or cells missing because if you miss three cells, you have
a significant change in the end of field cell density because what you
see from this specular micrograph is multiplied by 10^6^. Precision of
the readings is an important factor in the analysis of any endothelium.
We have estimated that the precision to be two percent in the ideal
situation which was published in our study of LASIK patients. In this
particular case we had one single clinical site, photographer and one
single reader. When you undertake multi-center study where you have
numerous photographers and then you then send this to a reading center
and one single reader, the precision is somewhere between eight to 10
percent.

The outcomes of our analysis of the corneal endothelium are shown in
this slide and include endothelial cell density, percent hexagonality,
or pleomorphism and coefficient of variation or polymegathism. Studies
indicate that stress corneas present \-- have a percent hexagonality of
less than 45 and a coefficient of variation greater than 45.

Published studies and studies from my own laboratory have shown that
morphology is the best indicator of corneal endothelial stress and
instability. I would now like to share with you some examples where
endothelial morphology has been demonstrated to be the most sensitive
measure of corneal endothelium stability. These examples are
pseudophakic bullous, diabetes, and contact lens wear.

In this seminal paper, published by Rao and Aquavella in 1984, they
studied patients implanted with iris fixated lenses in patients whose
corneas made clear shown in the yellow bars, were compared to patients
who ultimately developed corneal edema in the blue bars. Interesting,
these authors found no difference between the two groups with regard to
percent endothelial cell loss. However, there was a marked difference in
coefficient of variation indicating that morphology is a more sensitive
indicator for the development of bullous keratopathy.

In the second illustration, the corneal endothelium is illustrated in
diabetes and this was published from one of our papers in 1984 where we
reviewed the endothelium of both Type 1 and Type 2 diabetics. In this
study we showed there was no significant difference in endothelial cell
density but there was a significant difference \-- decrease in percent
hexagonality and a significant increase in coefficient of variation.

The next example that shows the importance of morphology is related to
endothelial cell density is provided in a study by McRae and Matsuda, et
al, and they compared patients who used contact lenses for more than 20
years and compared to age-match controls. Again there was no significant
difference in endothelial cell density, a significant decrease in
hexagonality and a significant increase in the coefficient of variation.

The three examples I\'ve shown demonstrate the corneal endothelial
morphometric changes are the first indicators of endothelial stress. The
percent hexagonality and coefficient of variation are more sensitive
indicators of endothelial stability than endothelial cell density.

I would now like to review the ICL STAAR PMA data on endothelial
morphology. This graph is a scattergram of all pre and post-operative
data points. In general, the majority of the points were between 2,000
and 3,000 cells per millimeter square with a small number our outlyers.
The dark bars in the center of the scattergram illustrate the mean plus
or minus 90 percent of the confidence interval. This slide shows a
similar scattergram but with data points for a consistent cohort of 37
eyes with specular microscopic data in all visits from preop to four
years.

This slide does show that the endothelial cell density remains unchanged
from three to four years.

DR. GRIMMETT: Do you know the confidence intervals at the last visit?

DR. EDELHAUSER: Yes, I have it. It\'s coming up in the next slide.

DR. GRIMMETT: Thank you.

DR. EDELHAUSER: The table shows the pair-wide comparison of endothelial
cell density at consecutive intervals beginning with the preop to three
months a minus .2 was measured and cell loss was observed and from three
months to one year a minus .9 percent observed. Between three and four
years, a plus .1 percent and a narrow confidence limits of 1.4 percent
to plus 1.6 percent. The percent hexagonality data shows no change over
the course of study in this cohort of patients.

For comparative purposes, a percent hexagonality of 45 would be an
indication of a stressed corneal endothelium. The coefficient of
variation data also shows no increase over the course of study of this
cohort. Again, for comparative purposes, a coefficient of variation of
45 would be an indication of a stressed corneal endothelium. In summary,
the specular microscopic data show a cumulative or a total mean
endothelial cell loss of 8.4 percent to 9.7 percent over a course of
four-year follow up with stabilization suggested at the four years. It
should be noted that there is no apparent mechanism for chronic cell
loss due to the ICL. This is supported by the absence of changes in the
percent hexagonality and coefficient of variation, which do not indicate
chronic endothelial cell stress in this study population. This
conclusion is supported by the previous reported data on pseudophakic
loss, diabetics and contact lens wear.

We don\'t have a long-term study of endothelium in high myopes in the
peer review literature. But we know that extrapolating endothelial cell
densities over time is complex. It should be noted that the endothelium
is not a homogenous population of cells from central to peripheral and
migration of endothelial cells must be considered in any long term
modeling of the endothelial cell density.

Recent data published from my laboratory in March of this year in the
AJO, addressed the issue of peripheral corneal endothelial cells. In
this study we found that if, indeed, you measure the corneal endothelium
here and then you go two millimeters off in the paracentral region,
there\'s a five percent increase in the corneal endothelium. And if you
go four millimeters off center, there is a 10 percent increase in
endothelial cell density.

Now, let\'s put this into perspective with this. The cell density within
a four millimeter button is roughly 34,740. The paracentral region has a
cell density of 119,845. And four millimeters off center in this area
where we have a high cell density, the cell density is calculated out to
be 264,632 cells per millimeter square. Now, this is not a study that
doesn\'t have backup because it had first been identified by Bert
Chimifane (ph) in 1984 and subsequently two papers in the German
literature in \`89 and \`90, all showing an increase in the peripheral
corneal endothelium. I do want to say that in this study we measured the
corneal endothelial cells in four different ways; non-contact specular
microscopy, contact specular microscopy, alizarin red staining of
corneas we received from the eye bank, and also fixed corneas where we
developed the nomogram to correlate with the pathologist the number of
corneal endothelial cells as measured by the nuclei in high power field
correlated to a nomogram of endothelial cell density.

The higher the endothelial cell density found in the paracentral and
peripheral cornea affords an additional reassurance of safety for the
endothelium in the patients implanted with the ICL. In summary,
stability appears to be achieved between three years and four years in
the ICL population. This data \-- these data are consistent with
endothelial remodeling and stabilization. The absence of any effect on
the percent hexagonality, coefficient of variation support the absence
of stress on the corneal endothelium. This would be consistent with an
implant placed behind the iris and suggests that the endothelial cell
loss observed in the ICL clinical trial is related to the initial
surgical procedure and not a chronic phenomena.

Ongoing surveillance of the corneal endothelium will be critical to
establishing the continual safety of the ICL and the study sponsor is
committed to collecting the additional four-year follow up patients.
Patients will also be asked to return for five-year specular microscopic
exams and the same rigor and precision will be used to evaluate that
corneal endothelium by the reading center. I would now like to turn the
podium over to Dr. John Vukich.

DR. VUKICH: Once again, I am Dr. John Vukich. A unique group in our
clinical trials represented by the patients with more than 15 diopters
of myopia. This group deserves special attention since concerns have
been expressed by both the FDA and panel reviewers regarding
acceptability of study outcomes in this population. I think we all
understand the unique challenges represented by this group of extremely
myopic patients. These include significant variability in simply
determining the end point of the manifest refraction. Many of these
patients have poor visual acuity even with their best spectacle
corrected acuity. In spite of this, the mean post-operative spherical
equivalent was reduced from minus 17.3 diopters to minus 2.2 diopters
with the implantable contact lens for an average correction of 88
percent of the pre-existing myopia. At the time of the ICL clinical
trial, lens powers were not available to achieve full correction to
emmetropia in all cases. Even with this limitation, 39 percent of eyes
with greater than 15 diopters of myopia achieved an uncorrected acuity
of 20/40 or better.

Substantial improvement was observed in the proportion of eyes with best
corrected acuity of 20/40 or better. The proportion of eyes with best
corrected acuity of 20/20 or better increased from 13 percent at
baseline to 42 percent at three years. We acknowledge that magnification
contributes to the observed improvement in best corrected acuity but
continue to believe that this improvement in best corrected vision is an
important benefit to the patient.

Any analysis of complications and adverse events in this population of
high myopes must be viewed relative to their baseline risk. A body of
published literature has established that the risk of spontaneous
complications such as retinal detachment and nuclear opacities is
significantly increased in high myopes. For example, the risk of
detachment of the retina is 26 times higher in myopes above minus 6
diopters. A significantly increased risk has also been established for
the incidents of nuclear opacities in highly myoptic patients. These
complications must be viewed in the context of the increased risk of the
population. Given the additional risk it should not be surprising that a
higher rate of complications was observed in the subset of highly myopic
patients.

Review of these complications which have already been presented as part
of the safety data for the total study population revealed that two
retinal detachments and four nuclear opacities were observed in six
eyes. Only the eye with complicated detachment requiring silicone oil
has had an irreversible loss of vision. In fact, this is the only eye in
the entire clinical trial in this category.

With the exception of the eye with retinal detachment requiring silicone
oil, all of these patients were satisfied with the outcome of ICL
implantation and would be willing to undergo surgery again. We have
shown that these patients had a substantial improvement uncorrected
visual acuity and over half of these eyes experienced a gain in best
corrected acuity. We believe that these are the very patients that stand
to gain the most from implantation of an ICL particularly in the absence
of alternative devices or surgeries for the correction or reduction of
their myopia.

In summary, the data presented to you on the outcomes in this PMA serve
to establish the safety and effectiveness of the myopic ICL for its
intended use in myopia from minus 3 to minus 20 diopters. We believe
that the concerns raised by the FDA and panel reviewers can and should
be addressed. To this end, we are committed to long-term surveillance of
the study population with regard to endothelial cell analysis. We also
believe that a comprehensive training program is an essential part of
achieving successful outcomes with the ICL and plan to require formal
training and certification for all surgeons who use this device.

Finally, we believe that labeling can be developed to adequately
communicate the risks as well as the benefits of the ICL and we welcome
labeling recommendations from both FDA and panel. This will allow
surgeons and patients to make informed decisions on the use of the ICL
and the appropriateness of this device for each individual patient. We
believe that the data presented to you today and the safeguards we are
proposing in terms of long-term patient surveillance, surgeon training
and adequate labeling support a panel recommendation for approval of the
ICL as an important option in the management of myopia. Thank you and
this concludes the formal presentation by the sponsor.

DR. WEISS: I\'d like to thank the sponsor for their presentation and if
they\'d remain at the podium, we will begin for questions from the panel
to sponsor on their presentation. Dr. Macsai?

DR. MACSAI: My question is directed at Dr. Edelhauser. The slide you
showed of the 37 patients, the standard cohort of endothelial cells
changing, on the next slide you said you would address the coefficient
variation confidence intervals and that slide was not for that 37
patient cohort. This is new information and I think that data would help
us figure out more information about the endothelial cells.

DR. EDELHAUSER: Yes, I\'d like to turn this \-- this was data that came
back to us.

DR. WEISS: Please, would you be able to identify yourself each time you
speak in the mike for the transcription.

DR. EDELHAUSER: I\'m Dr. Edelhauser. This data came from Dr. Gray, the
statistician from the FDA when he sent his review back to STAAR where he
then broke out and calculated this cohort of patients from the start or
the pre-op all the way to four years.

DR. MACSAI: But what is the \-- this is Dr. Macsai.

DR. SANDERS: Dr. Gray did not include that in \--

DR. WEISS: Please identify yourself.

DR. SANDERS: Dr. Sanders. We used the analysis that Dr. Gray provided us
on the Internet and it did not include the confidence intervals.

DR. MACSAI: Dr. Macsai speaking. But does STAAR have the same patients
followed from pre-op all the way through to four years, those 37
patients? Do you have that information, can you provide that information
to us?

DR. VUKICH: We do have those patients and again, this is an analysis \--
I\'m sorry, Dr. John Vukich. We do have that analysis available and can
provide that to the panel.

DR. MACSAI: Thank you.

DR. WEISS: Dr. Grimmett?

DR. GRIMMETT: Sure, Dr. Michael Grimmett. I have a number of questions
as you can well imagine. The first one to Dr. Edelhauser; I really
appreciated your review of the endothelial morphology data and I would
just like to ask you regarding that data of endothelial stress, has it
ever been stratisfied (sic) by corneal age, that is do younger corneas
have a blunted endothelial morphometric alteration as compared to old
corneas with less endothelial cushion or reserve?

DR. EDELHAUSER: Dr. Edelhauser. The best data stratification that I can
think of to answer the question is the data that we published in \`84 on
the diabetic corneas. In there we broke it down in terms of decades. And
indeed, if you look at the bar graph that is published in that paper,
you will find that there is \-- as one ages, there is both a progressive
decreased in percent hexagonality and an increase in coefficient of
variation, so they \-- as the cornea does age, you know, you see these
changes and that\'s in a diabetic population, you know, compared to
controls.

DR. GRIMMETT: Okay, Dr. Grimmett again. Then can you infer that a
younger cornea, because if its higher reserve, higher cushion, will have
a blunted response in terms of hexagonality and coefficient of
variation?

DR. EDELHAUSER: Yes, I think you can. I think the corneal endothelial
cells are certainly more robust in a younger population and I certainly
have seen this in laboratory studies where for example, if calcium free
solution is placed on a corneal endothelium and you break the
endothelial junctions, the \-- in an older cornea, you know, about 40 or
so, those junctions won\'t come back in an in vitro situation but they
certainly will with younger tissue.

DR. GRIMMETT: Okay. Dr. Grimmett again, just as a reminder, this study
ranged to age 21 or so up to 45 and an average age in the 30s I believe.
So from the discussion we\'ve just had, this particular cohort may not
show as much change in morphometric parameters as a 60, 70-year old
cornea, something like that.

DR. EDELHAUSER: Dr. Edelhauser, that\'s true.

DR. WEISS: I just had a follow-up question as far as that goes. For a
patient who\'s destined to develop corneal edema from continued cell
loss, would you say 100 percent of the time they\'re going have the
first sign as a change in the percent hexagonality or coefficient of
variation? Is that always the first sign?

DR. EDELHAUSER: From our experience, yes, you see this and let me just
illustrate it in terms of patients who undergo cataract surgery for
example, the \-- when the percent hexagonality and the coefficient of
variation start to come back or the cells become more regular, the
chances of that cornea going onto a post-operative corneal edema are
very much less, so you do see that once stability is established, you do
have a normal functioning corneal endothelium

DR. WEISS: But just in relationship to Dr. Grimmett\'s point, in a
younger patient, it would be \-- those changes might be more subtle but
would they always be able to be picked up, do you think, as a first
sign?

DR. EDELHAUSER: They might, but don\'t forget, this would have to be
done with specular microscopy and when you are sampling the cornea, you
are taking central corneal endothelial cells in a very, very small
population, small area. I mean, you\'re roughly counting 100, 150 cells
and are looking at the endothelium of that out of a population say of
450,000 cells. So you may not pick it up and certainly our past studies
have shown that you do see changes in the superior region if you do
cataract surgery there. You\'ll pick that up in the peripheral area very
readily where you have damaged the endothelium.

DR. WEISS: So it\'s possible in a younger patient there might be a
subtle change in these \-- in the coefficient of variation of the
percent hexagonality which might not initially be picked up but then
later on as things developed got picked up and that could lead to
corneal edema.

DR. EDELHAUSER: Possibly, yeah, and I mean, it goes in hand in hand with
total cell analysis, too, because you know that corneal decompensation
is going to occur somewhere between 500 and 800 cells per millimeter
square.

DR. WEISS: Thank you. Dr. Sugar, Dr. Bandeen-Roche, Dr. Matoba and then
Dr. Mathers.

DR. SUGAR: Two things. One is a comment on what Dr. Edelhauser said and
what he said in his presentation. Certainly, you didn\'t measure the
peripheral corneal endothelial cell densities in any of these patients
and presumably the trauma was greatest in the periphery, so that it\'s
conceivable that the central measurements are a distant reflection of
what really counts. And I agree that the increased hexagonality and the
decreased coefficient of variation over time implies that the
endothelial cells in the center are doing better, but you don\'t \--
your reassurance from the data on the periphery is not specifically
appropo of this study because you didn\'t look at it, correct?

DR. EDELHAUSER: Yes.

DR. SUGAR: The other issue is, I guess for John Vukich. In terms of the
powers of the lenses \-- I assume we can ask about anything just stick
with endothelium.

DR. WEISS: Dr. Sugar, you can ask about anything you want.

DR. SUGAR: I\'ll limit myself.

DR. WEISS: And that applies to everyone else on the panel.

DR. SUGAR: Okay. When you started this study, did you know that the
powers of the lenses that you had were insufficient for totally
correcting the patient population that you were investigating? And is
\-- if that is so, is there an engineering reason or a reason why you
didn\'t have lenses of higher power to correct what you wanted to, that
is are there thickness limitations, optic size limitations that keep you
from having a higher power?

DR. VUKICH: At the time of the initiation of the study, we had
anticipated that we would be able to correct the full range. It became
clear that at the higher powers the effective power within the eye was
less than the engineering estimates and at that point. Due to
manufacturing limitations we found that we could only manufacture at
that time up to a minus 20 lens but the effective power within the eye
was approximately 16 to 16-1/2 diopters.

At this point those manufacturing limitations are not longer applicable
but, of course, that wasn\'t germane to this clinical trial.

DR. SUGAR: And one other, you said anything?

DR. WEISS: Yes.

DR. SUGAR: You talk about repositioning lenses and you talk about
sizing. Repositioning lenses was for haptics that went in front of the
iris, for lenses that propellered, what was that and the sizing, are you
talking about vaulting or are you talking about something that doesn\'t
go \-- that isn\'t sufficiently long to be stable or so long that it
causes iris pombe (ph) or some other problem?

DR. VUKICH: There were four eyes that underwent repositioning. Two of
these were for a haptic that was malpositioned, not anterior to the iris
but appeared to be folded without flap presentation. One of these was a
rotation or actually a decentration, a slight decentration that was
recentered without removal and then finally there was one eye that had
an edge and one side that captured the pupil in the perioperative area,
periopterative period that was readjusted.

DR. SUGAR: Did any lenses ever propeller? Were they ever small enough
that they rotated?

DR. VUKICH: No, we did not observe rotational changes in any of our
patients throughout the course of the trial.

DR. WEISS: Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Karen Bandeen-Roche, and I have a few questions about
the specular microscopy. First is a clarification question, so there
were 67 eyes followed to four years. As Dr. Grimmett pointed out, two
separate 57 patient cohorts preop to four year and three year to four
year, and so by my calculations that leads to 47 patients at baseline
three years and four years and then two 10-patient cohorts that missed
either baseline or three years.

And I just want to make sure, by my calculations, the \-- and you may
need to get somebody to check on this, the mean cell density in that 47
patient group was 2496, in the group that did not have the three-year
visit, 1779 and in the group that did not have the baseline visit 2269
or I guess rounding up to 2270. And so can someone check whether that\'s
correct or \--

DR. VUKICH: We will look into that and have an answer for you.

DR. BANDEEN-ROCHE: Okay, now, three quick other questions. First,
regarding the plot that Dr. Macsai asked for, what would also be very
useful would be to have a plot just like you showed for the 37 patient
cohort along with overlaid on the same plot, the patients who had
three-year data to just compare. Do you know if it\'s possible to show
the panel something like that?

DR. VUKICH: We do have that available and can give that to the panel as
well.

DR. BANDEEN-ROCHE: Okay. I\'m interested in how representative the
patients with four-year data are of the entire cohort. So that\'s part
of what the first two questions were getting at. Could you tell us the
number of investigators who contributed to the 67-patient cohort and
anything else that would help us about how representative they are
besides the anterior chamber depth which we already know about?

DR. VUKICH: These eyes were done as a sub-study and the number of
investigators that actually contributed again, I\'ll have to look up
that particular number for you. There were 12 sites that did participate
in the entire trial, however. Nine actually did the specular microscopy.

DR. BANDEEN-ROCHE: Right, and so the number who actually had four-year
data, that would be helpful.

DR. VUKICH: Four-year data and we\'ll get that information. I\'m sorry,
I don\'t have that with me.

DR. BANDEEN-ROCHE: Okay, thank you. And finally, I guess a question for
Dr. Edelhauser. Certainly an unlimited amount of cell loss would not be
benign. I mean, could you give me an idea for the degree of cell loss
that would be of concern and that would be expected to cause stress
independently of hexagonal cells or CV?

DR. EDELHAUSER: Well, if we go back and look at the literature, the data
that we have in the literature, for example, says that in a normal
population, not a high myopic population, the cell loss per year is .6
percent, and that seems to be consistent, say .6 to 1 percent per year,
which goes. The only other comparative data that I can think about as we
\-- and this is not really the best comparative data, is the data
published from Bill Bourne, and this is 10-year data that he has
published with various types of intraocular lenses. He\'s used three
different types of lenses. The only trouble with this is that his
average age population was 70 at that particular time and he used a
medallion iris suture lens. He used a trans-iridectomy clip lens and he
used a posterior chamber lens. He could show no difference in cell loss
in any one of those three and the cell loss ranged from 2.8, 2.6 and 2.9
percent. So that\'s kind of the upper level where we do know that if you
have that type of cell loss that you still have clear cornea in a
70-year old population.

DR. BANDEEN-ROCHE: Thank you.

DR. WEISS: Dr. Matoba?

DR. MATOBA: Alice Matoba. My question goes back to the age issue raised
by Dr. Grimmett. You enrolled patients, ages 21 to 45. Could you tell us
how you selected 45 as the cutoff point?

DR. VUKICH: That was the recommendation and guidance of the FDA for
enrollment and I believe this was primarily to look at issues of aging
as a compounding variable in the formation of lens opacities.

DR. MATOBA: And then in your labeling, I notice that the patient
information states that you must be 21 to 45 to receive this implant.
Does that mean that you intend to limit the use of the implant to
patients 45 years or younger?

DR. VUKICH: That is the only age range on which we have data to support
the safety of this product and would be consistent with our labeling.

DR. MATOBA: Okay, and then as the patient ages, what do you think
happens to the vaulting, amount of clearance that you have as the lens
becomes more nuclear sclerotic with age.

DR. VUKICH: Well, we do know that over time we can anticipate an
increase in the anterior, posterior dimension of the crystalline lens.
We do have information internationally with up to 10 years of experience
that suggests that there doesn\'t seem to be a significant change in the
vaulting characteristics which is somewhat counter-intuitive. We believe
that there is also an age related change in the ciliary sulcus diameter
as well. And so there may be several things going on at once that can
influence the characteristics that fit within the eye over time.

Nevertheless, we simply have to accept that as an unknowable piece of
information until those time periods have been observed in greater
quantities and greater patients have been observed.

DR. MATOBA: But you\'re saying the information you do have indicates
that the clearance doesn\'t change significantly over time.

DR. VUKICH: Throughout the course of our trial, which clearly is the
best controlled, we have no evidence but again, this is only three years
but at this point, we\'ve been carefully monitoring this internationally
where there has been longer data follow-up but at this point, we have
not seen that as a trend.

DR. WEISS: Dr. Mathers, Dr. Schein, Dr. McMahon and Dr. Grimmett.

DR. MATHERS: I have a question for Dr. Edelhauser. If the morphologic
change in the endothelium is so sensitive, why doesn\'t it show
something when we know that the endothelial cell count is actually
falling by these measurements?

DR. EDELHAUSER: Well, I think that you\'re dealing with essentially a
stable \-- Dr. Edelhauser \-- a stable endothelium and the way cells in
a normal population that you would see. For instance, we do know we lose
cells over a lifetime that if we say .6 to 1 percent. We don\'t see
marked changed there either because one, it\'s an apoptotic change that
usually occurs. You\'re losing a cell. The adjacent cell then slides
into then cover up the area and I think that what we\'re seeing here is
just a distribution over the whole surface of the cornea.

I can say that we \-- I have seen this and we\'ve published papers on
this where if you look at the regional areas of corneas. For example, in
cataract surgery, if you look superiorly, centrally and inferiorly, you
can see these changes markedly and don\'t forget, in this study, these
\-- as these were specular micrographs that were taken.

DR. MATHERS: Is your explanation inconsistent with the concept that you
could have progressive stable loss rate of one, two, three percent and
have a maintenance of a hexagonality as it would be, because the process
is essentially just an accelerated but similar to a normal loss rate.
It\'s just faster, so you\'d still maintain hexagonality.

DR. EDELHAUSER: You could. I mean, again, it\'s going to depend upon the
\-- you\'re expecting a change to occur over the total corneal
endothelium and that may not be the specific case that we\'re seeing.

DR. MATHERS: Do you think it would be helpful in understanding what\'s
happening to the endothelium to have images that incorporated more than
93 cells on a given patient? It seems to me that when you\'re looking at
the snapshot of the endothelium and as you pointed out, this is a very
small area that you\'re trying to extrapolate then to the entire cornea.
Did you only \-- for these readings, did you use the single image for
each patient time point or do you use five?

DR. EDELHAUSER: We use single image, single image and to answer your
question, yes, it would be but the only way that you can get large field
or wide field specular micrographs is either with contact specular
microscopy and there\'s no algorithm to go ahead and automatically
digitize that other than tracing cells and putting it into a computer,
or more recently, there is the possibility of using the confocal and
that\'s certainly a possibility. That gives you a wonderful wide field.

DR. MATHERS: You mentioned that you \-- with Bourne\'s study on
endothelium loss in iris fixed lenses, that sort of thing, that he found
a loss rate of 2.7 and it was consistent or that \-- and also a clear
cornea. You\'re not maintaining that a loss rate of 2.7 would be able to
sustain a clear cornea over a long period of time, I would think. I
mean, you\'re not suggesting that.

DR. EDELHAUSER: Well, if you make the assumption that there\'s not a
possibility of some mechanism to produce more corneal endothelial cells,
and I think recent evidence has been shown that ARVO \-- that we\'re
seeing is that there is the potential that the peripheral corneal
endothelial cells have adult stem cells there. This hasn\'t been
confirmed. There\'s leading indication that you can measure telomerase
activity out there which show \-- with telomerase activity you only find
in cancer cells and stem cells.

You can see that cells do stain with BrdU which is \-- and so I think
this is a world of research that is developing about the potential of
endothelial cells to be replenished.

DR. MATHERS: But there is a loss rate at which eventually you will run
out of endothelial cells, I\'m sure, you maintain.

DR. EDELHAUSER: Yes, uh-huh, right.

DR. MATHERS: Thank you.

DR. WEISS: Dr. Schein?

DR. SCHEIN: This is Oliver Schein. I\'m going to limit questions or
comments to the endothelial area at this time. I remember in 1995 when
the first data was presented to the panel on photo refractive
keratotectomy there was endothelial cell counts and morphology was
performed and the sponsor was pleased and amused to see a large and
statistically significant improvement in the morphology from pre-PRK to
two years.

And this was explained that the majority of individuals before PRK were
chronic contact lens users which effected not the cell count but the
morphology and the removal of the contact lens allowed the remodeling
that appeared favorable over time. Can you please give us some summary
of the contact lens wear in this patient population before the surgery
and perhaps speculate on how that might impact your estimates of
stabilization in the morphology.

DR. VUKICH: Let me lead off by saying that contact lens wear was common
in our patient population. However, we do not have an exact number of
contact lens wearers pre-operatively. That was not recorded as
pre-operative entry criteria other than they had to be out of their
lenses for six weeks prior to the entry exam. So we have to make the
assumption the majority were. We believe that to be true but we can\'t
give you the percent.

We do know that these patients actually showed stability not improvement
over time. And so that when we look at the morphometric analysis through
time, we did not see a worsening with improvement of a simpler stable
population.

DR. SCHEIN: But if you\'re presenting comparison of means, you can\'t
actually determine that. You have to look within subgroups to arrive at
such a conclusion. Across an entire population if there is an
improvement, that would balance worsening and appear as if there were
stabilization.

That gets at a second issue. If a majority of the population were
wearing contact lenses, that\'s the acuity that I\'d be most interested
in as a baseline comparison. It\'s kind of a habitual vision. It\'s the
vision the patient enters the trial with. The second issue related to
endothelial cell count that struck me was not so much the concern about
progressive cell loss but of absolute cell loss when you look at the
entire cohort. And again, if you simply present a mean, it doesn\'t get
at the safety issues that we\'re concerned with.

So I interpreted one table as showing that about a third, slightly more
than a third of individuals lost 10 percent or more of the central
endothelial cell count comparing baseline to three years. Tell me if
I\'ve done that correctly. And about 20 percent lost 15 percent or more.
Is that correct?

DR. EDELHAUSER: I\'d have to \-- Dr. Edelhauser. Don, you\'ll have to
\--

DR. SLADE: Steve Slade. While they\'re getting that, I might just
address, Oliver, your point about the contact lens being the habitual
vision, that\'s a good point. On the other hand, this was developed with
best spectical visual acuity as a target with FDA guidance and, of
course, as a standard for refractive surgery and if you look at the
patient\'s satisfaction rates, they were very high and if they were
comparing their post-operative vision to what they were used to in
contact lenses, and if that were markedly better and we had reduced
them, I don\'t think the satisfaction rates would have been quite so
high.

DR. SCHEIN: You\'ve got me now on digression which I wasn\'t going to
raise now. The satisfaction scale that you use appeared to only have
three options which doesn\'t give a lot of room a very strong ceiling
and floor effect with only three options for a response. And there are
at least two well validated, available, three kinds of visual function
questionnaires directed towards populations like this that I think could
be used to get more detail.

DR. WEISS: I would ask \-- I would have the sponsor just given the
advantage of not having to identify themselves any more because I\'m
told the transcriptist knows your voice. I would also ask the panel
members if we could limit our questions because now we\'re over. So if
we could just get to the cogent points quickly and give the sponsor the
ability to answer those. Are there any other questions you have Dr.
Schein?

DR. SCHEIN: I\'m just waiting for the \-- was I correct on the
endothelial cell count?

DR. SANDERS: Yeah, I believe you were correct on the numbers. I think
one has to remember that that was the cumulative \-- you were talking
the cumulative loss between pre-op to three years.

DR. SCHEIN: Correct.

DR. SANDERS: Yes. And again, I think we have to also keep in mind that
some of that \-- given that the counting variability is eight to 10
percent, that that enters into the equation, the numbers you did give us
are very similar to what we would calculate.

DR. WEISS: Dr. McMahon, Dr. Grimmett, Dr. Coleman, Dr. Ho, then Dr.
Macsai and Dr. McCulley.

DR. McMAHON: Dr. McMahon. This is a question for Dr. Vukich. I believe
two and a half percent of implanted lenses were implanted initially up
side down. And the majority of those, I believe occurred in the first 10
cases, though in Dr. Grimmett\'s review he pointed out that a number of
them occurred downstream. The question I have, is this an issue of
surgical training or is this an issue where the device needs to be more
clearly labeled as to which is right, left, to minimize those sorts of
things?

DR. VUKICH: There\'s clearly a learning curve in this, in that half of
these did occur early in the experience, within the first eight cases of
any individual surgeon. This technique is an important part of our
training program. We\'ve identified that if this lens is loaded properly
and carefully under the microscope in the cartridge, that we can
significantly minimize the risk of an uncontrolled entry into the
anterior chamber. And so I believe firmly that this is something that
can be controlled and in fact, in my personal experience of having put
90 of the lenses in at our site, not a single one went in up side down.
I\'m also in charge of the training to address this issue. So I think it
is something that clearly is a concern but we believe it\'s an issue
that isn\'t a matter of identifying the right side up. It\'s just a
matter of doing it properly in the first place.

DR. WEISS: Dr. Grimmett.

DR. GRIMMETT: Michael Grimmett. Dr. Slade mentioned that this study was
IDE-approved in 1995. What was the first date of the V4 lens
implantation? Quite a bit later?

DR. SLADE: All of the \-- Steve Slade. I believe all of this data was
before.

DR. GRIMMETT: Correct, \`89, \`99 something like that?

DR. SLADE: \`98.

DR. GRIMMETT: \`98, okay. Was gonioscopy performed on any patient in
this study?

DR. SLADE: Gonioscopy was performed on all patients preoperatively in
this study.

DR. GRIMMETT: Preop, okay. I didn\'t note it on the clinical study
report form or in the PMA materials. You have that somewhere then. We
just didn\'t see it; is that correct?

DR. VUKICH: Dr. Vukich. It was on the preoperative checklist for
inclusion in the study and gonioscopy was required for every patient as
an entry criteria.

DR. GRIMMETT: Okay, good, but just to confirm it was not performed
post-op on any patient.

DR. SLADE: It was not a required examination.

DR. GRIMMETT: Okay, was angle anatomy viewed with ultrasound in the
ultrasound sub-study?

DR. VUKICH: Yes, it was.

DR. GRIMMETT: It was, good. Was the data in the PMA somewhere?

DR. VUKICH: It was not.

DR. GRIMMETT: It was not, okay. Of the up side down lens insertions that
we just heard about from Dr. McMahon, were they related at all to using
the plunger versus the screw injector style, like 13 used plunger and 3
used the screw injector?

DR. VUKICH: We did look at that as a variable and we are unable to look
at any evidence that the screw \-- that the actual injection mechanism
itself was a factor. Again, we firmly believe that it was how the lens
was loaded in the cartridge as opposed to how it is pushed through the
cartridge.

DR. GRIMMETT: Okay.

DR. SLADE: It might be worthwhile \-- the lens, it\'s very apparent, the
lens because of the vault, because of the markings before you load is
which is right side and which is not. And the cartridge is the same
whether you use it with the screw type injector or the plunger.

DR. GRIMMETT: Okay, all right. Your materials indicate your
white-to-white measurements had an accuracy of a tenth of a millimeter.
My Castroviejo\'s calipers in the OR have an accuracy in one millimeter
increments. What calipers were you using to get .1?

DR. VUKICH: The same ones you are.

DR. GRIMMETT: Oh, okay.

DR. VUKICH: Calibrate them against the steel rule under a microscope.

DR. GRIMMETT: But they\'re only one millimeter increments. So any unit
underneath one millimeter is a shear guess; isn\'t that correct?

DR. VUKICH: There would be an estimate, yes, below that level, correct.

DR. GRIMMETT: Okay, I\'ve used them and, boy, when I want them at 3.3,
it\'s awful hard to set it at that. And I guess my last question I\'ll
make it, I\'ll just skip some of these, we\'ll get to it later, in your
materials you stated that your version 4 lens has an additional .13 to
.21 millimeters of vault compared to version 3. And I was just curious,
did you substantiate that by in vivo measurements or was this a design
parameter and you postulated it or how do you know that?

DR. VUKICH: It was a manufacturing and design parameter. This is an
engineering issue. External to the eye, this would be the vault that was
designed.

DR. GRIMMETT: Okay, thank you very much.

DR. WEISS: Dr. Coleman?

DR. COLEMAN: This is Dr. Coleman and I have a question about two of your
subjects developed glaucoma in this study and I was questioning how you
define glaucoma. Was that based on optic nerve changes or visual field
loss?

DR. VUKICH: Actually, two of our patients were treated with beta
blockers, neither of which showed optic nerve changes or visual field
changes. So I think they would be best categorized as ocular
hypertensive so there was not the diagnosis of visual field loss or
glaucoma as we would classically define it.

DR. COLEMAN: You might want to change that. In addition, you said that
you did do angle morphology via ultrasound but that\'s not available in
the PMA. Is that \--

DR. VUKICH: That angle was observed. There was a sub-study of forty
patients that were observed with a P40 unit, a Paradigm unit and we did
look at angle morphology. There is within the PMA a description,
pictures as well as a commentary of the results of that study.

DR. COLEMAN: Okay, and then in terms of post-operative gonioscopy was
not done, not even in the subjects who were diagnosed with glaucoma or
is that not available or \--

DR. VUKICH: That information was not a required part of the
post-operative follow up and I do not have that information as part of
the PMA.

DR. WEISS: Dr. Macsai?

DR. MACSAI: My questions are mostly to Dr. Edelhauser again. Sorry,
Hank.

DR. EDELHAUSER: No problem.

DR. MACSAI: When this lens is inserted, the most damage to the
endothelium should occur in the periphery. If the surgeon is following
the technique, they\'re not supposed to go anywhere near the central
cornea. It\'s defined as a no-touch zone. The manipulation of the
haptics is done way at the periphery and they\'re tucked under the iris
with a little lens manipulator, haptic manipulator device as Dr. Slade
showed us in his slide. So given that and the presentation you\'ve said
about how the peripheral endothelial cell counts is greater than the
central in your well-established published articles, and the fact that
we\'re talking about implanting this in 22-year old patients, I have
some level of confusion I\'m asking you to help me with.

In a guidance draft from a meeting in 10/02 accepted endothelial cell
loss rate was 1.5 percent, yet in an ANSI document that I think is also
a draft, it was set at two percent. So let me ask this question to you.
In your 22-year old child that is being implanted with this intraocular
lens because they are minus 13 and too thin for LASIK and contact lens
intolerant, what is an acceptable cell loss rate, not coefficient of
variation, so that when they are 82 they still have a functioning
endothelium?

What is the number? Is it .9? Is it .6? Is it 1.5? Is it 2?

DR. EDELHAUSER: Good question and it\'s hard to come up with a number
because the thing that I think would be ideal to answer that question
would be is that if we had a longitudinal study of high myopes and
looked and actually measured the cell loss, I think this would be very
important. Unfortunately, this is not in the literature. So the \-- what
you \-- in order to answer that question, you know, it has jumped around
between 1 to 2 percent as to where we stand with it. One can do all
kinds of mathematical calculations to see, you know, how many years
would the endothelial cells be depleted, half percent, one percent, two
percent, and this all assumes a linear decline which I don\'t think is
completely accurate at this particular stage based on the new
information.

So to answer your question, I don\'t know what the exact level would be
with this without some good longitudinal data to be able to make an
absolute judgment on. And I think one of the things that all of the
endothelial studies suffer from is that we don\'t have good
epidemiological data on various populations for the corneal endothelium
with regard to aging and various types of subsets like high myopia for
example.

DR. MACSAI: Well, given that lack of security and an absolute number,
you know, I\'m wary of creating another closed loop anterior chamber IOL
disaster that I think most of the cornea surgeons in this room
experienced. So what do you think \-- I mean, is there a problem with
vault and does that correlate with endothelial cell damage? We saw laser
flare meter data, not fluoroscopy data, and it looked good but I\'ve
posed to the sponsors and I continue to have this concern, vault is good
because cataracts are bad but does vault cause posterior chamber \-- I
mean, posterior iris chafing? Does it release pigment? We don\'t know.
We haven\'t looked for sample EC lines on gonioscopy.

Does that cause some chronic inflammation that over the 60-year life
expectancy of this 22-year old, may effect their endothelial cells.
Someone needs to, you know, provide some data from the sponsor regarding
this concern.

DR. VUKICH: Well, there\'s two things that I think we are putting
together. One would be the initial \-- that could account for some
initial cell loss

DR. MACSAI: And then to propose there\'s an increased rate of loss,
there has to be some ongoing irritation to accelerate above baseline.
That ongoing accelerated rate, we believe, would be consistent with the
morphometric analysis. If we\'re going to see some sort of insult,
whether it be inflammation of which we detected none, whether it would
be a mechanical of which again, we would have to postulate some contact
with the cornea that we simply have not observed. These chambers have
remained well-formed and we have, again, not seen a mechanism by which
we can take a posterior chamber lens and equate this into ongoing
corneal endothelial trauma. We would really have to propose a new
mechanism for a chronic ongoing accelerated loss of endothelial cells
that takes into account normal morphology and no other known cause of
this accelerated loss. We believe a lot of what we\'re seeing here is
just an extended remodeling period. We have some insult similar to what
we\'d expect in clear corneal cataract surgery and there is remodeling
that stabilizes the population back to its, again, normal redistribution
and that, we believe takes as long as three years and we simply can\'t
see an accelerated rate. So I think projecting is difficult but we\'ve
certainly accepted the limitations of the data we have and are committed
to long-term follow up. It\'s an important issue and I think it needs
monitoring.

DR. MACSAI: Have \-- you know, when you talk about long-term insult, my
concern is not lens corneal touch. My concern is lens iris touch. My
concern is that you know, pigment release and has the sponsor in some
way separated those with the good high vault, segregate those out, look
at their flare meter, look at their angles, look at their
transillumination defects, and look at their endothelial cell loss, that
particular group, because I think that would help answer the question.

DR. SANDERS: Well, we do have data on three lenses were replaced because
they were too long, which were the highest vault and if you look at the
final endothelial cell densities, 3300, 2400, 2700. They were the
highest cell densities at the later time periods so it appears that
these cases are not the ones that demonstrate cell loss with time.

DR. MACSAI: But they were replaced.

DR. SANDERS: Yes, but they were replaced after a fairly long period in
the eye.

DR. SUGAR: Can I ask a clarification from Marian? Are you implying that
pigment release causes endothelial cell loss because I\'m not aware of
that?

DR. MACSAI: I\'m not implying pigment release causes endothelial cell
loss. I\'m implying pigment release implies touch. Touch may insight
chronic inflammation and may have some role in this. I don\'t know. I
ask the questions of the sponsor because I don\'t know.

DR. WEISS: Dr. McCulley and then Dr. Ho.

DR. McCULLEY: I\'ve been around \-- Jim McCulley. I\'ve been around
since prior to the beginning of clinical specular microscopy. Been
through decades of frustrations of trying to listen to people make sense
out of and make points based on cell density. And having listened to \--
read everything that was provided, having listened to what everyone has
said, quite honestly, I\'m at a point where it seems to me that what
you\'ve presented at least my interpretation of it, would be that we
have surgical trauma, endothelial cell loss, and no evidence for
anything except continued remodeling. And no evidence for any other
mechanism for continued endothelial cell loss or death other than the
normal apoptotic death. So I\'m not sure where, you know, one could go
further with this or what we would ask you to do other than the
surveillance that you\'re doing except to ask is there some other more
sensitive way of looking for inflammation which wasn\'t a part of your
PMA. So I\'m not even sure how fair that question is.

DR. SANDERS: With regard to the inflammation, ocular inflammation was
the subject of my PhD thesis so I did quite a bit of work in this area
and that\'s why we included in the PMA five \-- I mean, the laser cell
flare meter has been basically thought to be too sensitive a measure of
inflammation and it\'s not even allowed for inflammatory studies because
it\'s too easy to show a decrease in inflammation between groups, and
five separate studies in the published literature have shown no
inflammatory response after the early post-operative period with this
implantable contact lens.

DR. McCULLEY: Well, then I guess what I would hope is I envision
potential hours of discussion about small points relative to endothelial
cell loss and cell density in something that is less than an ideal
science. So I would hope that the panel would really press Hank, who is
the world\'s expert in my experience on endothelial specular microscopy
with any other issues rather than us trying to figure out what\'s what
among ourselves. If we can have \-- so I guess my plea is \-- to the
panel is, please press Hank while he\'s here to give us the information
that will be more expert than we\'re at to be able to generate amongst
ourselves and hopefully have a more efficient discussion of this because
to me this is surgical trauma remodeling.

DR. WEISS: Dr. Ho.

DR. HO: Allen Ho. But is there any evidence that this sub-clinical
inflammation has a deleterious effect on the cornea?

DR. VUKICH: We have not demonstrated any subclinical information, no.

DR. HO: Is there anything in the literature?

DR. McCULLEY: I think \-- Jim McCulley. They have no evidence for
subclinical inflammation and depending on how you define subclinical
which presumably would be what we see at the slip lamp, they\'ve gone
another step forward, don\'t have any. What we could do would be again,
intuition. My intuition tells me what I\'ve said. It would be
intuitively to go back to some of the closed-loop AC IOLs that actually
didn\'t have sub-clinical, they had clinical inflammation that led to
loss of endothelium, so I\'m not sure that maybe in some of those eyes
some of us didn\'t see the cell and flare that was going along with
those AC IOLs but I think if you have chronic inflammation or chronic
rise in intraocular pressure, there is data that suggests there is
endothelial cell damage over time.

But we don\'t have any of that there and that\'s one of the things that
intuitively leads me to my conclusion, we have no proposed \-- we have
no support for any mechanism for any continued endothelial cell loss
beyond the apoptotic aging.

DR. WEISS: Yeah, I would prefer if we could keep the panel discussion in
the panel discussion portion and keep the questions while the sponsor is
up there because we have limited time. Do you have any other questions
specifically for the sponsor?

DR. HO: I do. The only patient that had == Allen Ho \-- that had severe
sustainable loss of vision in this trial was a patient who had a retinal
detachment and in a group of very high myopes we would expect perhaps
without intervention by natural history that you might see retinal
detachment.

However, one of the predisposing factors to retinal detachment in high
myopes is clearly retinal breaks and lattice degeneration. Do you have
any data about number one, lattice degeneration retinal breaks
pre-operatively and was indirect ophthalmoscopy part of the study
procedures pre and post-operatively?

DR. VUKICH: A dilated funduscopic examination was required at several
intervals throughout the follow-up period and detailed information was
collected by the investigators specific to peripheral retinal findings.
We don\'t have that collated specifically but also entry criteria did
require a stable retinal exam. Any pre-existing holes or tears or
retinal changes that would be considered high risk, of course, were
excluded.

DR. HO: They were excluded. Stable retinal breaks were included in this
or were they treated preoperatively with laser, for example?

DR. VUKICH: We do have a patient, I believe, who had \-- we had one
patient was treated for an acute retinal break.

DR. HO: Yeah, I think that\'s really important to flesh out for a
potential consumer of this kind of technology because, you know, that\'s
where you\'re losing an eye. However, you may not lose that eye based on
your intervention. It simply may be natural history. So I think that\'s
\-- I would like to see that information. Thank you.

DR. WEISS: Do you think the optic size of 4.65 had any impact on visual
acuity in younger patients who had larger pupils or is this something
you didn\'t look at?

DR. VUKICH: Well, visual acuity and quality were two different things.
The visual acuity didn\'t seem to have an impact in terms of the
improvement in best spectacle corrected acuity. Those were the patients
who actually had the most improvement quality of vision by subject of
symptoms. We can stratify that by level and can provide that, yes.

DR. WEISS: So you would be able to look at the size of the pupils to see
if it had any adverse effect. Dr. \--

DR. VUKICH: Well, excuse me, let me qualify that by saying, pupil size
measurement was not a part of this clinical exam, either preoperatively
or during the course of the trial, so we could only stratify it by level
of myopia, not by pupil size.

DR. WEISS: Okay, so that\'s an unknown factor.

DR. VUKICH: Correct.

DR. WEISS: Dr. Grimmett?

DR. GRIMMETT: A quick one for Dr. Sanders. Campbell estimated that
pigment particles can be as small as one micrometer in size. Does that
laser cell meter detect particles that small?

DR. SANDERS: Yes, it does. The standards that are used are in the two
micron range and those are meant to be certainly large enough. One
micron sized particles should be detected by the Kowan machine.

DR. GRIMMETT: You had about 20 patients after the three-month period or
so, 25 or something like that up to two years, something like that.

DR. SANDERS: Correct, and the cell measurements were essentially below
one per area that was seen on average.

DR. GRIMMETT: In those 20, okay, thank you.

DR. SANDERS: Yes.

DR. SLADE: Yeah, Steve Slade, one quick point to address Dr. Macsai\'s
concern about the vaulting, I just want to make it clear that while
angle examination, gonioscopy, was not part of the exam, we certainly
did slit lamp exams at multiple intervals and at no point did we ever
find peripheral touch, so we were looking at grading angles in that
fashion and at no point was the vaulting such that it actually caused
touch or PAS.

DR. WEISS: Thank you. Dr. Mathers?

DR. MATHERS: For Dr. Edelhauser, if you\'re going to postulate that
remodeling is the process, it might be helpful to know \-- to see these
cells and watch them remodel because they\'re not being created.
They\'ve got to be out there. Could you help us by letting us know how
many cells you like to see on a cornea to understand the remodeling
process. You\'re looking at 93 here. What would you recommend that we
try to look at if we\'re going to actually understand if remodeling is
the issue versus cell loss on a given patient?

DR. EDELHAUSER: I think that one, it\'s important to do more than \-- if
you want right now the information, more than just central specular
microscopy. Obviously, if we have these pooled cells out in the
periphery, it would be interesting to see what\'s happening with those.
I mean, and to get a larger cell number, now the \-- most of the
instruments that we used in specular microscopy you\'re limited to
pretty much about four millimeters in the center, unless you really
encourage the patient you can get out to maybe four millimeters off
center to look at the periphery. It\'s not an easy measurement to
obtain.

DR. MATHERS: But there\'s a half a million cells in that area, so \--

DR. EDELHAUSER: Yeah, so I mean, one \-- if one had to say predict the
ideal way to really evaluate it, is I think some of the ways that we \--
that article we published in the AJO is that we did take eight or nine
readings across the cornea; one central, four paracentral and for far
peripheral and then if you do that, you can \-- and then the interesting
thing when you do that, Bill, is that you find out that there\'s a
higher percentage of corneal endothelial cells in the superior region.
And similarly the German Daus all found the same thing. So you have a
16-percent increase in peripheral endothelial cells in the superior
region.

DR. MATHERS: Would you recommend that \-- matching that against controls
as a means to obtain this understanding?

DR. EDELHAUSER: Well, if we\'re going to really map out what\'s
happening in the cornea, with any type of surgical situation with
remodeling one would have to do that.

DR. WEISS: Dr. Bradley has one brief question. I will ask a question and
then we\'re going to have a 10-minute break.

DR. BRADLEY: You might need a 10-minute break after my question. I\'m
bringing \-- I\'d like to just go back to the issue that Dr. Weiss
raised a few minutes ago about pupil size. There seems to be a certain
irony here. I mean, one of the motivations for the product is that there
are certain people out there whose myopia level is too high although
cornea too thin to perform LASIK simply because \-- perform LASIK and
have the standard 6.5 millimeter diameter optical zone.

The replacement product is only having potentially a 4.65 millimeter
optical zone. And one of the reasons why we have a large optical zone
with LASIK is because we are concerned about pupil size issues. And I\'m
a bit concerned that we have so little information about pupil sizes of
these patients even \-- we would anticipate for example, with young
adults mesopic light levels that at least half of the light would be
passing into the eye outside of the optical zone of the ICL.

Under those circumstances, one can only imagine that the image quality
would be very poor. Having said all that, the data seems to point that
the patients are quite happy with their nighttime driving, your mesopic
contrast sensitivity test with a glare source showed perfectly good
results and I\'m completed confused by that. I wonder if the sponsor
could clarify how that could possibly happen with such a small pupil
size.

DR. VUKICH: Well, we\'ll start by looking at pupil size. Certainly, when
we developed the protocol in 1995, I don\'t believe that the interest or
the understanding of how these pupil sizes could interact with optical
quality were fully understood. That said, pupil size we neither an entry
criteria nor a parameter that was measured throughout the course of the
trial. I think the only way that we can answer that is to go back to the
patient\'s satisfaction surveys and the quality of vision that they
report inasmuch as the patients, in fact, didn\'t seem to be bothered by
the theoretical concerns of an optic size smaller than their pupil. Of
course, they didn\'t know this but what they saw they seemed satisfied
with.

I understand and appreciate the concerns even with pupil size. However,
there seems to be some variability in the response or the effect of the
pupil size that we\'re understanding now with LASIK where it may not be
as much of a correlation as we perhaps, intuitively may expect. So we
don\'t understand the mechanism why a smaller optical size at the level
of the lens inside the eye may not have as much influence but yet, we
simply have to go back to the results and I believe that they are
consistent with patient satisfaction and with the use of this device.

To speak to vision quality, there was a subset in a published report
looking at vision quality in patients looking at induced aberrations and
we found post-LASIK versus ICL, that the ICL patients had one-third as
much spherical aberration and half as much coma. And so we certainly
believe that it\'s at least in comparison to LASIK, probably better in
that regard at least.

DR. WEISS: One last question and this is sort of a bottom line question
for Dr. Edelhauser because it seems that the main concern of the panel
is the impact on the endothelium. Would you be surprised if this lens
was a contributory factor in causing corneal edema in any of the
patients on whom it was implanted?

DR. EDELHAUSER: At this stage, no, because the cell density of these
patients were well above, you know, 23, 2400.

DR. WEISS: I should say eventually. If any of these patients eventually
developed corneal edema, in conjunction with having this placed, would
that surprise you or do you think that would be totally independent of
having this lens placed?

DR. EDELHAUSER: Well, when you think about having a lens behind the iris
and not rubbing onto the corneal endothelium, it\'s hard to imagine, you
know, the mechanism of what would cause this \-- a marked decrease in
corneal endothelial cells.

DR. WEISS: So you would be \-- that as a complication would be
surprising to you even 20 years down the line.

DR. EDELHAUSER: Yeah.

DR. WEISS: Okay.

DR. SLADE: Just one quick thing, this lens has been implanted outside
the U.S., tens of thousands of cases over 10 years and while reporting
that experience is not FDA quality, I do believe we would know if this
lens ever created a corneal decompensation if the patient had to have a
graft and we know of none in that experience.

DR. WEISS: Thank you. We\'re going to take a 10-minute break and I\'d
ask you to be back here promptly and then we\'re going to go onto the
FDA presentation.

(A brief recess was taken.)

DR. WEISS: Donna Lochner will be introducing the FDA presentation.

MS. LOCHNER: Thank you, Dr. Weiss. Because this is the first phakic IOL
to be brought before the panel, I would like to briefly present how
FDA\'s guidance to industry on the design of phakic IOL studies has
evolved beginning with the October \`98 panel meeting. In 1999 ANSI
standards and later the ISO meetings began and they currently are held
every six months or so. Both the ANSI and ISO standards are expected to
be submitted for voting in 2004.

Today I\'ll provide just the highlights of the three panel discussions
and then summarize the current ANSI and ISO standards which have
incorporated all the major recommendations of the panel with some minor
exceptions. FDA issued a draft guidance document in 2000 and expects to
issue a final guidance when the ANSI standards are finalized. So this
first slide \-- I think I went \-- this first slide is for the October
23rd, 1998 meeting which, as I said was the first discussion by the
panel and at that meeting, the panel recommended that effectiveness
criteria generally followed the refractive laser guidance. For example,
with respect to the uncorrected VA loss of BSCVA, and also recommended
that adverse events in the first year should generally follow the IOL
grid for aphakia as a starting point for the study design.

The panel recommended a sample size of 500 subjects and this was
primarily because they felt that as a new indication, new technology,
they should take a more conservative approach and the 500 subjects was
consistent with what was originally done with IOL aphakia studies.
Further, they recommended mesopic contrast and sensitivity testing be
done and mesopic pupil size measurements be done. That a questionnaire
for visual complaints be administered and that pachymetry, dilated lens
and fundus evaluations, topography, keratometry and gonioscopy
evaluations be performed.

With regards to specular microscopy, the panel recommended a sample size
to allow detection of 2.5 percent per year and they obtained this figure
from the Bourne article that was referred earlier in the discussion this
morning. There was a suggestion that all patients be tested but they
felt that FDA should try to power the studies to detect the 2.5 percent
per year. They felt PMA data was needed to three years and if there was
a loss or the loss was progressing, a five-year study should be
performed. With respect to lens opacities, the panel recommended a
clinical grading system and three-year data be collected.

The May 12th meeting was held to receive the panel\'s input prior to
publication of FDA\'s draft guide and at that meeting, the panel
generally endorsed our proposals to power the studies to be able to
detect a 1.5 percent loss in the specular microscopy study per year and
the 1.5 percent figure came after iterating several hypothetical annual
losses from a phakic IOL taking an average endothelial cell densities at
different age ranges from the literature and determining the age at
which the hypothetical annual loss would result in corneal
decompensation for the various age groupings. From there we assigned a
standard deviation of five percent and sort of arrived at \-- which was
sort of arrived at as being a reasonable loss so that even young adults
would be in their 70s prior to decompensation and that the sample size
would still remain reasonable for these studies.

The panel endorsed this approach and also asked for data analysis to
include a stratification by age. And they further recommended that the
analysis look at the mean rate of loss and a frequency analysis to show
the percent of patients losing greater than 10 percent over the course
of the study. With respect to lens opacities, the panel again
recommended a preoperative and post-operative clinical grading system
and at this meeting they also \-- there was quite a bit of discussion
about control group and felt that that was recommended. The panel also
again emphasized gonioscopy and dilated fundus exam.

After another two years of meetings with ANSI and ISO we brought a
composite of the standards to the panel but with a focused review of
endothelial cell density, lens opacity and the contra-sensitivity study.
We assigned primary reviewers for each of these three topics and also
invited speakers to address endothelial cell design and lens opacity
clinical study design issues. The panel recommended that the cell
density studies be able to detect the 1.5 percent annual loss and this,
again, was based upon entry criteria on cell density and acceptable
density for the life of the patient. Depending upon the standard
deviation, they commented that this will equate to about 200 to 300
eyes. They recommended use of a central reading center or other methods
with similar precision and validity. They recommended the three-year
data was needed for the PMA and also that an intermediate measure
between the two and three-year point might be needed to help to
establish linearity.

Depending upon the three-year data, the panel recommended that
additional two years post-marketing study may be needed. And finally,
again, the frequency analysis was requested. With respect to lens
opacities, again, the panel recommended a clinical rating system and the
three-year data also was needed to address the issue of lens opacity and
that consideration will be given to longer term at least a five-year
post-marketing study. Once a PMA has been reviewed, the panel felt it
was useful to look at laser flare and high resolution ultrasound for
source of any opacities. And they felt that two or more lines loss with
glare or one line without glare would be the level that would be
considered clinically significant for any opacity.

They further recommended that contrast sensitivity testing be done on
all patients to document the severity of any future opacity. With
respect to the contrast sensitivity discussion, the major recommendation
that came out of that was that the panel felt a clinically significant
decrease in contrast sensitivity should be set at .3 log units and
again, the panel emphasized gonioscopy and further stated at this
meeting that consideration should be given to collection of data
post-market depending upon how the PMA data looked.

Again, as I said, all of this culminated in the current draft ANSI and
ISO standards with recommendations for a three-year, 300-subject
preoperative control study. Safety end points from the FDA\'s aphakic
IOL grid are also used as control data in these standards and now I\'ll
just briefly go through the current recommendations and the most current
versions of these standards and that is that the following evaluations
be performed; in corrected CVA, distance and near, BSCVA distance and
near, manifest and cycloplegic refractions, a subject questionnaire, a
slit lamp exam including aqueous cell and flare, gonioscopic exam,
corneal edema, pupillary irregularities, iris atrophy and pigment
dispersion.

These standards recommended a dilated fundus exam, that IOP testing be
performed, mesopic pupil size be measured and that pachymetry,
preoperative axial length, anterior chamber duct measurement and
kerotometry be performed. With respect to specular microscopy, the
standards assume a 10 percent surgical loss and recommend that the
studies be able to deduct a two-percent loss per year. The standards
recommend that all 300 subjects be tested so that at least 200 good
images would be obtained.

They recommend use of a central reading center and they recommend that
100 to 150 cells be counted. With respect to lens opacities, again the
standards recommend a clinical grading system and they recommend that a
change in contrast sensitivity performance from preop to each post-op
visit at which an opacity is observed be performed to document any
significance to the opacity. The standards recommend contrast
sensitivity be performed under mesop and mesopic with glare and the
sample size recommended is 61 subjects.

Now, I\'d like to thank and acknowledge the PMA review team for this
application. Dr. Alexander, who is the lead reviewer for the PMA, Dr.
Eydelman, the clinical reviewer, Dr. Gray who performed the statistical
review, Don Calogero, our jack of all trades who performed engineering,
contrast sensitivity and specular microscopy reviews. Susanna Jones
reviewed the toxicology. Susan Gouge, microbiology, Charles Sawyer,
patient labeling, Pam Reynolds performed the bio-research monitoring
review and Vertleen Covington on the quality systems or good
manufacturing practices review. And last but not least, I have to give a
special thanks to Sally Thornton, who due to the expedited nature of
this PMA really had to do above and beyond the amount of normal running
around and we couldn\'t have gotten here today without her excellent
support.

Now, Dr. Eydelman will present the clinical questions.

DR. EYDELMAN: Good morning. This PMA is truly precedent setting and I
wanted you to be aware of it for several reasons. First of all, there
are currently no phakic intraocular lenses approved in the U.S. There
are also no currently approved devices requiring intraocular surgery for
correction of refractive error. Thirdly, there are no current FDA
approved devices for the correction of myopia greater than 15 diopters.
In addition, FDA approved IOLs for use only in adults 60 years of age
and older until this year.

Currently, responses may require lowering age for indication to all
adults by reference to our recent publication. This is the first time,
therefore, that you\'re going to be considering a PMA for an IOL
intended solely for implantation in young adults. As you heard, this PMA
received an expedited review status. That truly meant much shorter
turnaround time for both the sponsor and us. To make a point of it, I
want you to be aware that the last major clinical amendment wasn\'t
received by FDA till September 3rd.

As a result of all this, I haven\'t been able to receive the sponsor\'s
final panel presentation until today, so please forgive any redundancies
that I might have in my presentation. As you have all seen, this was a
very large PMA with numerous analysis and I will not try to summarize
all of it. I\'m merely trying to bring your attention to some
information which is relevant to the questions that we ask for your
consideration.

Regarding lens opacification, there were five eyes in the whole PMA that
developed nuclear opacities of two plus at the LOCS scale at two to
three years. There were 14 cases of ASC opacities of trace or more.
Eleven of them occurred at or before the six months and three cases at
one year to 26 months post-op. In view of these, do you believe that the
three-year follow up is sufficient to establish a lens opacification
profile associated with this device? If not, what is your
recommendation?

Eleven out of the 14 cases of ASC appeared at or before the six-month
visit suggesting surgical trauma. Combining surgical experience with V3
and V4 models, 50 percent of 87.5 percent if you exclude the problematic
site number 15, of early ASC cases occurred within the first eight
surgical cases. In the Canadian trial performed by three inexperienced
surgeons, 22.5 percent of cases developed ASC opacification.

The Dominican Republic study which was performed under supervision of a
surgical proctor, demonstrated a rate of 4.8 percent. In light of these
findings, do you believe surgeon experience to be an important factor in
ASC development, secondary to surgical trauma? If yes, do you believe
that future users of this lens should be required to undergo special
training?

Vault measurements in the study were clinical estimates comparing the
slit lamp appearance of the corneal thickness to the interval centrally
between the crystalline lens and the ICL. Five hundred micron corneal
thickness was assumed for conversion from a percentage of corneal
thickness to microns. All measurements in an individual case at every
visit were averaged to derive at a vault measurement. So as you can see,
it was not a very precise measurement estimate. However, it was done.

Patients were graded as having poor vault if investigators consistently
graded the space between ICL and crystalline lens as less than 10
percent of the central corneal thickness and that equated to about 50
microns. Twenty-four cases of the V4 cohort with this technique were
determined to have poor vault, 16.7 percent of them or four out of 24 V4
cases with poor vault, subsequently developed ASC opacification in
contrast only two percent of cases with good vault had ASC.

All three cases of significant ASC opacification of late onset defined
as greater than six months in V4 cohort were in the eyes with poor
vault. In V3 cohort, 41 percent of cases with poor vault developed ASC
versus nine percent of cases with good vault. Gonvers, et al, in his
recent publication further supported the relationship of vaulting to
cataract information. In the PMA the sponsor recommended replacement of
the ICL only in cases of poor vault that exhibited early ASC in areas of
ICL touch in subjects with UCVA worse than 20/50. Do you agree with this
recommendation? If not, what would you recommend?

In the clinical trial, sizing was determined by the horizontal
white-to-white and ACD, anterior chamber depth measurements. Inherent
measurement error associated with caliper measurements was judged by the
sponsor to be plus or minus .1 millimeter. Anterior chamber depths in
the study was measured by ultrasound, Orbscan and IOL master. From the
literature review, the sponsor concluded that results may differ by as
much as .3 millimeters between different measurement methods.

Our own literature review revealed lack of correlation of white-to-white
measurements and the sulcus-to-sulcus dimension. We also believed that
the literature shows that none of the external measurements, including
anterior chamber depth and axial length, have been able to accurately
predict internal ocular dimensions. The sponsor believes that this
literature evidence currently available is anecdotal and they further
point out that all the safety and efficacy data available were obtained
with a current sizing algorithm based on white-to-white and ACD
measurements.

It\'s interesting to note that looking at the distribution of the ICL
implanted, 50 percent were performed with 12.5 millimeters, versus 7.6
percent was 11.5 millimeter lens. In the overall PMA cohort, 1.5 percent
of the lenses were replaced due to inappropriate sizing. Do you believe
that the method currently recommended by the sponsor for determination
of the overall diameter of the ICL to be inserted is appropriate? If
not, what do you recommend?

As you heard previously, we asked the sponsor to break up their cohort
into four refractive groups. Fifteen to 20 diopter group contained 31
eyes at three years. I want to make sure that you\'re aware that while
preliminary discussion for refractive laser guidance for myopia greater
than seven diopters was held a the \`97 panel meeting. There was no
consensus reached on several issues and therefore, there is no currently
available guidance for acceptable safety and efficacy outcomes for high
myopes after refractive surgery. For eyes with MRSE greater than 15
diopters, in the ICL cohort, there were 3.8 percent or two eyes that
lost greater than two lines, 3.8 percent that lost 2 lines and 17.3
percent that lost 1 line. If you calculate it out, it turns out that at
15 diopters of myopia, magnification factor account for a one-line loss
being equivalent to a two-line loss. Therefore, we ask the sponsor to
include that in the analysis of their high myopia group.

Thus, if you add it up, total loss of one line or greater was 25 percent
for the small cohort.

Some additional safety outcomes for these eyes were retinal detachment
at 3.8 percent, ASC opacification of 5.8 percent and as of 9/15, only
\-- the sponsor informed us that only one eye of these was clinically
\-- had clinically significant ASC and that is 1.9 percent. Clinically
significant nuclear cataract in 7.7 percent, ICL removal/cataract
extraction performed in 3.8 percent and again, 3.8 percent had an
increase of greater than two diopter cylinder.

As you heard, currently limitation of ICL power is minus 20 diopters.
Inadvertently a lot of eyes with MRSE greater than 15 diopters were
targeted for under-correction. Eleven point five percent of them were
targeted for greater than three diopters, 28.8 for greater than two and
65.4 for greater than one. Looking at predictability, 23.3 percent had
accuracy within half diopter, 53.3 was within one diopter. Combining the
targeted under-correction was a predictability that you saw resulted in
rather large range for resultant MRSE for this group at three years. As
you can see, it ranged from minus .85 diopters to plus .5 with 10
percent of the eyes ending up greater than four diopter myopia, 26.6
greater than three diopters.

Looking at all eyes with preop MRSE greater than 15 diopters 38.7
percent of them were able to achieve 20/40 or better. There were no eyes
available that were targeted for emmetropia and had preop of 20/20 or
better. While all eyes in this sub-group were \-- while there were no
eyes that were \-- there were no patients that were unsatisfied, looking
at very extremely satisfied patients, you see that for the group of
greater than 15 diopters, the satisfaction percentage drops somewhat to
75 percent.

Does the safety and efficacy data for eyes with preoperative myopia of
greater than 15 to 20 diopters support approval of this refractive
range? If approval for eyes with preoperative MRSE greater than 15 to 20
is recommended, is the term \"correction of\" as it relates to this
refractive range, appropriate in the indication statement? If not, what
alternative term do you recommend?

Any time we at FDA consider risk benefit analysis for each of the
refractive groups, we have to consider two factors. First, is a safety
and efficacy profile for each refractive group with the device in
question. In addition, we look at safety and efficacy profile for the
currently approved or alternate devices available; in this case,
glasses, contacts, LASIK, for each of the refractive groups? With this
in mind, does the safety and effectiveness outcomes support approval of
STAAR ICL for the eyes with the following preoperative MRSE, minus 3 to
minus 7, greater than 7 to 10, and from greater from 10 to 15 diopters?
Twenty patients in overall PMA cohort required treatment other than
IOP-lowering meds in the early post-op period. Seventeen of them
requiring additional irodotomies, and three requiring additional
irrigation/aspiration procedure. In these 20 eyes, IOP ranged as high as
65, with IOP spikes observed between one and 21 days post-op. Most of
them, however, were seen in one to two days post-op.

Incidents of early post-op spikes was stratified by study site and was
shown to range between zero to 20 percent. The differences were not
found to be statistically significant. Do you believe that specific
recommendations regarding early post-op follow up are needed in the
labeling? I want to bring your attention to the fact that the labeling
you currently have is not \-- did not undergo final FDA\'s review. We
always correct all the inconsistencies. Patient symptoms and quality of
vision assessment stratified by refractive groups would automatically be
included. Demographics is always included.

What we are asking your input on is issues unique to ICL that need to be
communicated in physician and patient labeling, possibly as a warning or
precaution. In addition, we\'re asking you to consider issues that will
be common to all phakic IOLs, such as possible requirement for exclusion
of subjects with low endothelial cell density as a function of age. This
would be consistent with ANSI PIOL draft standards recommendation for
clinical studies. It would, however, imply access to specular microscope
for all implanting surgeons.

In addition, recommendations for gonioscopy and mesopic pupil size
assessment preop and post-op in all patients. This is consistent, once
again, with our standards recommendation for all clinical studies.
Overall, we want to know what additional labeling recommendations do you
have. Now, I would like to introduce Dr. Gerry Gray who will review all
of the endothelial cell data analysis and when the Chair is ready, I\'ll
be happy to project all questions as they appear in your handout.

DR. GRAY: Good morning. My name is Gerry Gray. I\'m the team leader for
cardiovascular and ophthalmic statistics and I was the statistical
reviewer for this PMA. My comments are going to be restricted to the
specular microscopy sub-study. This is an overview of the design. We\'ve
heard it several times. We\'re talking about endothelial cell counts and
measurements on endothelial cells based on photographs from a specular
microscope and all the images were read at a core center with one
reader.

The study was originally designed to have a preoperative and then
three-month, one-year, two-year follow up. During the course of the
study it was modified to add three and four-year visits. And the purpose
was to investigate the effects on endothelial cells. There were a total
of 306 eyes that were enrolled in this sub-study and it had at least one
count. I\'m just going to go through a little bit about the
accountability of the eyes because it gets a little confusing here.

The pattern of missing is not quite standard where everyone has a preop
visit and then people start to drop off after that. It\'s a fair amount
different. In fact, there were \-- 94 of the 306 patients had no
preoperative visit. Six people had preop and one subsequent. Thirty-four
had preop, two subsequent and 172 had preop and then three of them were
after that, and the small numbers after that tell you where the
person\'s last visit was.

And all this accountability information is based on a data set that was
submitted to me by the sponsor for analysis. So actually, I think it was
a SAS formatted data set. A couple of more accountability combinations;
154 patients had preop and three-year visits, 57 comes up a couple of
times. It\'s not the same 57 patients but 57 had three and four-year
visits, 57 had preop and four-year visits. A total of 67 people had all
the visits up to three years and a total of 37 had all visits up to four
years. So there\'s 37 patients out of these 306 that had all the visits.

So here\'s a plot that we\'ve seen before. It\'s the raw results from
the data \-- from the study, excuse me. The year or the time has been
jittered a little bit to show the distribution there. There are preop
measurements and then three months, one year, two years, three years and
four years. The dashed blue line here just simply connects the means at
those time points. And when we look at this, there\'s really two
questions that are key here. The first one is how \-- at what point in
time can we say that any effect of the actual surgical procedure,
whether it would be just lost due to surgical trauma and/or some amount
of remodeling, at what point in time would we say that is negligible and
we can ignore it and use the data after that to get some estimate of
what long-term loss might be? So that\'s the first key question that we
need to think about.

And then the second thing is what happens off to the right-hand side of
this graph, what happens after five, 10, 20 years down the road? Just to
set the stage a little bit, this is \-- these numbers here are the mean
cell counts for various cohorts of patients that you might think about
using in this study. The first cohort is all eyes. That\'s just all 306
eyes that were measured whenever, the baseline preoperative measurement,
the mean was 2657 and it steadily declined after that to 2355 at the
four-year point.

The next cohort, I couldn\'t fit it in very well, so I call it pre and
two plus. Those are all the patients that have a preoperative
measurement and then they had at least two measurements after that. So
that\'s 206 of the 306 patients and you can see there, it\'s fairly
similar actually to what we get with all eyes. The next two cohorts are
somewhat different. The cohort that only has three and four-year
measurements and this is a cohort that in the analysis presented to us
by the sponsor for the three to four-year loss they used. You\'ll note
that the main difference here is at the three-year point that
measurement of 2355 is somewhat lower and it\'s actually in fact, lower
than the average measurement they got at four years for those 57
patients.

And then finally, an even smaller subset was everyone who had all the
visits and that shows a similar pattern to the three and four-year one,
and I presume these are the numbers that were used to make that plot
that came up in the sponsor\'s presentation. So over the duration of the
study, over the three and four years we\'re talking about here, the
estimates of cell loss are fairly stable regardless of how you calculate
them. At three years, the range of estimates is 8.5 to 8.9 percent. If
you use the 154 patients who had preoperative and then three-year \-- a
three-year visit, the estimate is 8.7 percent. And the competence
interval for that is anywhere between a 10.3 and 7.1 percent loss. In
raw numbers that\'s 220, 235 cells per millimeter square and that
calculation includes anything that happened to the patients between
preop and the three-year point which would be any initial operational
loss, any kind of remodeling, any normal loss due to aging over that
period.

And at four years, we\'ve added on a little bit here and it\'s anywhere
from 8.4 to 9.7 percent loss. Okay, now the big question, of course, is
what\'s the steady-state long-term loss that we can expect to see.
What\'s the long-term rate of change in the endothelial cell density we
might think we would see? And it turns out that this estimate depends
mostly on those \-- on the question of how long we believe the effects
of the implantation persist, at what time point can we say whatever
remodeling or operative loss we have seen in negligible at this point.
And that translates into which of the cohorts we actually used to do
that estimation. As you saw in the previous slide, the table of cell
densities, the two cohorts on the bottom that only had \-- that had
three and four-year measurements had a markedly lower three-year cell
count than the others and that\'s the main difference in terms of what
you get out in the estimates.

The analysis that was presented to us by the sponsor in this PMA was
basically using the percent change between the three and four-year time
points, using only those patients who had both three and four-year
measurements. That\'s the 57-patient cohort and it properly did some
statistics to account for a correlation within a patient between eyes.
And the net result there is an estimated percent change of .07 percent,
that is a slight gain. In fact, it was one cell per millimeter squared
with a confidence interval between minus 1.4 and positive 1.6 percent.

Now other cohorts you\'ll recall, have relatively higher three-year
counts and you can do a lot of different kinds of analyses but the
bottom line is that the various analyses using those other cohorts and
using all time points or time points other than just the three and
four-year, produce a change of around minus two percent per year. If you
go the fancy statistics route and do random coefficients regression, you
get a loss of minus 1.9 percent per year. If you believe that whatever
\-- that the time cutoff for the operational and/or remodeling change is
three months and just use the data after three months, and go through an
analysis, it\'s exactly like the one done by the sponsor, in other
words, just use the changes from time point T to T plus one, you get an
estimate of minus two percent per year.

If you believe that any trauma or remodeling is done after two years and
you use the two to three-year difference plus the three to four-year
differences, you get an estimate of minus 1.8 percent. And the
confidence intervals change a little bit. The one for the \-- using the
regression is probably the smallest because it has a model to help it
make the balance smaller, but those are fairly consistent estimates
compared to the difference between them and the one that only uses the
three and four-year data.

So the key question, of course, is where is that cutoff between
operative and/or remodeling loss and whatever you might call
steady-state, long-term loss. And all I can do is statistics, right? I
don\'t have the clinical knowledge but I have the data, so using the
data that we do have, the question here from the statistical point of
view is we see that there\'s some amount \-- in many of the cohorts,
there\'s some amount of leveling off after the three-year point between
three and four years and the question is, is that statistically
significantly different than whatever the slope we saw between three
months and one year, one year and two years, two years and three years.
And the answer to that is no. If you\'ll recall the previous plot, it
showed the dotted line that connected the means, it looked pretty much
like a straight line and the statistics confirm that. There\'s no strong
evidence that the rate of endothelial cell loss between three and four
years is any different than the rate \-- the annual rate before that. So
in the data we have, there\'s not strong evidence that it\'s different.
Of course, we only have 57 people at four years and that could be do to
just random fluctuation or we just don\'t have a big enough sample at
four years to have much statistical power but that\'s what we have.

And just in case you care about the details, this was all based on a
piecewise linear model that assumes there\'s a preoperative loss between
zero and three months and then after that, it\'s steady decline either
to three years and then a change to four years or it\'s straight from
three months on. But the implication of all this from the data we have
is that is that the steady state loss should be estimated using all the
data after three months. And if you\'ll recall from a previous slide,
even if we want to go to two years, it doesn\'t make that much
difference here.

And so my best guess is due to long-term loss would be that we have \--
first of all, there\'s a mean preoperative measure of 2651 and with the
first three months, the absolute loss is about 1.9 percent, so about a
two-percent loss over the first three months, and then after that, the
rate of loss per year is about 1.9 percent.

If we extend this model a little bit to include a three and four-year
slope, which again was not warranted by the statistics probably, you do
get a pretty similar estimate to what the sponsor had between three and
four years of an actual slight gain. So here\'s the results from the two
different fits, the two main different kinds of fit that I\'m talking
about. First of all, there\'s a blue line here that\'s just like the one
you saw in the previous plot that\'s pretty much overlaid by the black
line. The black line is the fit that I was describing where we had a
linear drop at the three months and then a straight line after that. And
the green line out at the end is the analysis that was presented to us
by the sponsor which is just using the patients who have three and
four-year data. And you look at this plot and you say, well, that\'s not
that much different because you know, the only thing different is maybe
the difference between the mean at three years there, but the problem is
that we don\'t really care that much at the four-year point. What we
care is what happens after 10, 20, 30 years and when you make the plot
\-- when you show the time span we\'re talking about those are quite a
bit different results.

And if you believe the three to four \-- using the three to four-year
data, we\'re basically a flat line, slight increase over time on the
endothelial cell density. If you believe that the loss is going to
continue linearly at 1.9 percent per year forever, then after about 20
years you\'re at the 1500 cells per millimeter squared and somewhere
around 35 years you\'re down to 800. I don\'t have any \-- I don\'t show
any errors around these lines, in the error bars. If you know much \--
if you know about errors for regression the errors go, they move outward
the further away you get from the center of the data and if I put them
on here, they would \-- these estimates are pretty much meaningless I
think after 15 to 20 years. You don\'t have very much confidence at all
in them.

And that brings me to, of course, the caveats that the statisticians
always give about extrapolation. It\'s always a questionable exercise to
extrapolate beyond the range of the data we have and especially when
we\'re talking about the range we have here. It\'s highly \-- any
extrapolation you would make would be highly dependent on the model we
use and the assumptions we want to make and both those lines that you
saw previously assume that whatever linear trend you saw between three
and four years is going to continue forever beyond that.

And it\'s probably in this case a lot more important to think about if
it\'s necessary to obtain good long-term data and if so, how to go about
doing that. Okay, now, I\'m going to switch gears a little bit and talk
about individual patients because maybe more important than the average
cell loss through time which is described by the linear fits are
questions like what proportions of patients will show a cell loss
greater than some critical amount. In other words, what proportion of
patients will have cell densities less than 1500 or 800 cells per
millimeter squared in 10, 20 or 30 years.

And from my point of view, the problem is you can\'t really answer this
with much confidence using the data we have here. But let me just
summarize what we do have here. If you\'ll recall one of the previous
\-- the fancy statistical model I used previously actually gives me an
estimate for each eye of what the post-operative ECD change for that eye
is and then after that, what\'s the annual change through time, and so
you have a distribution of those estimates for each eye.

And using that, you can get \-- you can create tables like this that
tell you something like in this case four and a half \-- excuse me, 10
percent of the patients will have an initial loss of four and a half
percent or more and 10 percent of the patients will have an annual loss
of 2.9 percent or more. Now, that\'s based on again, I\'m making some
assumption that whatever we\'ve seen in the first three or four years is
going to continue however far in the future you want to go. Okay, and
finally, there were some co-variants that seemed to be significant
predictors of endothelial cell loss, notably is the anterior chamber
depth which was a statistically significant predictor of cell loss
regardless of how you analyze it really. The sponsor presented analysis
in the PMA that showed the used binned data, in other words, they broke
the ACD into four different groups based on three, three and a half,
four millimeter cuts and then presented the cell loss for each of those
groups.

A bunch of other co-periods didn\'t appear to be significant predictors
of cell loss. Just to help put the ACD effect into context, I created
this graph here that takes \-- for each eye, you take all the possible
annual differences that you got for that eye and calculate from those
the percentage loss for that eye and then average those for that one
eye. So on the Y axis is for each eye now an annual percentage ECD
change that we see in the four years \-- after three months. I threw out
the first few months because that seemed to be somewhat different. And
then platted on the X axis is the ACD measurement for that eye.

And the point is that, remember the average ACD is around 3.5 and the
average cell \-- annual cell loss was right here, it\'s around two
percent and down here it says estimated slope is 1.6, so you know that
the difference between \-- if this right here is about two percent loss,
and someone that\'s a half a unit to the left is going to have a loss
that\'s about 0.8 percent more, 2.8 percent, and someone who is a half a
unit to the right is going to have about 0.8 percent, less cell loss.
They\'re loss is going to be about 1.2 percent per year. This is just an
attempt to kind of put the \-- take the statistical significance of the
ACD effects and try to put it in some terms that might be hopefully
relevant.

So after all that, there\'s two main questions here for the panel. The
first one is that the mean change between three and four years in that
57-patient cohort that had both of those was an actual gain of .1
percent in endothelial cell density, so is there sufficient data to
support the conclusion that the losses in the first three years are
reflective of surgical trauma with some prolonged remodeling period that
culminates in a stabilization after three years and if not, what minimum
eyes in follow up would you try to make a recommendation that we might
need to make that assessment?

The second question relating to the anterior chamber depth eyes with the
smaller anterior depth of 2.8 to 3 had a greater loss of endothelial
cells than the eyes with a greater than 3 millimeter ACD. So the
question is, do the outcomes of the ACD analysis provide some assurance
of safety in this device for eyes in the lower end and then the upper
end of the ACD spectrum? Thank you very much for your attention.

DR. WEISS: Thank you. We will now have questions for the FDA from the
panel. I\'m just going to start off, just to clarify for myself about
the endothelial cell loss in terms of determination whether it levels
off or increases between three to four years versus whether it continues
dropping. From what I understood you to say, if you look at the cohort
of 57 which is what the sponsor was looking at between three to four
years, you could possibly say that it was going to level off, but if you
look at the other cohorts, it does not show that. Am I misinterpreting
it or is that basically \--

DR. GRAY: That\'s correct. Your estimated amount of endothelial cell
loss depends primarily on which cohort you use and the one cohort \--
the cohort that has either the three and four-year measurement that has
three and four-year measurements has a lower three-year count and
therefore, you get basically a flat line after that.

DR. WEISS: So we have a choice of basically looking at the cohort of 306
and if we look at the cohort of 306, it does not support leveling off
between three to four years. If we look at the cohort of 206, it does
not support leveling off at three to four years. And if we look at the
cohort of 37?

DR. GRAY: Well, when you say \"support\" it might mean a different thing
to you than to me. When you get down to the 57 or 37 patients, there is
more of a leveling off but on the other hand, there\'s more air because
you have fewer patients. So I didn\'t actually do the test with the 37
patient cohort, but my guess is that you couldn\'t say statistically
that there was a difference, but I didn\'t actually do that.

DR. WEISS: But certainly for the larger groups, which would have more
statistical strength, it shows no leveling off.

DR. GRAY: That\'s correct. I personally used \-- concentrated on the
group that had a preoperative measurement and then two or more
measurements after that because that was the one that I \-- in order to
do these tests you have to be able to fit a model of some sort.

DR. WEISS: So we\'re talking about if you look at the group of 206,
which had the preoperative measurement and measurements at each of these
time points, or at some of these time points, at least on two.

DR. GRAY: Two or more, yes.

DR. WEISS: At two or more of those time points. If you looked at that
group, this did not support leveling off between three to four years.

DR. GRAY: From a statistical point of view doing the test for leveling,
that\'s correct, it did not support it.

DR. WEISS: Okay, thank you. Dr. Grimmett?

DR. GRIMMETT: Michael Grimmett. Dr. Gray, I appreciate your comments. On
the group of 37, you may not have run the analysis at the end but did
you calculate the rates of or the confidence intervals for the
endothelial cell loss, what it ranges between for the 37 eyes at year
four? Did you show that? I mean, I know for the 57 it was a 90 percent
confidence interval was 1.4 something. Did you do the same thing for the
37 eyes? It\'s probably wider, right?

DR. GRAY: No, I didn\'t do that. It would most likely be wider because
of the sample size is three-quarters. So that would increase it by some
amount, yes.

DR. GRIMMETT: Okay, thank you.

DR. WEISS: Dr. Bradley?

DR. BRADLEY: Dr. Gray, on one of your last slides there you showed us
the relationship between anterior chamber depth and cell loss and you
did a linear regression that 1.6 percent per millimeter.

DR. GRAY: Yes.

DR. BRADLEY: Did you do the analysis to find out how much of the
variance was explained by the linear model? That becomes quite an
important number for us.

DR. GRAY: Well, that was part of the analysis but I don\'t have that
number here on me. The reason I \-- I guess their point is that there is
a statistically \-- when you ask how much of the variation is explained,
there is a statistically significant \-- that slope is significantly
different than zero, okay, so from a statistical point of view there is
\-- that\'s a significant slope. And what I was trying to get at was
that what\'s the clinical relevance of that and that\'s where \-- why I
made the plot that calculated the 1.6 percent per year. But I don\'t
have that number on me.

DR. BRADLEY: Yeah, but it\'s the clinical significance that\'s driving
my question here in a sense that the linear regression might be highly
significant but it may explain a very tiny amount of the variance and
thus making policy based upon a parameter which explains only a tiny
amount of the variance is really meaningless. So if we had that number
or after the meeting somehow that number could be available, that might
help policy.

DR. WEISS: Dr. Bandeen-Roche, Dr. McCulley and then Dr. Mathers.

DR. BANDEEN-ROCHE: Thank you for your presentation. I just have a brief
clarification question which is that the numbers that you cited for the
four-year mean cell counts differ from the calculations that I cited
earlier. And so for instance the three, four-year mean that you cited
three years and four years is 2355 and 2356 and reading from Volume 4 of
4, page MD19, those numbers are cited as 2455 and 2456. Now, this in a
way sounds like a little point but it goes to the representativeness,
the relative representativeness of the various cohorts. So I don\'t know
whether it\'s clear which one of those is right.

DR. GRAY: I\'m not, those all differ by exactly 100?

DR. BANDEEN-ROCHE: Yes, yes.

DR. GRAY: So my first guess is somebody has a typo because that\'s
probably not just a coincidence that they\'re both exactly 100 off.
These calculations that you see here, the mean cell, the sponsor sent me
a data set at the end of July, July 25th, that has the endothelial cell
counts that I later discovered they were rounded \-- these are mean so
they were rounded off to the nearest cell, the one I got. And that \--
the numbers you see here are what I calculated using the data set that I
was sent.

Now, if the three and four years \-- if the two-year number is correct
of 2428, then I would say 2455 and 2456 are probably not correct,
because that would mean that there was an increase between two years and
three years as well.

DR. BANDEEN-ROCHE: Okay, thank you.

DR. WEISS: Dr. McCulley?

DR. McCULLEY: Yeah, I\'ve already expressed a little bit of skepticism
about the emphasis being put on cell density but I know those are the
numbers you had when you did your analysis, but from a clinical
standpoint just over the years, I\'m a little skeptical about putting
too terribly much weight on something that can vary depending on where
you take the count and the variability over time, the reproducibility,
so I remain a little skeptical in that regard based on my clinical
experience and what I\'ve seen in reviewing papers and hearing
presentations over many years.

So I guess then my question is, did you do any statistical analysis
assessing the size and shape variation over time of the cells?

DR. GRAY: No, I did not do that. I used the results that we were
submitted to us by the sponsor which seemed to indicate there was really
not an issue. So I didn\'t \--

DR. McCULLEY: Not, an issue, I\'m sorry, meaning what, that there
wasn\'t a change over time?

DR. GRAY: There did not seem to be a change through time for either the
percent hexagonal or the CV and I didn\'t dig into that further. I used
the same thing that you got in the submission, which is the analysis
that the sponsor did.

DR. McCULLEY: Yeah, I mean, in the absence of data, I don\'t really know
for sure what\'s right here and your extrapolation caveats, I think, are
good and it would be nice to have the very long-term data, but at least
from a cell density standpoint, my impression is that the critical cell
density for corneal edema is 800 plus/minus 400 roughly tremendous range
and tremendous variability. And that these other factors seem to play a
very critical role and it would be more comforting for me to know that
we had more data to support the size and shape didn\'t change over time.
The numbers just aren\'t \-- or the density isn\'t the only thing and
there\'s tremendous variability in the measurement methodologies.

DR. WEISS: One thing, and I hope that we can pull this perhaps on the
lunch break is one difficult item is for the August 2002 panel meeting
when we had some of the people who were working with sponsor actually
consult and guide the panel as far as what the requirements should be
for such a study, I do not recall any such emphasis on hexagonality and
coefficient of variation. The number \-- the cell density is what was
emphasized. Dr. Grimmett can comment in terms if your recollection is
any different.

DR. GRIMMETT: Yeah, Mike Grimmett. I was the assigned primary reviewer
for endothelial analysis at that meeting in August of \`02 and in the
presentation I made and included in the outline were the references that
Dr. Edelhauser was citing regarding the sensitivity of pleomorphism and
polymegathism so it was covered. I don\'t think the sponsor emphasized
it or the presenters emphasized it but I did cover it in my
presentation, making very similar comments to what Dr. Edelhauser said.

DR. WEISS: Dr. Mathers?

DR. MATHERS: Thank you for the clarity of your presentation. I thought
it was very helpful. In the written work that we were given beforehand,
you note that the \-- by your model one you had an endothelial cell
density loss in absolute numbers of about 49 cells per year and 20
percent of the population actually had a cell loss of 100 cells per
year. That\'s what you\'re saying. Am I correct in assuming then that
that 20 percent of the population in this population would then have an
endothelial cell loss rate of about 3.8 percent per year by that
calculation? If the 4.9 is average and the average is 1.9 by your model
1, it seems to me that would give a 20 percent of this group that were
having a loss of 3.8 percent per year. I mean, that\'s the logical
conclusion.

DR. GRAY: That is a conclusion that I didn\'t actually calculate. It\'s
very difficult \-- the problem is it\'s hard enough to estimate the mean
function here and now we\'re trying to estimate the line below which
only 10 percent of the people are going to be. And that actually is not
\-- is even harder statistically.

DR. MATHERS: Right, okay.

DR. GRAY: The best estimate I can do right now, based on the data we
have are what I gave in the presentation, which is that 25 percent of
the people will have 2.3 percent or more. Now, if I understand your
confidence limits on that, it would be pretty wide.

DR. MATHERS: Right.

DR. GRAY: I\'m not sure exactly what they are. I haven\'t \-- I don\'t
have them on me.

DR. WEISS: Seeing no other \-- Dr. Macsai?

DR. MACSAI: I have three brief comments and I thought all your
presentations were great, thank you. The first, they all revolve around
endothelium but the first is to Donna. In all your presentations about
ANSI and the guidance documents, nowhere did you mention a history of
contact lens work and in light of all this discussion about endothelial
cell remodeling, I would ask the agency to consider adding that so that
that \-- I think it\'s a critical piece of information to help us in the
future on any intraocular device.

So I didn\'t see it. Maybe it\'s there.

MS. LOCHNER: It was discussed at some of the earlier panel meetings and
the end result was that I think given considerations to the population
you\'re treating and that there is going to be contact lens wear and
what\'s the practical thing to impose on a clinical study, in the end
the panel didn\'t give that emphasis, but I do hear what you\'re saying
and I appreciate the comment.

DR. MACSAI: I\'m simply asking for history so that you could segregate
out \--

MS. LOCHNER: Oh, yes, yes.

DR. MACSAI: \-- who wore lenses and who didn\'t preoperatively. It helps
analyze this endothelial cell data.

MS. LOCHNER: Yes, and I think many studies will be able to do that.

DR. MACSAI: Okay, the second two questions are for Dr. Gray. In this
data set you received from the sponsor, do you know if patients who had
exchanges at the time of implantation or subsequent to the time of
implantation were excluded because that would skew this data, I think
significantly?

DR. EYDELMAN: I think I actually touched on this in my review. I believe
there were two different analysis. In the overall analysis by the
sponsor, the data for the eyes that underwent secondary procedure were
included, but they were excluded in the analysis where they were
determining ACD significance.

DR. MACSAI: But were they excluded in measuring endothelial cell density
long term?

DR. EYDELMAN: They weren\'t excluded from continuation of collection of
data if that\'s what you\'re asking. We don\'t have the analysis for
those eyes separated out.

DR. MACSAI: Well, do we have an analysis of the eyes that had the lens
put in once and only once and never touched again and what happened to
the endothelial cells?

DR. EYDELMAN: I believe that would be the analysis where the tables for
the ACD depth significance were performed.

DR. MACSAI: And then I would ask Dr. Gray, looking at those tables, does
your slope still hold to the green versus the black slide number 15 or
whatever it was, 13, sorry?

DR. GRAY: I guess I\'m \-- first of all, I\'m not entirely sure because
I don\'t recall the exact \-- I didn\'t actually do that analysis both
ways to compare but the key difference between the estimates that we saw
was the fact that the 37 or the 57 patients had a lower, a much lower
count at the three-year time point than the other group and that\'s what
is driving most of the difference. All the other methods of analysis and
different groups of patients that you include, if you get beyond just
the three and four-year data, you have a switch and so all of a sudden,
it\'s about two percent, 1.8, 1.9, 2 and so it really comes down to a
question of what time point you think the remodeling is over or whatever
happens during the surgery is done with and beyond that, we can consider
steady state. And then you get into the whole issue of what does that
even mean and how can we extrapolate 20 years down the road which is
sort of unanswerable, I think, with the data we have.

DR. MACSAI: Maybe I\'m not getting something here.

DR. EYDELMAN: Let me just try to add, we don\'t have exactly what
you\'re asking for, Dr. Macsai. We don\'t have the analysis of just the
eyes that had secondary intervention, the endothelial cell separated
out. What I do want to point out were that there were few eyes to start
out with and chances are some of them did not have the analysis all
together. As far as I\'m aware, PMA did not contain breakdown for the
\-- on this issue. Certainly your recommendation can look upon it after
the panel.

DR. WEISS: Since we\'re running 40 minutes behind and we haven\'t gotten
into a discussion, I\'m going to have one brief comment by Dr. McCulley,
and then we\'re going to go to five minutes of questions for the sponsor
and then break for a 45-minute lunch.

DR. McCULLEY: Okay, a critical question seems to be in humans, how long
does it take for the endothelium to remodel after an injury and is it
degree of injury dependent, is it age dependent? I don\'t know the
answers to those questions but that seems to be absolutely \-- the
answer to that seems to be absolutely critical in knowing how to
interpret the cell density and the cell shape and size change. Do we
know that? Do we know how long it takes to \-- and maybe when the
sponsor comes back, Hank will know. But that\'s a key question to all of
this.

DR. WEISS: I want to thank FDA for an excellent analysis and
presentation. Sponsor, would you be able to answer or address some of
these issues?

So you have five minutes to answer all our questions. While the sponsor
is setting up, when we break for lunch, I\'ll just point out, this will
be abbreviated. It will be 45 minutes, not an hour as listed in
deference to the fact that we are running over significantly at this
early point in time.

MS. THORNTON: Are you ready, Dr. Vukich?

DR. VUKICH: Pardon me?

MS. THORNTON: Are you ready?

DR. VUKICH: I believe so. For some reason, I believe the projector was
changed out from underneath us. Okay. We would like to just take a
moment to respond to a couple of the questions that were requested of
the sponsor. For the number of sites that were contributing to the
four-year analysis, this data was collected at eight of the nine sites
that were collecting specular micrographs. We were able to calculate the
confidence interval for the 37-eye consistent cohort of eyes at all of
the intervals and that will be the graph that follows.

There was clarification that we will need from Dr. Bandeen-Roche on her
request for information on an overlie of one of our cohorts, but it may
take a little more time than we have available and a little more
clarification on exactly what we would like to provide. This is the
90-percent confidence interval of the mean for the 37-eye cohort and at
four years, which I think is the point of interest. It was 2244 to 2509.
I see we\'re taking notes here. Okay, good. This is the entire cohort
then for the endothelial cell density. For a point of clarification,
this cohort did include all patients and these were also \-- who were
examined and did include patients who had secondary procedures so in
some essence it does look at a worse case scenario.

A separate analysis of the data, subtracting those patients out has been
done. We can tell you that it shows no difference in our estimation. We
were hoping it would, but it didn\'t.

There was one final question that we\'d like to address and that was
from Dr. Bradley. There was a question concerning pupil size and quality
of vision. We wanted to point out that our contrast sensitivities were
all done under mesopic illumination at 3 candelas per meter squared.
Although we did not have pupil size to correlate with that, there would
be some assumption that the pupils would be at least smaller than under
photopic conditions and that with and without glare there was no
demonstrable difference at post-operative contrast sensitivity and in
fact, at four of the five measured intervals, there was actually an
improvement in contrast sensitivity so we hope that speaks to the
quality of vision at least under mesopic conditions.

Finally, we\'d like to thank the members of the FDA panel for their
thoughtful and thorough review of all of this information. Thank you.

DR. WEISS: Thank you for making it brief.

DR. McCULLEY: Does Hank have an answer to my question?

DR. WEISS: We\'ll find out. Can you make it \-- can you give a brief
answer and if the answer is, we don\'t have the information, then that
is the answer.

DR. EDELHAUSER: I think that is the answer. We don\'t really have the
information. The only really data that we can rely on is probably the
keratoplasty data from Bill Bourne which showed a market drop-off, you
know, and that\'s not really the data we\'re after. So we don\'t have
the data.

DR. WEISS: No data. Forty-five minutes for lunch and then we\'ll be
starting promptly.

(Whereupon, the proceedings in the above‑entitled matter went off the
record at 12:22 p.m. and went back on the record at 1:14 p.m.)

DR. WEISS: Can everyone from the panel take their seat, please. We\'re
going to continue the Committee deliberations on this PMA with
presentations from Primary Panel Reviewers, beginning with Dr. Marian
Macsai‑Kaplan. I will remind Panel Members and Sponsor, and FDA, et
cetera, that we are now about an hour behind, so I would suggest or
request that all comments be short, to the point, and have the purpose
of moving this PMA ahead.

DR. MACSAI: I\'m done.

DR. WEISS: With that non‑intimidating introduction, I have Dr. Macsai.

DR. MACSAI: I would like to first acknowledge a few things. One is, that
the Sponsors did an amazing job on a really fast track PMA, and that the
FDA did an outstanding job in getting us this information as fast as it
could be gotten. And I want to really thank Sally for being in such
close communication. This was a difficult PMA to review I think for all
of the reviewers.

The Sponsor has gone through a lot, and so has the FDA, so I\'m going to
try and limit my comments, but I have a few things I just feel obliged
to say.

First of all, you saw in the distribution of the patients enrolled in
the study, that the vast majority were Caucasian. And from previous
devices we looked at, we realized that we do need to look at the affects
in non‑Caucasian patients. The Sponsor did supply data from the
Dominican Republic data set, and I think it would be important for that
to be included in anything made available to the public, segregated by
refractive error, to help the non‑Caucasian population with their
expectations.

Second of all, exclusion criteria were included, and 65 eyes with
pre‑existing conditions were included in the study. The results of what
happened to those 65 eyes should also be made available by the Sponsor
to the Agency, because from those 65 eyes, we may glean information that
would help patients who might be treated in an off‑label manner.

In addition, in the exclusion criteria, limbal pathology was not
included, and must be included if a white‑to‑white measurement is
required to size this IOL.

Another additional criteria that must be included for exclusion is what
the lower limit of endothelial cell counts are per age group. And I
would reference Dr. Grimmett\'s excellent review for that.

I\'m going to now address efficacy, and then the questions put forward
by the Agency. Efficacy of this device is really good, very good. And
I\'m going to just limit by comments by saying that I was happy to see
the efficacy of this data in the 3 to 7, 7 to 10, and 10 to 15 diopter
groups, and leave the over 15 diopter group for later in my discussion.

I would have some questions why a refractive surgeon might use this in a
minus 3 diopter group, and until I personally see data that this is
superior to refractive surgery already out there, I would personally
wonder about that issue.

Regarding the specular microscopy data, which was my question 1 in the
original questions provided by Dr. Eydelman to us, I feel uncomfortable,
plain and simple. I feel uncomfortable because we haven\'t set a limit
of what is the minimal number of endothelial cells that a patient needs
to have. We\'re talking about implanting a device in a 22 year old
patient, taking worse case scenario, as the Sponsor said earlier.

We\'ve segregated out the patients that had complications, replacements,
removal, and if you take a 22 year old and assume that they don\'t
become in need of a cataract until they\'re 62, assuming they\'re
myopic, they have a higher prevalence of nuclear sclerotic cataracts,
you\'re talking about the device remaining in place for 40 years. And at
40 years, according to Dr. Gray\'s chart, they\'re going to drop to a
dangerous limit. And so my discomfort comes from the fact that the
surgeons who participated in this trial are the best of the best. They
have the best hands, they have the best experience. I\'ve had the
privilege of being taught by some, and observing them, and they are
really the best there is, so we\'re taking a device and releasing it to
Joe Q. Average surgeon, and this device will be seen as sort of a drive‑
through procedure, I\'m afraid, where you drive in, you get your IOL,
you drive out, you move to Outer Mongolia, and we don\'t know what
happens to you. And we don\'t know what\'s going to happen in 10, 20,
30, 40 years to the endothelium. So I, of course, having experienced the
closed‑loop AC IOL induced pseudo phakic bullous keratopathy, am
concerned about this device and its effect on the endothelium. And that,
to me, is the biggest issue with this PMA. Everything else is really
pretty small in comparison to that.

Along those lines, we were asked to look at the anterior chamber depths.
And I think the Sponsor has shown, Dr. Gray has shown, everyone has
shown that in the hands of the best, with an anterior chamber depth less
than 3, this device induces a 50 percent higher endothelial cell loss.
So at this time, my recommendation would be that this device not be
labeled to be used in an eye under 3 millimeters anterior chamber depth.
And that if the Sponsor has further data, that can, of course, be looked
at in the future.

Question 2 is the nuclear opacities. Nuclear opacities in this
population developed at two time courses, early‑on, probably
surgically‑related. Later on, probably nuclear sclerosis developing in
these high myopes.

I didn\'t have a big problem with this, but it brings very much to the
surface the training of surgeons who are going to use this device. If
you look at the Canadian data in those three inexperienced surgeons,
there was a 22.5 incidence of anterior subcapsular opacities, while the
surgeons that were proctored in the Dominican Republic only had a 4.8
percent incidence of anterior subcapsular opacity development. So
clearly, that technique used in the Dominican Republic has some effect,
so the Sponsors are now left with a huge challenge; how do you take Joe
Q. Average surgeon and make him good enough to use this device?

And some of my suggestions would be that this device, this Collamer ICL
is very similar to the Collamer posterior chamber intraocular lens and
Toric intraocular lens that is currently available, and has been for
years, for cataract surgery. And that any surgeon who wants to implant
this device must first become proficient using that intraocular lens and
loading it in the shooter, which is the exact same, and implanting it in
the eye. And only after they\'re proficient with that device, should
they then be able to use this device. And they should be proctored one‑
on‑one in the use of this device.

But it brings to mind another concern, which is, if you look at the
analysis of the investigational sites, one surgeon at one site had a
significantly higher number of complications, and a significantly higher
number of IOL removals and exchanges. And remember, we\'re dealing with
the best of the best, so I raise this question to the Sponsor, pending
release to the general public, how is the Sponsor going to monitor this?
If the Sponsor has to supply these IOLs to someone who\'s exchanging
them too often, or repositioning them too often, the Sponsor seemingly
should have some kind of tracking method for this, and further training
required prior to the release of this device. And it\'s a big, onerous
task, but we\'re talking about putting this in young people with clear
lenses, so I think that there\'s a degree of responsibility the Sponsor
will have on this post‑approval.

Regarding the Agency\'s question about removal, and if there\'s areas of
touch, and if the uncorrected vision is worse than 20/50, I thought
these were fine caveats, but I would also raise the question to both the
Agency and the Sponsor, if there is an anterior subcapsular cataract in
the visual pathway, should that also be added as a reason for removal?

Question 3 regarded the use of the horizontal white‑to‑white in the
anterior chamber depth measurements to determine the sizing of the ICL.
I too, like Dr. Grimmett, went back to my operating room and looked at
what I had available to measure white‑to‑white, and it\'s just a little,
I think, Castroviejo caliper, and mine goes by 1 millimeter increments.

I, like Dr. Vukich and Dr. Slade, was trained in a time that we did
extra caps, we measured white‑to‑white. I think my residents have done
five extra caps in their entire training. I don\'t think they know how
to measure white‑to‑white. I think the Sponsor is going to either have a
huge task of teaching them how to do it, or find a better technique. And
for that, I would recommend consideration of the Orbscan, which we now
know has been shown in the Wang article from the Development of
Ophthalmology Journal to be reproducible. It also supplies your anterior
chamber depth.

I\'m not endorsing that product. I hold no interest in that product, but
it\'s out there, and it would give a reliable reproducible measurement
for the beginning surgeon. Regardless though, if the patient has limbal
pathology, you cannot ascertain a white‑to‑white measurement; therefore,
that is an exclusion criteria in my mind for this device.

Question 4. There are currently no devices approved in the U.S. for
correction of myopia greater than 15 diopters. True. So I feel once
again very uncomfortable here.

First of all, clearly this device in that population does not correct
myopia, it only reduces it. So in light of Dr. Eydelman\'s question, we
have to change \"correction of\" to \"reduction of\". But I worry that
we, as a panel, are going to arbitrarily set a standard by approving
this in this age range.

I look to the Agency, and ANSI in their wisdom for guidance, and my
feeling is once a guidance document is developed in this population,
minus 15 to minus 20, and the Sponsor has this engineering thing worked
out, that at that time, once the guidance document is set, if the device
meets the guidance document criteria, approval is a no‑brainer. But at
this time, we have no guidance, and I\'m uncomfortable with arbitrary
approval, which would set a standard, because I am certain there will be
more phakic IOLs to come in the future.

Question 5, does safety and effectiveness data support approval of the
STAAR ICL for the eyes with the following pre‑operative MRSE, minus 3 to
minus 7, minus 7 to minus 10, minus 10 to minus 15. And in general, my
response to this question is yes. However, there remains this
outstanding issue regarding endothelial cell loss, sizing of the IOL,
cataract information. I\'m not uncomfortable with the cataract
formation, sizing of the IOL is fixable. And I guess I feel if Dr.
Edelhauser doesn\'t have the answer for endothelial cell loss, I don\'t
know who will. And so, we\'re functioning in a big old gray zone. And
maybe a warning that might be appropriate is that endothelial cell count
must be done on these patients pre‑operatively, and should be done on
these patients post‑operatively for a very long time. And if there is a
decrease long‑term in endothelial cell count, not from an otherwise
obvious condition, such as a high fema, trauma, iritis, that perhaps
this device should be explanted to protect these patients from pseudo
phakic bullous ‑‑ from bullous keratopathy at some time in the future.

The Sponsor Question 6, management of acute intraocular pressure rises
in post‑operative period. Well, I\'m disappointed that gonioscopy was
not performed post‑operatively in these patients, and I think that Dr.
Lochner\'s presentation has addressed this issue. A mistake was made in
the development of this PMA protocol, and it will have to be rectified
in the future. But perhaps if the PIs were made farther in advance ‑ I
don\'t know, one week seems awfully early to me ‑ the PI would have
healed, and not of them might have been included. And there wouldn\'t be
a need for reopening in the future.

In addition, I think the Sponsor must mandate that the surgeon check the
pressure within 4 to 6 hours after placement of the device, and again in
24 hours, so that if it\'s the viscoelastic, this can be addressed.

Question 7, Sponsors have reported that a number of patients noted glare
and/or halos post‑operatively. Again, I\'m disappointed because though
Dr. Schallhorn might feel pupil does not make a difference, and I know
this lens is much farther inside the eye, I think we could have learned
a great deal from that information. And I would ask the Agency to
mandate pupil measurements in the future, so that our patients can have
a better idea of what to expect from a device. Without it, we can\'t
answer the question, so we\'re kind of left ‑‑ we need to include the
data about glare and halos, what patients experienced. We need to
include the data about the quality of vision pre‑operatively. It was
poor at 11.6 percent of patients pre‑operatively, but at 36 months, it
was still poor in 5.8 percent of patients. And that\'s a little
disconcerting, because if you read the recently published paper where
they compared an eye with an ICL and an eye with LASIK, those patients
were doing great. And I have no doubt that the refractive quality with
this device for patients will be better than a minus 10 LASIK. And that
the higher order aberrations will be less with this device than a minus
10 LASIK. But I\'m still wondering why 5.8 percent of the patients rated
their vision poor. Who were they, and why was it poor? So that concludes
my presentation. Thank you.

DR. WEISS: Thank you very much, Dr. Macsai. We\'re going to have Dr.
Joel Sugar, who\'s the second primary reviewer.

DR. SUGAR: Thank you. I\'m going to just skip through various parts of
my review. Of course, I want to thank and compliment the Sponsor and the
FDA reviewers for the excellent job they did in both putting the data
together, and then analyzing the information.

The accountability was good in the study. The efficacy was good up to
the minus 15 diopter range, and beyond that range, certainly reduction
of myopia should be the indication, or the labeling should be for
reduction of myopia, not for correction of myopia. The stability was
good.

In terms of safety, the loss of lines of best corrected visual acuity, I
thought was very acceptable. I think that you can play games about the
fact that the minification has changed and, therefore, you should lose
less lines, but what matters to the patient is how well they see. And if
they don\'t lose lines of vision, even though they should have
theoretically gained a line of vision, I think they\'re still
benefitted.

I was concerned about the patients who required enlargement of their
laser iridotomies post‑operatively because of elevated interocular
pressures. In my review, I had the wrong time periods because I measured
from the baseline examination, not from the day of treatment. I\'m
concerned about the Sponsor developing a better means of assessing the
iridotomies, both their spacing and their size, so that these patients
won\'t have the pressure elevations as high as 65, as were noted in the
presentations.

The retinal detachments, I think were acceptable given the population
that was being assessed. The cataracts, I think, were acceptable given
the population that was being assessed. Although I have concern about
the recommendation for removing the lens when anterior subcapsular
cataract is seen at an acuity of 20/50 or greater, I would be more
concerned about removing it when there\'s progression of cataract. If,
however, I had the data that I don\'t have, which is, is going in and
taking the IOL out, putting a new one cause more progression of the ASC
or not, and I don\'t think we\'ve been presented with any information to
tell us whether that does or does not happen.

I\'m also concerned in terms of the issue of cataracts, since these are
patients who will develop cataracts in the long run, like all of us. Is
axial length measurable through the IOL easily or not? Does a new
algorithm have to be developed for ultrasonic, or whatever technique is
used for measuring axial length?

People who have their axial length measured, their anterior chamber
depth measured ultrasonically could presumably have that data, their
axial length captured concurrently and presented to the patient. And it
would, I think, make sense, since this is an implant, that the patients
be given a card with the data on the lens implanted. But also, if
there\'s data on their axial length, that that be captured, unless it\'s
easy to measure their axial length with the IOL in place, and it would
be nice to know that from the Sponsor. It would also be nice to know
whether exchanging the lens in and of itself induces another order of
complications.

Endothelial cell loss has, I think, been very well discussed, and I
guess I do feel that, contrary to what I wrote in my review, that
anterior chamber depth less than 3 should probably be contraindicated
for this lens.

There are a few other minor issues. There\'s some in the labeling that I
mentioned in my review. For example, in the brochure it says that
surgeons should never touch the center of the optic with instruments
when it\'s in the eye. I don\'t know if that\'s because of concern about
leaving imprints on the lens, or it\'s because pushing the lens, pushing
the IOL into the crystalline lens could induce cataract. It would be
worth having a statement in the brochure saying why that\'s an issue.

The statements made, again, in the labeling, that this device has \"been
shown to improve the overall quality of vision\", I think that\'s too
broad a brush to paint this with. I think you need specific data saying
that some patients have overall vision improvement, some don\'t, and
give data.

The brochure should also, I think, have a picture of the device, and a
picture of the positioning so that even if someone\'s taking a course,
they will have some hard copy information, should a question arise about
lens positioning; although it seems pretty obvious.

In terms of the specific questions, is there sufficient data to suggest
that there\'s remodeling? I think that there is. I\'m concerned that we
capture more data in four years, and definitely capture data at five
years on endothelial cell loss. I don\'t think that we should wait for
that information to approve the product.

I already talked about the anterior chamber depth. Do I believe surgeon
experience is an issue? Absolutely, and that\'s been addressed by the
Sponsor, saying that there will be mandated training. I also talked
about the anterior subcapsular cataract, that we need more information
on what secondary interventions do.

Do I believe the method for determination of overall diameter is
appropriate? I think that it is. I think that white‑to‑white is not as
difficult to measure as has been implied. While Orbscan gives it a .1
millimeter on a standard printout, it gives you the white‑to‑white up to
.1 millimeter, I don\'t think that that ‑‑ and that\'s been shown to be
reproducible, I don\'t know that it\'s been shown to be any better than
manual white‑to‑white measurements. And certainly, hasn\'t been shown
with this device to provide any advantages. And it\'s a substantial
expense for the average practitioner, who may not have the Orbscan.

We talked about the greater than 15. I think that the device should be
approved for correction of myopia up to minus 15 diopters, and for
reduction of myopia beyond that level. And I think that ends my review.
Thank you.

DR. WEISS: Thank you very much, Dr. Sugar. The last reviewer, Dr.
Grimmett.

DR. GRIMMETT: I\'m pleased to have the privilege to make a few comments
about the application. I apologize for any redundancy. I didn\'t have
any of the talks before during the preparation of my talk. Additionally,
part of my purpose and mission is to get the information in the public
record, so that interested patients in the future can search relevant
issues regarding this device.

You\'ve obviously all read my review, the cure for insomnia, and I will
try to highlight just a few of those issues, but will not go over the
data in excruciating detail. You can be happy about that.

Before I dig into the PMA, I\'d like to go over a few background issues
regarding the application to help us in our overall analysis. First, I
want to review a few issues related to phakic IOL lens vault. Proper
lens vaulting is clearly critical to the success of this phakic IOL.
Excessive vault over the crystalline lens will push the iris forward,
and has the following potential complications; angle closure, angle
synechiae, iris chafing with potential complications of pigment
dispersion and pigmentary glaucoma, iris sphincter erosion, iris
translumination defects, and alteration of the normal aqueous dynamics
that is pupilary block.

On the flip side, a poor vault in the ‑‑ over the crystalline lens has
the potential to induce cataracts due to IOL crystalline lens contact.
Moreover, if the IOL is too short, it\'s theoretically possible for it
to be mobile, with possible rotation or anteroposterior movement.
Clearly, the vault has to be just right to minimize complications, and
the tolerances are expected to be low.

With an older version of the ICL, Version 3, the Sponsor believes that
poor lens vault led to a higher right of anterior subcapsular opacities,
quoting results from Sanders, in the Journal of Refractive Surgery in
2002. The current application states that Version 4 has an additional
.13 to .21 millimeters of anterior vault, as compared to Version 3. And
while I didn\'t find data in the PMA to substantiate that, the Sponsor
clarified today that\'s a design issue.

In the literature, Gonvers & Associates examined central vaulting with
digitized slit lamp photographs in 75 eyes. They had 24 V3s and 51 V4s.
At three months, the central vaulting of the 24 V3s was slightly less
than the central vault of the 51 V4s, but the difference in their study
was not statistically different. And they concluded, \"The change in
design between models V3 and V4 did not achieve its goal, which was an
increase in vaulting.\" I just bring that up because I didn\'t see any
data in this application to substantiate the assertion in vivo.
Certainly, it\'s important to keep in mind that increased vaulting may
reduce cataractogenesis at the expense of iris and angle complications.

In the application, when looking at vaulting, one gets the impression
that the phakic IOL vault is a static situation, but I don\'t ‑‑ this
couldn\'t be further from the truth. Stable phakic IOL vaulting on a
day‑to‑day basis is probably not achievable for numerous reasons. Number
one, accommodation has been shown to decrease anterior chamber depth by
about a quarter of a millimeter, increase the lens thickness by .28
millimeters, and it decreases the radius or curvature of the anterior
surface of the crystalline lens.

Number two, lens vaulting may differ, depending on whether the patient
is supine or prone; that is, gravitational effects. And number three,
the light reflex has been shown to cause a reduction in the phakic IOL
anterior capsular distance. Therefore, on a day‑ to‑day basis, the
actual lens vault is probably a dynamic variable.

Here\'s an ultrasonic image from Kim and colleagues in AJO in 1998. The
third image on the top shows accommodation on a 30 centimeter target,
and displays a decreased distance between the IOL and the crystalline
lens right there, due to changes in lens thickness and radius of
curvature.

The fourth image shows a relationship of the phakic IOL to the
crystalline lens in total darkness right here. And then the relevant
change when shining a penlight on this eye. In this particular case,
there\'s IOL lens contact with simply a light reflex. Based upon these
data, perfectly static phakic IOL crystalline lens relationships on a
day‑to‑day basis are improbable.

Moreover, stable IOL vault over the lifetime of the eye is probably not
achievable either for numerous reasons. One, the soft IOL material may
flatten with time. Dr. Vukich, I believe, mentioned European or outside
the United States data over 10 years, that it may not. There is an
article in the literature that indicates that it may. I believe it\'s
from Arne.

Number two, aging has been shown to increase the lens thickness by 1.24
millimeters from age 40 to age 65. Number three, plate phakic IOLs may
rotate or have mobility. And number four, the ciliary sulcus diameter
has been shown to decrease by approximately 1 millimeter in diameter
from age 40 to 80.

All of these day‑to‑day and lifetime issues may lead to intermittent or
permanent IOL crystalline lens contact, and may lead to
cataractogenesis, pigment dispersion, subclinical inflammation, and/or
disruption of the normal aqueous humer dynamics. Given these factors, I
can\'t imagine that ICL positioning will be stable and problem‑free for
the lifetime of a given patient, especially since this device is
intended for young recipients.

Let\'s talk about issues related to the sizing of these IOLs. The sizing
of the ICL myopic lenses was determined by the horizontal white‑to‑white
and the anterior chamber depth measurements in the following fashion.
For anterior chamber depths 2.8 to 3‑1/2, they added half millimeter to
the white‑to‑white, and for anterior chambers greater than 3‑1/2, they
added 1 millimeter to the white‑ to‑white. For in‑between sizes, there
was a rounding down and rounding up protocol.

Hence, STAAR\'s sizing methodology is based upon white‑to‑white
measurements. However, valid scientific evidence exists saying that
white‑to‑white measurement do not correlate to the sulcus dimension. So
white‑to‑white measurement does not ‑‑ is not a good surrogate marker of
the variable of interest, the sulcus diameter.

Here is just one piece of information from Reinstein\'s study, in which
he examined white‑to‑white values with calibrated photographs and
sulcus‑to‑sulcus dimensions with high frequency ultrasound. All this
information is in the public domain. It\'s right off the Internet.

The top value shows that of myopic eyes, plotting white‑to‑white on the
X axis, and sulcus‑to‑sulcus on the Y axis, that there\'s no correlation
for myopic eyes. The same was true for hyperopic eyes.

These data imply that a one‑size fits all phakic IOL would seemingly
have just a good chance of success or failure as basing the ICL upon the
horizontal corneal diameter.

Let\'s go ahead and look at a few examples of basing the ICL on
white‑to‑white measurements to display this fact. Here\'s a case where
white‑to‑white is 11‑1/2 OU. Put the ICL based on that, bravo, it looks
pretty good ‑ adequate lens vault in both eyes, left and right, so
we\'re pleased with ourselves on this case.

The next one we have an asymmetric white‑to‑white, 11‑1/2 on the right,
and 12 on the left. However, despite differing white‑to‑ white
measurements, the lenses were over‑sized in both by about the same
amount, rather than an asymmetric amount, and the vault is excessive,
causing angle closure, as you can probably see.

Here\'s a case where the same white‑to‑white existed on both sides, but
the vault was excessive on the right, and non‑existent on the left, with
lens IOL touch. I simply would say that because there\'s valid
scientific evidence indicating there\'s a lack of correlation between
white‑to‑white and sulcus‑to‑sulcus, that physician labeling should
include relevant material facts indicating the lack of the correlation.
In fact, in knowing this data now, it\'s amazing to me that the vault
data within the application is as good as it looks.

We\'ll review a few issues related to glaucoma. And please pardon me,
Dr. Coleman. I will defer to your judgment on these issues. I\'m just
the cornea guy. Projected glaucoma risks for this device include pigment
dispersion syndrome, angle narrowing, and angle closure.

Regarding pigment dispersion syndrome, it\'s important to realize that
STAAR\'s study cohort fit squarely within the known risk factors for
pigment dispersion syndrome; that is, myopia young age in Caucasian
race. Pigment dispersion syndrome is at least as common in women as in
men.

One study quoted about a 2‑1/2 percent incidence of pigment dispersion
in Caucasians. Simply using this figure based on the number of
Caucasians in the STAAR PMA, we\'d expect six in this study to have
pigment dispersion. The Sponsor reports zero, both before and after ICL
implantation. Let\'s look to the literature.

A published study found pigment dispersion in the angle in 9 of 58 eyes,
or 15‑1/2 percent at 18 months. The authors postulated that the STAAR
ICL pushes the iris anteriorly, and optic iris chafing leads to pigment
dispersion syndrome in a subset of patients.

A 1998 study, using ultrasound after ICL implantation, found angle
narrowing in all eyes, and peripheral anterior synechiae in 2 out of 9
eyes, or 22 percent. The ICL was in wide contact with the iris in all
eyes.

For this study, I reviewed the submitted PMA materials, and reviewed
both the pre‑op and post‑op clinical study report forms. I didn\'t find
any gonioscopy data, which I was shocked to see that. I also didn\'t
find any ultrasound data presented to determine angle anatomy
alterations following the ICL. It\'s my opinion that the lack of these
data is a disservice to present and future patients with the STAAR ICL,
and represents a major study design error.

Gonioscopy can assess angle pigment deposition, a sensitive and common
finding in pigment dispersion syndrome. Perhaps no patient was diagnosed
with pigment dispersion syndrome because no one looked at the angle
post‑op.

Moreover, gonioscopy can determine angle narrowing and synechiae.
Further, if no gonioscopy examinations were performed, other relevant
features could be missed, vascularization and other preoperative
abnormalities.

The theoretical risk to the angle can be easily surmised given the
design and intended use of this phakic IOL, and it\'s my belief that the
initial study design should have included gonioscopy, whether or not it
was mandated by the FDA.

Let\'s review issues related to pupil diameter and the lens optic
diameter. It\'s well known that dim illumination mydriasis can be robust
in the young. Dr. Vukich indicated that when this study was designed,
that those parameters were not well known. Being an old guy, I beg to
differ. Back in about 1993‑94, I reviewed issues related to pupil
diameter with small optical zone radial keratotomy. My literature review
at that time revealed that the mydriasis being robust in the young was
documented, well know, and in the literature at that time. I believe
that predates the design of this particular study.

STAAR\'s study cohort ranged from 22 to 45 years of age, and we\'ve
heard that the lens optic diameter is 465 to 55. Given the young age of
the cohort, as Dr. Bradley already noted, it\'s reasonable to expect
that some patients will have dim illumination pupil diameters that
exceed the lens optic diameter. We, therefore, have an expectation that
some patients may experience halos and dim illumination, or have
nighttime visual aberrations.

Looking to the literature, Arne found a higher frequency of halos with
small optic diameter ICLs. The rate of halos correlated to the
difference between the scotopic pupil diameter and the optical zone
size. Due to these halos, these authors recommended intentional
under‑correction for high myopia; that is, using a larger optic diameter
lens followed by LASIK.

Hence, another study design error in this PMA is the absence of pupil
size measurements. Relevant analysis should have included the rate of
visual aberrations with increasing optic pupil mismatch. Regrettably,
this was not performed for our review.

In the absence of this pupil size information, the best we can do is
stratify the patient\'s symptoms by the lens optic diameter. I couldn\'t
find this information in the materials given to me, but it should be
required for later FDA review. Also, each symptom category should be
reported separately; that is, separately none and mild, rather than
lumping the categories in the current tables. Of course, this
information presumes that the small lens optic patients do not have
skewed pupil sizes one way or the other. We\'ll simply never know.

Let\'s go on to endothelial cell loss. The threshold analyses that I
presented in Appendix 1 of my written review show maximum rates of
annual cell loss to reach various target levels at the time of death.
Clearly, there\'s many assumptions that are made, including an annual
instantaneous cell loss, and that it\'s linear, and it doesn\'t include
information regarding stem cell repopulation. However, using these
figures, if we desire a 1500 cell for millimeter square density at
death, a .9 percent annual loss rate is the maximum, inclusive of all
age ranges; that is, the 20 to 30 year old range. And if we desire an
800 cell per millimeter square density at death, a 1.9 percent annual
loss is the maximum.

It\'s important to remind ourselves that 50 percent of patients will
have endothelial cell densities that fall below the normal mean cut‑off
values; and, therefore, younger patients, that 20 to 30 age group, have
a significantly higher risk of running out of endothelial cells during
their lifetime if these rates are continuous. And now to the PMA itself.

Regarding the study population, the total eyes show with the blue bars
indicate very good follow‑up. I certainly recognize the difficulty of
carrying out such a large study for an extended period of time, and
commend the Sponsor for their efforts. The purple bars show endothelial
data on approximately 200 eyes, with a large drop‑off at the 48 month
interval shown out here as 67 eyes.

I find it ironic, some studies we reveal at panel only have 6 and 12
month data, and we\'re always wrestling with not enough data. And here a
Sponsor has run a 3 and 4 year study, and we\'re still wrestling with
not enough data. I just found that amazing.

Unfortunately, the endothelial data in the written PMA have varying
ends, and there\'s no consistent cohort of eyes followed through each
and every examination interval. The data we\'ve seen today with that 37
eye consistent cohort was not provided to me in the materials that I
reviewed. That made the evaluation difficult.

Just one housekeeping item, and I believe Malvina already alluded to
this. The inclusion criteria had a stable refraction within a half
diopter over the prior year. The indications for use statement had a 1
diopter over the prior year, obviously, needs to be matched or
reconciled.

Regarding the exclusion criteria, we know that phakic IOLs can alter the
corneal endothelial. Dr. Macsai alluded to this. The corneal endothelial
status was omitted from the exclusion criteria, and given the young age
of these patients, I believe it would be a relevant material fact to be
considered prior to implantation of this device.

Certainly, if a young patient had an abnormal endothelial layer, I would
not recommend this device as a clinician. There is no question that I
wanted pre‑op specular endothelial analysis for this cosmetic elective
procedure, where the alternative is glasses or contact lenses.

On to some safety issues. Let\'s discuss the learning curve associated
with phakic IOL implantation. I believe we\'re all in agreement that the
labeling should include relevant learning curve issues. Of the 13 upside
down lens insertions, 11 occurred within the investigator\'s first 22
procedures, 6 out of 13 developed in AST in the early post‑op period. Of
the 14 eyes that developed anterior subcapsular cataracts, most occurred
within each investigator\'s first 8 surgical cases. One investigator
accounted for a disproportionate share of the ASCs, a 9.4 percent rate,
and that same investigator accounted for both cataract extractions in
the study. To lessen the impact of learning curve issues for the
patient, I\'d favor specialized course training or case supervision by
an experienced surgeon for early cases.

On to change in best spectacle corrected visual acuity. As compared to
the lower dioptic groups, there are larger post‑op gains of best
corrected visual acuity, 20/20 or better, in the high myopia group. For
the less than 7 diopter group shown in the orange, there is an 8.3
percent gain pre‑op among 36. For the 7 to 10 diopter group shown in the
maroon, there\'s a 15.6 gain pre‑op among 36, and for the greater than
10 diopter group shown down here in the blue, there\'s about a 20.4
percent gain pre‑op among 36. These are findings strongly argued for an
induced magnification effect as a result of the surgery.

In looking at greater than or equal to one line of best corrected visual
acuity loss, high myopes have an increased rate of vision loss with time
as compared to lower myopes. And we\'ve already heard that for this
particular group, a one line loss is the equivalent of a two line loss
due to induced magnification as a result of the surgery.

The rate of greater than one line loss goes up to about 16 percent. I\'m
not sure why that would exactly be. I don\'t know if that has to do with
lens optic pupil mismatch or other issues, but I\'m not sure it\'s well
delineated. It\'s certainly not clear in my mind as the ultimate
etiology of that.

Another way to look at the same issue, the mean improvement in lines of
vision, high myopes with time decline in improvement starting at 6
months, one line improvement down to .4, two line improvement at 36
months. Certainly, appropriate labeling should mention this trend.

On to interocular pressure, 20 of 526 eyes, or 3.8 percent had pressure
spikes in the early post‑op period, 11 reached 40 to 50, 4 reached 55 to
58, and 1 reached a whopping 65 millimeters of mercury. Most of the
spikes occurred by day one or two, 17 needed additional YAG, 3 required
AC washout for retained viscoelastic. Clearly, these pressure elevations
are not trivial. Myopic disks are perhaps slightly more susceptible to
damage from elevation of IOP than ametropic or hyperopic disks.

Patient and physician labeling should highlight the issue in order to
appropriately plan early post‑op exams. As a clinician, I might consider
the use of Diamox on a case‑by‑case basis.

With regard to chronic pressure elevation, the overall cohort shows an
increasing trend for patients to experience an increase in pressure
greater than 5, looking at the graph, at 6 months about a little under 3
percent, and at 36 months something over 6 percent, 6‑1/2 percent had a
change in baseline pressure.

Pre‑op, looking at patients with a pressure greater than 21, about 3
percent had pressures greater than 21, and at 36 months about 6 percent
had pressures greater than 21. Two patients were diagnosed with glaucoma
and treated topically.

Given the potential for the STAAR lens to alter pressure regulation for
the factors previously mentioned, I\'m concerned about this finding. We
must recognize these recipients are young, expected to live many future
years. At a minimum, labeling should emphasize this particular issue. I
again note that the STAAR study omitted gonioscopy for a device that
affects the angle. Gonioscopy can assess pigment deposition, a sensitive
and common progressive finding in pigment dispersion syndrome. Angle
grade and synechiae formation are also relevant findings. Inexplicably,
gonioscopy wasn\'t done. If I were a clinician, I would be doing
gonioscopy.

The corneal endothelial data ‑ in the materials provide there was no
true consistent cohort data for each and every examination interval.
There was fluctuating denominators at the various examination intervals,
and this made our analysis difficult. We\'ve seen data today on 37 eyes
that had consistent cohort data, but the remainder of the application
does not.

While this is not a consistent cohort of eyes, there appears to be
progressive endothelial cell loss over time. The total at four years is
insufficient to make conclusive statements, but the cell loss does not
stabilize over the study period. These cell loss rates, if continuous,
constitute a serious safety issue that may jeopardize approval of this
device.

Looking at the 154 eye consistent cohort at year 3, pre‑op to 36 months,
8.9 percent loss, that was higher than the table we just looked at with
8.4 percent. It took me a long time to figure out that there were two
disparate groups that had an \"N\" of 57, and both reported 4 year loss
rates, and both were called the consistent cohort. Two groups, pre‑op to
48 months, there was a 9‑ 1/2 percent endothelial loss. Three year to
four year there was a .041 percent endothelial gain, with the upper
limit of the 90 percent confidence interval at 1.43 percent loss per
year.

It\'s this one isolated group, as we\'ve heard, which the Sponsor is
making the argument for stability in conjunction with the morphometric
data that Dr. Edelhauser reviewed.

Let\'s look closer at this 57 eye cohort. This is a histogram that was
in the material somewhere, that outlines where these eyes fell in terms
of cells gained or cells lost. The mean cell density increased by one
cell. Overall, just looking on the number of eyes on either side as
zero, 31 eyes lost cell density, and 26 eyes gained. More eyes lost zero
to five here at 21, than gained zero to five. It\'s about even on either
side of 5 to 10, 8 versus 7. This is the group that had me wondering.

Here\'s a group out here gaining 10 to 15 percent of cells, versus only
one eye losing 10 to 15 percent. Of these 7 histogram analyses in the
application, this is the only one that had more eyes gaining 10 to 15,
than losing 10 to 15. Certainly, I\'m willing to accept random
measurement error that leads to an evenly matched set of gains and
losses. That is a true bell curve due to precision errors measuring
endothelial cell loss, but I can\'t come up with a physiologic reason
that five eyes have truly gained a sizeable percentage of endothelial
cells in 12 months. I\'m wondering whether these big ticket outliers up
here at 10 to 15 percent skewed the mean data and falsely elevated it,
leading us to a conclusion of stability.

We\'ve heard from Dr. Gray, and his comments were greatly appreciated by
me. I place great emphasis on statistical analysis of the data. He noted
that simple comparison of the two to three year loss versus the three to
four year loss is not appropriate due to the likelihood of producing
negatively correlated observations. And he mentioned that multiple ways
by saying that the three year loss was lower than the other data points.

He also noted there was not strong statistical evidence that the cell
loss levels off after year three. Additionally, of the 57 eye cohort
with both three and four year data, 10 out of 57, or 17‑1/2 percent had
more than 5 percent cell loss over 12 months. Those are pretty big
numbers if those are true for a young cohort.

Based upon these data, I remain scientifically unconvinced that this
procedure provides a reasonable assurance of safety for the corneal
endothelium in the long run. The preponderance of evidence that we were
offered was weighted toward an unsafe level of endothelial cell loss,
that if continuous, would jeopardize the safety of a future interocular
procedure or cause corneal edema during the patient\'s lifetime, or
both. I think we\'re all in agreement, we need a larger four year sample
size. I would agree that ongoing endothelial surveillance to year five
would be desirable, given the youth of the cohort.

I\'ll talk briefly about anterior chamber cell depth. We see that the
endothelial loss in eyes with shallow anterior chambers was 12.2 percent
over three years, while the loss was 8.4 percent for eyes with anterior
chambers greater than three. As Dr. Macsai noted, a 50 percent increase
in shallow chambers. I would not necessarily disagree with an abundance
of caution approach to limit the device to eyes with anterior chambers
greater than 3.

It\'s worthwhile noting that only 5‑1/2 percent of the total study
cohort would be excluded by this limitation. And, therefore, I don\'t
believe it\'s an onerous limitation that would exclude large numbers of
patients. I think it\'s reasonable to do that.

Something interesting in this 57 eye cohort, in addition to looking at
the histogram, if we look at the anterior chamber depths for 50 of these
eyes in that cohort with three to four year data, 50 eyes had an
anterior chamber depth greater than 3 millimeters. They gained .3 ‑
excuse me ‑ they lost .3 percent in endothelial cell loss from year
three to four, and there were 7 eyes with an anterior chamber depth that
was shallow, and they had a 2.9 percent gain in endothelial cells
between years three to four.

From my vantage point, that didn\'t make sense. That was a
counter‑intuitive result that contradicts the generalized study results
of a higher rate of loss in the shallow AC group. From my vantage point,
something smells wrong with that 57 eye cohort. I would love for that
four year cohort to be larger so that it would even it all, so that
we\'d have a better statistical sense of what\'s going on.

On to effectiveness, and at this point I\'m going to stipulate to Dr.
Slade\'s excellent presentation on effectiveness, and we\'re not going
to go over all this data, so yadda‑yadda‑yadda, the procedure seems
effective. That\'s enough of that.

In terms of willingness to have the ICL again, 5.6 percent less than 7
diopters were not willing to undergo it again. And in the greater than
15 diopter group, all patients were willing to undergo it again, despite
poor effectiveness and high rate of complications. I interpret this
finding just to mean that low myopes are less desperate for the surgery,
as compared to high myopes who appreciate help of any kind, even though
it may not be perfect.

And in conclusion, this does appear to be an effective device to reduce
myopia. We must be reasonably sure that the endothelial cell loss does
indeed stabilize following ICL implantation. It\'s critical to recognize
that these devices are intended for a young population with 50 plus
years to go. We can\'t afford an epidemic of bullous keratopathy for a
cosmetic elective procedure.

I\'m also concerned that while the morphometric data show that we don\'t
have a change in pleomorphism or polymegathism, what I\'m concerned
about is that there\'s evidence to suggest that younger corneas may
blunt our ability to see those changes. I\'m just wondering whether
we\'re not seeing much of a change for chronic stress simply due to the
fact that the cohort is a bunch of young corneas.

Dr. Edelhauser, I believe, was in general agreement that younger corneas
are robust, and may not show stress factors as readily as an older
cornea, so I\'m concerned that the data does not have statistical
evidence to show that it tapers off for sure, and I\'m concerned that
the younger corneas may blunt our ordinary morphometric data that would
ordinarily tell us there\'s stress.

I certainly need convincing with a larger \"N\" for the four year
endothelial data one way or another. I think that number needs to be
bigger. Thank you very much for your attention, and I apologize if it
was redundant.

DR. WEISS: Thank you, Dr. Grimmett, for your usual detailed, insightful
reviews.

We\'re going to now go on with panel discussion of this PMA. I\'m going
to ask the FDA if they\'d be so kind to come to the podium. And I would
also request that we go out of order of your questions. There\'s a
method to my madness, so I\'d like to start with question 3, which is a
discussion of how to decide what size to put in the eye. And in terms of
whether the currently recommended method measuring the white‑to‑white,
which was recommended by the sponsor is an appropriate way to do it. And
if not, what does the panel recommend.

I will remind you just in terms of what we\'ve heard from our reviewers,
Dr. Macsai was recommending using the Orbscan or something similar,
because the white‑to‑white is not very accurate. And Dr. Grimmett also
agreed, the white‑to‑white was not very accurate. But I\'d like us as a
panel to determine whether we\'re going to recommend that the labeling
include the way the panel ‑‑ the way the sponsor did the study, which is
measuring white‑to‑ white, or do we want something else. Dr. Sugar.

DR. SUGAR: I\'d like to recommend that we recommend no changes from the
Sponsor has recommended, given that we don\'t have anything better that
I\'m aware of. Certainly we don\'t ‑‑ while the white‑ to‑white doesn\'t
correlate with sulcus‑to‑sulcus dimensions, it is highly impractical to
do ultrasound biomycrospy as 20 or 50 megahertz. It\'s very unwieldy. At
50 megahertz you almost can\'t do it. You have to make a collage of the
pictures in order to measure it, and I don\'t think we have anything
better. If something better becomes available, it may be worth
recommending in the future.

DR. WEISS: Dr. Macsai.

DR. MACSAI: I respectfully disagree with Dr. Sugar, not about ultrasound
biomicroscopy, just about the irreproducibility, if that\'s a word, of
the caliper method. And that since you need an anterior chamber depth
measurement from the back of the cornea to the front of the lens,
you\'re getting two for one there with Orbscan. That\'s been validated
reproducible.

DR. SUGAR: I said measure white‑to‑white. You\'re talking about
measuring white‑to‑white in terms of what instrument? I didn\'t say what
instrument to use.

DR. MACSAI: Well, I did.

DR. SUGAR: That is, you\'re saying ‑‑ I understand ‑ that Orbscan is a
better way to measure white‑to‑white. And again, I don\'t ‑‑ I\'m not
aware of validation of that information apropos of this device.

DR. MACSAI: Well, then I guess we need to ask the Sponsor if they used
that technique, because I thought the Sponsor used many techniques. I
don\'t know if I\'m allowed to do that at this time, Madam Chairperson.

DR. WEISS: Not at this time. We can have them address it in the proper
time point, but not at this point. Does anyone else have any opinions on
that? We\'re going to get some musical accompaniment at the same time by
Dr. Bradley which is quite kind. Anyone else have any opinions on this
particular point? No, so I think that is ‑‑ does anyone have any
concerns about measuring it with calipers, aside from those that have
been expressed? So we will move on. I guess for the FDA, I think what\'s
been expressed is if the Sponsor has shown that Orbscan is any more
accurate than calipers, we would go with that, but I doubt that\'s what
they\'ve shown, because if they did, that would have been clearly
presented. Malvina.

DR. EYDELMAN: The nature of the question wasn\'t to try to determine the
instrumentation that\'s best to perform the measurement with. The
question ‑‑ during the study, the white‑to‑ white was only measured with
calipers. The Orbscan was used for ACD. What this question intends to
get at is whether the white‑to‑ white measurement is appropriate for
sizing of the ICL.

DR. WEISS: Well, I think the panel would probably agree that it may not
be great, but we don\'t have another option. And nothing else was done
in the study, so we don\'t have a choice. Would anyone disagree with me,
any of the primary reviewers disagree with that spin? So the answer is,
we think it\'s just great, since we have nothing else. We will go to
question 4.

DR. EYDELMAN: Did you want me to read it, or do you want me to just
project the question part?

DR. WEISS: Why don\'t we ‑‑ can you read the question part of the
question?

DR. EYDELMAN: Question 4(a), \"Does the safety and efficacy data for
eyes with preoperative myopia of greater than 15 to 20 diopters support
this range\"?

DR. WEISS: From what I understood from all of the primary reviewers,
everyone seemed to be in agreement that it supported this refractive
range if the labeling was changed to reduction of myopia, as opposed to
correction. Dr. Macsai.

DR. MACSAI: Maybe I misled you. I didn\'t mean that. I think that this
is something the Agency has to provide a guidance document on. I think
when the Agency tells us what are acceptable outcomes in the minus 15 to
minus 20 range, then we can approve it. But right now, we\'re throwing
the dice. It\'s arbitrary.

DR. WEISS: Dr. McCulley.

DR. McCULLEY: I have to ask a question of what the Agency expects of us.
If they bring something to us for an opinion, and they have a guidance
document, then we would apply our opinion, or use that in our decision
making. If they bring something to us and ask us an opinion where
there\'s not a guidance, then I think my impression would be the FDA
would be asking us to provide our best opinion based on what\'s provided
to us.

DR. WEISS: You\'re entirely correct. And also guidance documents are
just that, you don\'t have to adhere to guidance documents. They\'re
just meant as guidance. So with that in mind, Dr. Macsai, what is your
opinion sans guidance document?

DR. MACSAI: My opinion from history is once approved, guidance or no,
it\'s set as a standard for those that follow. And I urge the panel to
proceed with caution. I think it\'s arbitrary. I think the numbers are
limited, and I have trouble with it in this range of myopia because once
this is approved, every other device will be measured compared to this.
Whether appropriate or not, the comparison will be made.

DR. WEISS: I see Dr. Rosenthal shaking his head, and I think really what
we have to do ‑ this is not a guidance. This is, we have to decide on
the efficacy and safety of this particular device. And you can have the
labeling reflect. So, for example, as has been suggested by Dr. Sugar,
you could say that this does not ‑‑ this is not for correction of entire
myopia in above minus 15, but it\'s for reduction of myopia in this
group. Dr. Rosenthal.

DR. ROSENTHAL: May I just clarify, Dr. Macsai, that in fact, each Class
3 PMA must stand on its own, and a decision should be made without
comparison to data from any other PMA. And I think that\'s the way ‑‑
we\'ve been pretty consistent about that over the past 7 or 8 years. So
hopefully, what decision you make on this will not bear on another
decision made on another device.

DR. WEISS: Dr. McCulley.

DR. McCULLEY: My impression is that often despite guidance to industry,
they will try to use prior PMAs and compare, despite the fact that
they\'re advised not to do that. We don\'t have any control over that.
But it really should not set anything that can be legitimately used in
the future in a PMA application or presentation.

DR. WEISS: And also, we\'ve just been, you know, guided by Dr.
Rosenthal, is that we should not be ‑‑ that should not reflect what your
opinion is at this particular point. Your opinion should stand alone for
the devices being brought forward to you. So with that in mind, without
thinking of the future or the past, just the moment, is this efficacious
for reducing myopia in patients who have more than a minus 15? Dr.
Schein, then Dr. McMahon.

DR. SCHEIN: Jayne, I hope I don\'t throw too much of a wrench in the
works, but it seems to me there\'s one overriding question that needs to
be addressed before getting into the sub‑levels. So assuming that
there\'s some consensus that there is efficacy, which I think I\'ve
heard some consensus, there also seems to be some consensus of concern
about certain adverse events.

DR. WEISS: Which we will get into, so this is ‑‑

DR. SCHEIN: Which you cannot separate this tension between having an
appearance of safety during a short time period, and uncertainty in a
long time period. You can analyze this all day long, and that
uncertainty will still be there. So my entire focus on these questions
has to do with the level of rigor and detail that one can request in a
post market setting. Everything else depends upon that.

DR. WEISS: Because these are going to be very ‑‑ this is going to be,
obviously, a much longer discussion and much more detailed, I\'m trying
to get some of the housekeeping out of the way. I understand this is not
scientific, but on the other hand, I think it\'ll work, so I\'d ask you
to bear with me.

DR. SCHEIN: Okay.

DR. WEISS: We may not get to the bottom line on all these questions, but
certainly, once we start getting involved in the question of what are
the endothelial cell specular microscopy data mean, are we talking about
post‑market studies, this is going to be a more lengthy discussion, and
I want to delay that lengthy discussion.

DR. SCHEIN: Okay. So to answer, I\'d say efficacy, yes ‑ safety,
unknown.

DR. WEISS: Fine. That\'s good enough. Dr. Matoba.

DR. MATOBA: Then maybe we should do the first of those questions first,
and then come back to this.

DR. WEISS: Well, I\'m actually mostly interested in efficacy, so I think
if the answer is it shows efficacy for reduction, then we have an
answer. And then I think for the question of safety, that\'s going to be
going across the refractive ranges. Is there any other discussion on
this particular question? We may need to come back to it.

SPEAKER: Can you get a sense of the panel for us?

DR. WEISS: I\'m just going to have a hand show, a brief vote. What ‑‑ if
the members of the panel could raise their hand if they believe that
this device is efficacious for reduction of myopia in patients with
refractive errors greater than minus 15. Those of you who believe it\'s
efficacious, we\'re not discussing safety at this moment, can you please
raise your hand.

(Vote taken.)

DR. WEISS: So I think that\'s ‑‑

SPEAKER: Is this a reduction, Jayne?

DR. WEISS: Reduction, yes. I think that\'s consensus, so that would
answer for efficacy. I\'m going to skip then to Question 6 on IOP rise,
if we could.

DR. EYDELMAN: There was a 4(b), but I was instructed to skip it.

DR. WEISS: What was 4(b)? I\'m sorry.

DR. SUGAR: Corrections to treatment.

DR. WEISS: Well, we did say reduction. We said reduction of myopia.
Question 6 relates to IOP increase. Would you be able to read that?

DR. EYDELMAN: Certainly. \"Do you believe that specific recommendations
regarding early post‑operative follow‑up are needed in the labeling\"?

DR. WEISS: So Dr. Macsai has suggested in relationship to the IOP rise
that it be suggested that the pressure be checked 4 to 6 hours later.
Dr. Sugar suggested that there should be ‑‑ the Sponsor should indicate
a better way to assess the size of the iridotomies when they\'re too
small. Could I have some discussion on these particular recommendations?
Dr. Macsai.

DR. MACSAI: I would also ask maybe Dr. Coleman to help us with the
question of timing of the iridotomies, if 7 days in advance is the
appropriate amount of time to ensure patency. And then the second part
is, which I forgot to mention in my verbal review, I did in my written
review, is whether or not irrigation and aspiration of the viscoelastic
would be recommended by the Sponsor, because that\'s what was used when
the pressure rise was thought to be due to retained viscoelastic in
those problematic cases.

DR. WEISS: Dr. Coleman.

DR. COLEMAN: This is Dr. Coleman. In terms of the timing, it\'s really
hard to tell from their data whether or not the problems that they had
with the iridotomies closing in the post‑op period was because the
iridotomies were done within 7 days of the surgery. They were still on
steroids when you look at the PMA at the time of surgery, so it would be
recommended that they actually had done the iridotomies at least two to
three weeks prior to surgery, confirmed the patency of the iridotomies
prior to placing the implant. And then also having the patients off of
steroids, because that would reduce their steroid responders, because
they also had problems in the PMA of individuals that they identified as
having interocular pressure elevations due to steroid response.

And in their labeling, they do have that irrigating with a 27‑ gauge
cannula to the wound is sufficient to flush viscoelastic from the eye. I
would say that\'s not true. Their own data shows that it\'s not
sufficient, and so you would ‑‑ they would need to change that wording,
and also to show in the labeling that if you don\'t flush the
viscoelastic from the eye, you can have some major problems with
interocular pressure spikes. So as Dr. Grimmett had mentioned, IV Diamox
may be beneficial in preventing these.

In terms of checking the interocular pressure afterwards, that would
need to be within like 4 to 6 hours of a procedure, and then the
following day they would also need to check it within 24 hours, and also
48 hours, because they had spikes up to two days. And it\'s well known
that viscoelastic can remain in the anterior chamber from 48 to 72
hours, if it\'s not flushed out.

DR. WEISS: Let me just clarify. You would then suggest in labeling that
it be indicated to check pressure 4 to 6 hours, and 48 hours. And what
are your time points?

DR. MACSAI: I would say 4 to 6, 24, and 48 hours.

DR. WEISS: Is that not onerous? We don\'t do that with cataract
extractions. Dr. McCulley.

DR. McCULLEY: The issue is ‑‑ I mean, if you\'re going to irrigate, as I
understand it, the way the viscoelastic was removed, it\'s a cohesive
viscoelastic. You tried to irrigate it out with a 27‑gauge cannula. Why
not use something like a Simcoe needle for I&A? I mean, I think that\'s
the point. Then there would be less concern. I still would go with the 4
to 6 hours, and the 24 hours, but I would think that would be a better
approach.

DR. COLEMAN: Because one of the problems is you get ‑‑ this is Dr.
Coleman. You get viscoelastic in the trabecular meshwork, and even
sometimes even irrigating it out, you don\'t get all the viscoelastic
out in certain eyes. And some of these eyes are going to be predisposed
to having interocular pressure spikes. Because of the study design, they
were already on steroids, and so that\'s predisposing them, in addition
to their being myopic.

DR. WEISS: How many procedures do we do that we require patients to come
back 4 to 6 hours later to check if we still have viscoelastic in them?
I mean, I think that\'s not ‑‑ that\'s fairly burdensome in my book.

DR. COLEMAN: Well, there may ‑‑ I think one of the issues is that if you
take eyes that run and spike pressures up to 55 or 65, and these eyes
are, you know, very painful and stuff, it\'s an issue in terms of in the
orange study when Dr. Grimmett had pointed out, where they looked at
those 50 eyes. They actually gave people IV Diamox on the table, and the
4 hours later post‑operatively, and they didn\'t report any of those
acute IOP pressure spikes.

DR. WEISS: But if we\'re talking about such a small percentage of eyes
that are ‑‑ in which that\'s happening, wouldn\'t it ‑‑

DR. COLEMAN: You don\'t know the long‑term ramifications of elevated
interocular pressure spikes to 65 for 24, 48, 72 hours, even in a young
person.

DR. WEISS: Dr. Mathers, and then Dr. McCulley.

DR. MATHERS: In common sense terms, I don\'t see that this is terribly
difficult from filling an eye with viscoelastic when you do cataract
surgery, measure pressure the next day, and if there\'s a problem, you
continue to measure it. It sounds to me like this would work if you did
that, but I certainly think it\'s necessary to measure it the next day.
And if you treat promptly, you perhaps will tolerate, like cataract
surgery patients do, a brief pressure rise.

DR. COLEMAN: This is Dr. Coleman. It\'s debatable how brief is 24 hours
with a pressure up to 65. And even if you potentially irrigate it, they
can re‑spike again. I mean, it\'s ‑‑ we see it in terms of the
management of individuals with cataract surgery, where we have to go for
48 hours, sometimes managing pressure spikes. Now these are eyes with
compromised angles, but you don\'t know how many of these individuals do
have already potentially compromised angles because we don\'t really
have the gonioscopy on it. And so it\'s some ‑‑ unfortunately, the issue
is muddied with the viscoelastic, the closed iridotomies, and then
potential problems with the angle due to the placement of the phakic
lens.

DR. WEISS: You know, I think on this particular issue, since it\'s ‑‑ we
can agree to disagree on this particular one, so that has ‑‑ the idea of
perhaps suggesting an IOP check in 4 to 6 hours, and 24 hours, and also
putting in labeling that the IOP rise may occur if viscoelastic is not
rinsed. Those have both been suggested. Can you elaborate, Dr. Sugar,
about the labeling advice you would want as far as the iridotomies go?

DR. SUGAR: I will ‑‑ well, I need to back up a little bit. I think that
there were only 2 or 3 patients that required re‑ irrigation of
viscoelastic out of 20 that had pressure elevations that were
substantial. I don\'t think that\'s sufficient to mandate a change in
the way you get rid of the viscoelastic.

There\'s a cost issue if you\'re going to have to have a machine to do
I&A , and having tubing and stuff, or even a Simcoe. I don\'t think
there\'s sufficient evidence to suggest that the techniques suggested by
the Sponsor should be altered. Your question was?

DR. WEISS: You had mentioned having a better way to assess the size of
the iridotomy when it\'s too small.

DR. SUGAR: I just wonder if the Sponsors had from those 17 patients that
needed their iridotomies enlarged, if there was ‑‑ you know, if the
distance between them was insufficient and, therefore, they were
covered, or if there was something about them that would suggest a
different approach to doing the irridotomies to make that less likely to
happen. I certainly think that Anne\'s suggestion that you do it longer
in advance, and you look and see that they\'re patent makes perfect
sense.

DR. WEISS: So basically, if the Sponsor could provide information of
what they\'ve learned for those iridotomies that had to be enlarged,
what was done incorrectly the first time around?

DR. SUGAR: If they have such information.

DR. WEISS: I think unless anyone has more comments on this question,
we\'ll go to Question number 1.

DR. McCULLEY: You\'ve skipped 5. Jayne, you skipped 5.

DR. WEISS: I know. Intentionally.

DR. McCULLEY: Okay.

DR. WEISS: Because I was afraid that Dr. Schein was going to be getting
out another wrench.

DR. McCULLEY: You pretty much rusted his wrench.

DR. WEISS: I have a feeling it was going to be headed in my direction,
so we\'ll go to 1. One is the question which has been sort of the most
emphasized point during the discussion, is about the significance of the
specular microscopy data. And I\'m going to hit a couple of things
concerning this question that maybe we can reach consensus on before we
get to the more contentious issue.

Dr. Grimmett and Dr. Macsai both suggested that a minimal number of
cells, specular microscopy be performed pre‑op, and that patients have a
minimal number of endothelial cells before consideration is made for
having this procedure. I\'d like to have some discussion on that by the
panel. Is that something that people agree with or not? Dr. McCulley.

DR. McCULLEY: Oh, I was just nodding to myself.

DR. WEISS: That\'s dangerous around here.

DR. McCULLEY: I see. I think that\'s reasonable. I think that to screen
patients to be certain that they have normal endothelium for age prior
to the procedure is wise and prudent.

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

DR. MATHERS: Some of the subjects had very little endothelial counts to
begin with, and that\'s going to be part of this population if you do
any sizeable number. I think it would be very unwise to not have some
lower cut‑off for endothelium. And I think it\'s appropriate to look at
endothelial cell counts.

DR. WEISS: Dr. Grimmett.

DR. GRIMMETT: I agree with Dr. McCulley, but I would ask Dr. McCulley,
would you set your lower threshold at like one standard deviation, or
two standard deviations lower than a normal mean value for that given
age range, or how would you set your threshold?

DR. McCULLEY: I suppose I\'d need ‑‑ you, again, have more confidence in
these counting things than I do. I guess I\'d want to look at the data
for normal, and for age, and one and two standard deviations before I
would answer that. I would just leave it loose and for right now that it
be normal for age. And I would think that would add additional comfort
to all of us, and those who are really concerned about the accuracy and
reproducibility of the density. But I think that would be a reasonable
thing to add, that should give us all more comfort with this whole
issue.

DR. GRIMMETT: Dr. Grimmett again. I agree with Dr. McCulley. I had
suggested a year ago to use age stratified normal means, plus or minus
one standard deviation. But I think that\'s debatable exactly where you
draw the line. Normal for 20 to 30, for example, is about 2950 plus or
minus 150 or so, something like that.

DR. WEISS: Dr. Macsai had also suggested in line with this that post‑op
endothelial cell counts be done, and consideration of explantation be
made if the cell count is dropping. Is that ‑‑ what does the panel ‑‑
Dr. McCulley. You\'re shaking your head again.

DR. McCULLEY: Again, we don\'t know ‑‑ we\'re missing so much
information. We need to know what the remodeling process of the
endothelial is over time based on degree of initial injury, surgical
injury, and age of the patient that has incurred the injury. So I\'m not
sure that I would know what to say in terms of when to do it, when not
to. I think it ends up being surgeon judgment to make those decisions. I
don\'t think we can dictate anything because we just simply don\'t know.

DR. WEISS: Dr. Sugar, then Dr. Schein.

DR. SUGAR: I agree that we don\'t know, and that we have no data, you
know ‑‑ having no reason to postulate a source of progressive
endothelial cell loss, and having no data on what that second
intervention would do to progressive endothelial cell loss, I would
think that that would be actually the opposite of the recommendation
that I would want to make.

DR. WEISS: Dr. Schein.

DR. SCHEIN: We can make a distinction between recommending doing a
monitoring test and the timing of an intervention. So by analogy, one
might recommend in a glaucoma setting, visual fields at a certain
frequency without recommending when a trabeculectomy be done. And I
think that there is a concern about long‑term endothelial attrition, it
makes sense to recommend that the only test that we have be performed on
some schedule.

DR. SUGAR: But we don\'t know what intervention.

DR. SCHEIN: Well, no, but we have an opportunity to, one, learn the
natural history. And the other is to describe to a patient that over the
last five years, you\'ve had a 25 percent loss of density.

DR. WEISS: Dr. Sugar.

DR. SUGAR: There\'s a difference between recommending that the Sponsor
get post‑marketing data on that, and recommending that the practitioner
do that, because we don\'t get that data. And presumably, the Sponsor
doesn\'t get that data.

DR. WEISS: Dr. Sugar\'s point is very important, and we\'re going to be
getting into whether there should be any post‑market studies, is data
that is interesting shouldn\'t be put in labeling. That\'s up to any of
us here or outside to do a study. But data that would be important, we
feel, for patient care, should be put in the labeling. So is the
specular microscopy post‑operatively important for patient care? And Dr.
Sugar would disagree. Dr. Mathers.

DR. MATHERS: I would agree that it is important to patient care. There
are some patients here that had very substantial loss in cell count, and
you would want to pick those up. And it would be important for that
patient\'s well‑being that you do so at some not short interval after
surgery, perhaps a year or something like that.

DR. WEISS: So if you\'re going to give guidance as far as when repeat
specular microscopy would be done, what would you suggest?

DR. MATHERS: As early as three months, possibly six, and at latest, one
year.

DR. WEISS: Somewhere between six months and a year. Dr. Macsai.

DR. MACSAI: That\'s not what I intended by my comment.

DR. WEISS: What did you intend?

DR. MACSAI: My intention was that in my hands and my practice, if I was
to implant this device, which appears to be an efficacious device, we
don\'t have an answer about the long‑term endothelial damage. And I, as
alluded to by both Dr. Sugar, Schein and Mathers, would want to know if
my patient was getting into trouble. And if they go from 28 to 2000,
there\'s trouble right here in River City, and it\'s time to decide if
that thing is safer in or out. And I don\'t want to wait until there\'s
microcystic edema and we\'re transplanting that cornea in a 4 year old.

DR. WEISS: What do you recommend for labeling though? This is what you
do when ‑‑

DR. MACSAI: I want to suggest ‑‑

DR. WEISS: You suggest, okay.

DR. MACSAI: ‑‑ that the practitioner follow their patients with
endothelial cell counts, because that\'s all we have.

SPEAKER: For what time?

DR. MACSAI: Well, my personal opinion, I would say five years. And when
we got all this long‑term data that comes in, and it shows that I\'m off
the wall, I\'ll be the first to stand up and say thank you. I\'m wrong,
and then we can change the labeling on the device, and that will be a
wonderful thing.

DR. WEISS: Well, actually, you know, we don\'t even have to ‑‑

DR. MACSAI: Annually for five years.

SPEAKER: Oh, annually.

DR. MACSAI: Is that what you want?

DR. WEISS: And actually, we don\'t even have to ‑‑ and I\'ll defer to
Dr. Rosenthal. We could just say if this was what we\'re trying to ‑‑
everything is a suggestion here. Even our vote is a suggestion. We could
say that ‑‑

DR. ROSENTHAL: If you suggest that you put it in labeling as a
suggestion, you put doctors in liability risk if they don\'t do it. So
if it\'s in the labeling, and it\'s not done, even as a suggestion, I
think it holds greater water than a suggestion.

DR. WEISS: So you might be suggesting to the malpractice attorney to
take that case.

DR. ROSENTHAL: Did I make myself clear?

DR. WEISS: Malvina.

SPEAKER: You put people at medical legal risk.

DR. WEISS: Yeah. Did you want to comment? No. Dr. Sugar and Dr. McMahon.

DR. ROSENTHAL: Excuse me. So therefore, I think what you put in as a
suggestion will be done.

SPEAKER: That will just be a suggestion, maybe wrong.

DR. WEISS: Dr. Sugar and then ‑‑

DR. SUGAR: To use Mike Grimmett\'s term arguendo, to play devil\'s
advocate, we don\'t know what to do with that information. I think that
it is appropriate in the labeling to suggest that practitioners monitor
corneal health subsequent to the procedure, period, and to deal with
however you see fit. We do not have any information that I am aware of
that suggests that knowing that the cell count is now 1200, and it was
2000 eight months ago, that any intervention that we\'re going to do is
going to alter that state. So how could we make a recommendation that
you gather that information so that you can alter that state, when you
don\'t know how to do it? That\'s ‑‑ my point is that if you go in and
take the IOL out, my suspicion is you\'re going to lose more endothelial
cells. You\'re not going to help the situation.

DR. WEISS: Well, you could say that physicians should monitor the
corneal health with such means as A, B, C, or D, and include this as the
possibilities.

DR. SUGAR: I think that as Ralph suggested, the more specific we get,
the more we constrain the practitioner.

DR. WEISS: Dr. Ho.

DR. HO: Furthermore, just as a retinal surgeon, give me a sense for what
percentage of anterior segment surgeons have or do specular microscopy.
Is this something that is routine?

SPEAKER: Yes. Routine.

SPEAKER: yeah.

DR. HO: Routine for all cataract surgeons? Okay.

DR. SUGAR: No, it is not. No, he\'s talking about the average doctor ‑‑

DR. WEISS: Dr. Macsai.

DR. MACSAI: When it was reimbursable ‑‑

DR. WEISS: Dr. Macsai.

DR. MACSAI: I\'m going to tell you when it was reimbursable it was
routine, so that the access to it, I think, remains.

DR. HO: Furthermore ‑‑

DR. WEISS: How about let\'s tell you who ‑‑ Dr. Ho. Yes.

DR. HO: But I suspect that this procedure, were it to be approved, would
be something that would be done by comprehensive ophthalmologists, as
well.

DR. WEISS: Dr. McCulley.

DR. McCULLEY: From a practical standpoint, there are a couple of issues
here. One, we\'ve already said we thought that a person should have
pre‑op specular microscopy. Number two, most people who are active in
these areas are going to have a specular microscope then to do it
post‑op. And if not, it\'s available in the community, so I don\'t think
we\'ll be limiting the market scope or the number of people doing this
if we require specular microscopy. On the other hand we did, we required
high frequency ultrasonography, we might. But with specular microscopy,
I don\'t think it\'s going to have a negative impact or be unfair to
have it pre‑op. But whether we do make a specific suggestion about it
post‑op or not, I feel less strongly about. I kind of lean toward Joel,
that we need to ‑‑ if I interpreted Joel correctly, we need to leave
that to the judgment of the physician. And then if we want a post‑market
study, then rather than suggesting that every ophthalmologist do it,
that we request a post‑market surveillance study on endothelial cell
count.

DR. WEISS: So I\'d just like a poll at this point in terms of how the
panel views this question. Those who would be in favor of suggesting or
mandating, or indicating in the labeling that endothelial cell counts
not only be performed preoperatively, but also be performed
post‑operatively, and we don\'t even have to indicate at what time
point. Those of you who would like them performed post‑operatively in
the labeling, could you please raise your hand.

(Vote taken.)

DR. WEISS: So we\'re almost split down the middle on that, so that issue
is not decided at this moment. Yes, Dr. McMahon.

DR. McMAHON: We\'re getting into a circular argument here. And we don\'t
have the data to know what\'s happening with the endothelium, so making
suggestions to the Sponsors and practitioners is not ‑‑ it\'s more
emotional than logical. And my suggestion is, is that we get the
information from the sponsor so that you can then address the labeling
question, which goes to a post‑market study, which goes to Dr.
Grimmett\'s seeing year four and year five data. And actually, directing
to this question, the answer is have we showed stability? The answer, I
think, is no, they haven\'t shown anything yet. The second part of the
question is, is how many eyes and for how long? And I think we should
decide.

DR. WEISS: We will in a moment. I want to get to the more difficult
stuff, and just get the simpler things out of the way. The anterior
chamber depth cut‑off of 3, should this ‑‑ would you be able to read
that portion of the question?

DR. EYDELMAN: \"Do the outcomes of the endothelial cell density analysis
provide reasonable assurance of safety for this device for eyes with 1
ACD of 2.8 to 3, and 2 ACD of greater than 3 millimeters.\"

DR. WEISS: And all the primary reviewers, Dr. Sugar, Dr. Macsai, Dr.
Grimmett, all suggested that this not be implanted in ACDs less than 3.
Is there any discussion on that from the panel? Dr. Bradley.

DR. BRADLEY: Dr. Gray, in his statistical presentation, showed no
evidence that there was a dichotomizing of the data. You did a linear
model to fit all of the data, and I queried Dr. Gray on how much of the
variance is explained by this linear model. It looked to me like not
much of it. And, therefore, I wonder about making judgments about a
certain threshold level of anterior chamber depth based upon that study.
It didn\'t seem to me that that was warranted. I wondered why one of the
proponents of this dichotomy would argue this case, and maybe Dr. Gray
could comment on it.

DR. WEISS: Any proponents want to argue this case? Dr. Sugar.

DR. SUGAR: Your point is, you know, the data, I think, does show that
there is a linear, an apparent linear relationship between anterior
chamber depth and endothelial cell loss. And the only question is, is
there a point where we should cut it off because there is no obvious
dichotomy, an obvious point to cut it off. Is that correct?

DR. BRADLEY: Two points, yeah. One is that there is no dichotomy in the
data themselves. And the other point is that this is a mean linear
regression, and the data were highly variable around that point. And it
looked like some other factor was the ‑‑ or factors were the primary
determiner of cell death, or cell loss, not the anterior chamber depth.

DR. WEISS: Dr. Eydelman, I think, has a comment.

DR. EYDELMAN: We actually ‑‑ well, the Sponsor has actually ran several
analyses, and there were no apparent other factors associated other than
anterior chamber depth. And if I may comment on your earlier statement;
yes, you\'re correct, from Dr. Gray\'s model, it is a linear
association.

One must keep in mind, however, that as we progress up that line, the
percentage of the overall population was that ACD depth is going to
increase, i.e., we know that below 3 there\'s only 5.5 percent of the
overall cohort. And when we get up to 3.5, we\'re close to 50 percent of
the cohort. So while it\'s possible that this line could be drawn
somewhere higher, just keep in mind that then you would be excluding a
higher percentage of patients from having the surgery.

DR. WEISS: Dr. Bradley.

DR. BRADLEY: Just an interpretational point. What you said is correct.
It\'s important though to realize that with such an exclusionary
criterion, you would be excluding candidates from the procedure who
would have a much smaller level of cell loss. And you would be including
patients who would have a much larger level of cell loss, simply because
of the variability in that population. And that was the question I was
asking Dr. Gray about, because it seemed there was so much variability
in that regression analysis. He\'s nodding his head there, so perhaps he
could ‑‑

DR. WEISS: Dr. Gray, did you want to address this?

DR. GRAY: Well, the question you asked me was how much of the
variability was explainable by ACD. And unfortunately, I don\'t have
that with me. But you are correct, the relationship appeared to be
linear without an obvious break, and there is a fair amount of spread
around the line. But the decision about where, if at all, to put a cut
point on the ACD is purely a judgment call at this point, I\'d say.

DR. WEISS: Dr. Grimmett.

DR. GRIMMETT: I was in agreement with making the cut‑off 2.8 to 3 for
three reasons. One, the data on that arbitrary break point showed 50
percent higher loss with a shallow depth. Number two, the cut‑off would
not be overly onerous, only 5‑1/2 percent of the cohort would be taken
out. Number three, my review of the literature back last year at our
guidance discussion showed that the closer that phakic IOLs are ‑‑ the
closer they are to the endothelium, the greater risk to the endothelium
with angle supported having a higher risk than high risk clip versus
posterior chamber. So I was using all three in combination just to make
that determination.

DR. WEISS: Aside from Dr. Bradley, does anyone else have any concerns
about limiting it? Dr. Bandeen‑Roche and then Dr. McCulley.

DR. BANDEEN‑ROCHE: Yes. I have two comments. First, I agree with Dr.
McMahon that the primary point, as far as I\'m concerned, is whether
stability has, in fact, been achieved. And, you know, I am not at all
convinced that it has been, so at that point, the distinction between
2.8 to 3, versus 3 and above, I think is totally arbitrary.

The second point just goes back to a point that Dr. Bradley was making
about what else might have explained the variance. And I wanted to ask
Dr. Gray were you able to reproduce, or did you even try to reproduce
the sponsor\'s analysis of what were the factors related to cell loss,
and finding only ACD being the only thing that was related?

DR. GRAY: Well, that\'s a hard question to answer.

DR. BANDEEN‑ROCHE: Sorry.

DR. GRAY: There\'s a ‑‑ we had a fairly complicated situation in terms
of the data because we had multiple measurements per person over time.
We have baselines, and there\'s a lot of missing data. It\'s difficult
to know how to actually model it. The Sponsor went through a particular
procedure where they cut up ‑‑ they binned the data into categories, and
they checked quite a number of potential co‑variates, and the only one
that ended up to be significant was the anterior chamber depth.

If you do some alternative analyses using things like the percent of
hexagonal cells at baseline, or the endothelial cell density at
baseline, sometimes those show up to be significant predictors. It\'s
not obvious how to, for an individual patient though, say whether they
are at high or low risk of having a high rate of endothelial cell loss.
That\'s a very difficult procedure which we didn\'t go through, and that
would take some amount of effort on everyone\'s part to do that.

DR. BANDEEN‑ROCHE: Thank you.

DR. WEISS: Dr. McCulley.

DR. McCULLEY: My comment was with Mike. I don\'t think it\'s so much the
distance, necessarily, as how you\'re fixating it. So you\'re taking AC
versus, you know, a posterior chamber. I think it\'s apt to be more
influenced by the way you\'re fixating than the distance, except for
possibly surgical trauma. If you\'ve got a bigger space to work in, less
problems ‑ smaller space to work in, more damage. But I\'m not convinced
that just the distance ‑‑ if you start throwing in, and try to
extrapolate that, the AC to iris to PC, that that holds up. It\'s apples
and oranges, and grapefruits.

DR. GRIMMETT: Mike Grimmett. Certainly with the angle supported lens
data, there were some minimum distances that had some very unacceptable
rates of endothelial cell loss for the angle supported data in and of
itself. And grant it, some patients are eye‑ rubbers, which would deform
the cornea, touch the edge of the IOL. So certainly for the anterior
chamber at the angle supported phakic IOLs, I think there\'s a very
strong argument that the closer that the optic is to the endothelium,
the higher the rate of endothelial cell loss.

Now, obviously, trying to translate that to all three groups with some
meta‑analysis, obviously, you get fairly sticky in that. But at least in
that one group, I think the data is fairly strong.

DR. WEISS: Dr. McCulley.

DR. McCULLEY: You\'d have to keep it within the category of lens type,
fixation type.

DR. GRIMMETT: Anyway, enough.

DR. WEISS: Just a ‑‑ I think we\'re at the point that panel members are
calling for time out. That definitely means we\'ve belabored that one.
But I\'m not sure we have a consensus on that, but I guess we will go to
‑‑

DR. ROSENTHAL: Vote.

DR. WEISS: It doesn\'t actually really matter if we have a consensus on
it or not.

DR. ROSENTHAL: It helps the FDA. It helps us a lot.

DR. WEISS: At this point?

DR. ROSENTHAL: It depends what you ultimately say, but we need ‑ ‑

DR. WEISS: Well, do you want the consensus right now?

DR. ROSENTHAL: Yeah.

DR. WEISS: Fine. Let\'s have ‑‑ okay. For those of you who want to limit
it, please vote that you\'d like to limit it to 3 and above anterior
chamber depth.

DR. EYDELMAN: It\'s actually above 3.

DR. WEISS: Above 3.

(Vote taken.)

DR. WEISS: Okay. So I guess we do have a fairly good consensus. We\'re
going to ‑‑ if you could read Question 1(a).

DR. EYDELMAN: I guess I\'ll read the whole thing. \"The main change
between 3 and 4 years in 57 eyes was a gain of .1. A decrease in
co‑efficient variation and increasing percentage of hexagonality were
observed. Is there sufficient data to support the Sponsor\'s conclusion
that the losses in the first three years are reflective of the surgical
trauma was a prolonged remodeling culminating in stabilization of cell
loss after three years.\"

DR. WEISS: And I\'m going to just cut the question off there. We spent
quite a bit of time having the data presented to us in different
formats, showing us the impressions of this, so I don\'t know that we
have to discuss this. But I would like to get an impression of the
panel\'s opinion on this particular one by vote. And for those of you
who agree there\'s sufficient data to support the Sponsor\'s conclusion
that there is stabilization of cell loss after three years, for those of
you who agree with that statement, can you raise your hand.

(Vote taken.)

DR. WEISS: So what I can see is that no one on the panel believes that
there is a stabilization of cell loss ‑‑ that the data support that
there is necessarily ‑‑ well, why don\'t you phrase it, Dr. McCulley.

DR. McCULLEY: Well, I mean, your question was ‑‑ we don\'t know. The
question was, do we agree the Sponsor has presented data that assures us
that there\'s stabilization after three years. We don\'t have that data.

DR. WEISS: Fine.

DR. McCULLEY: We have an opinion, but it\'s opinion based on things, not
based on data. I like to base it on data.

DR. WEISS: That\'s fine.

DR. McCULLEY: We don\'t have data to support that.

DR. WEISS: So we do not have any data ‑‑

DR. McCULLEY: Up to three years, and then we can argue the three to four
years.

DR. WEISS: Okay. We do not have data showing that there is stabilization
at that period of time.

DR. EYDELMAN: So what is the minimum number of eyes, and the minimum
length of follow‑up that you recommend for this assessment?

DR. WEISS: And what this is getting to, I think is, in order to get this
information, are we talking about any ‑‑

DR. BRADLEY: Let Karen answer that.

DR. WEISS: Well, are we talking about any further studies, longer
studies? Dr. Bandeen‑Roche.

DR. BANDEEN‑ROCHE: Yeah. I mean, I would consider it entirely a question
of a minimum number. I mean, if you\'re looking for a number to
establish a power, I mean, I would hope that you would at least try to
establish power to ensure a rate of decline less than something, or a
precision to establish what the post three year rate of decline is.

I would also encourage you not to only focus on the mean, as Dr.
Grimmett has raised; that it\'s also important to think about what are
the proportion who are declining at an unacceptable rate. And so one
could do power calculations or precision calculations to establish a
number sufficient for that quantity. But it does also go to
representativeness of the cohort, you know. And so that\'s certainly
unlaying my question about how many providers was it. You know, I would
be totally less convinced about the quality of the data if it was the
one or two best surgeons who had provided the 67 eyes. It sounds like it
was not, that that was not the case. But I don\'t have any feel for how
representative the 67 eyes that we have are. And, moreover, if I look at
Dr. Gray\'s data, one thing that I have been worried about was
regression to the mean. And so, for instance, if the eyes that are
contributing to that 3 to 4 year, the 57 eyes, I guess, 3 to 4 year
interval were those who had declined, you know, particularly far from 2
to 3, or were particularly low. Then one could expect somewhat of an
improvement just due to regression to the mean, let alone things like
contact lenses and issues like that. And so, indeed, according to Dr.
Gray\'s table, all visits, the cohort of 37 has a mean cell count, 100
cells less than all of the other eyes at three years. So that is in the
direction of that concern.

And I guess a final point that I would make would be everyone has been
commenting that we\'re in a gray zone, that the physicians who
participated in this study were the best of the best. And so I would not
at all just settle for a 95 percent confidence found, you know, just
barely squeaking in there at a level of a 95 percent confidence found. I
think that I would recommend a bit more assurance than that, taking into
account the fact that this is a precedent, that these are the best
physicians who participated in this study.

DR. WEISS: I think we have to be careful about this best physicians
talking about lack of data. I\'m sure these were good docs and good
surgeons, but creating this extra god‑like category, I think we should
take out of the discussion.

DR. BANDEEN‑ROCHE: That\'s a point well‑taken. That\'s a point
well‑taken. Nonetheless, I mean, we hardly expect better performance in
the field than we do in a clinical trial.

DR. McCULLEY: You don\'t have data to support that statement, do you? Do
you have data to support that statement? You do. Okay.

DR. ROSENTHAL: With all kinds of devices.

DR. McCULLEY: All right.

DR. WEISS: What I would then like to lead to is since there\'s agreement
‑‑

DR. ROSENTHAL: Wait.

DR. WEISS: Yes.

DR. ROSENTHAL: I want to make sure I said the right thing. Once they go
out in the field, they tend to have more problems than they do within
the clinical trial.

DR. McCULLEY: But you don\'t have data to support that the people who do
the trials are the best of the best.

DR. ROSENTHAL: No.

DR. McCULLEY: I think that is opinion ‑‑

DR. MACSAI: That\'s my opinion.

DR. McCULLEY: That is Marian\'s opinion, and it should not be in our
discussions.

DR. WEISS: So we\'re going to take out the \"god\" factor out of the
discussion.

(Laughter.)

DR. WEISS: But what I would like to introduce into the discussion is the
fact that since there is consensus that there\'s no data demonstrating
stabilization of cell loss between 3 and 4 years, what would please the
panel to do perhaps to demonstrate that the issue of endothelial cell
damage is not present here? Dr. McCulley.

DR. McCULLEY: Yeah. My impression that we ‑‑ I could not argue the point
and present data to absolutely support that we have stabilization. My
impression of everything presented is I would lean toward we probably
do. At least ‑‑ or that we probably will. At least to the point where I
would be comfortable not voting on this, that if the panel recommended
approvable, that I would be comfortable with that, with some form of
continued surveillance or gathering of data about the stability or lack
thereof of the endothelium.

DR. WEISS: Okay. So if we\'re talking about post‑market study, would we
be talking about a post‑market study following the initial cohort, or
would we be talking about ‑‑ and would we require those patients who
have had preoperative endothelial cell counts, or would we be talking
about getting a new cohort with specified time points at which they\'ve
had endothelial cell counts? Dr. Schein, and then Dr. Sugar, then Dr.
Mathers.

DR. SCHEIN: I would argue that one needs both, but for different
reasons. So on the specific question of the data related to the
endothelial cell count, the existing cohort will tell us a lot more
about the natural history. I mean, if there\'s a three year lead time on
any new cases that come along.

On the other hand, when I use the word \"post‑market surveillance\", it
doesn\'t at all mean a continuation of a pre‑ market cohort, because the
question from a public health perspective is very different. And what
you\'re worried about is a situation, which I think we have here, where
you\'ve got reasonable short‑term safety, and some ‑‑ an inclination ‑
if I could speak generally, you know, to approve based on that, but
concern about longer‑term issues which cannot be addressed from this
particular pre‑market cohort.

It\'s an analogous situation with the extended wear contact lenses,
which is currently undergoing a 5,000 person study looking just for
ulcerative keratitis. So the concerns here are not just adequate length
of follow‑up for endothelial cell count, but the representativeness. We
don\'t have to get into the glorified surgical skill, but there are
means of examples where you go from an efficacy study pre‑market, to an
effectiveness evaluation, which is how the product is actually used once
it\'s approved. And it never performs as well. So one needs some kind of
way to sample cases from a post‑market setting, from surgeons and
different kinds of patients, to look at big outcomes; corneal failure,
new treatment for glaucoma, retinal detachment, and cataract, because
there has been some concern in my mind about some of these other
complications, which have all been reported on a per‑eye basis; whereas,
obviously, retinal detachment is a per‑patient issue.

DR. WEISS: Can you tell me the study ‑‑ the number of patients, numbers
of years that you would suggest if we\'re just actually going to make it
concrete? What would you like?

DR. McCULLEY: For which purpose?

DR. WEISS: For both.

DR. McCULLEY: No, I\'d have to do some sample size calculations.

DR. WEISS: So you would like ‑‑

DR. McCULLEY: But even this is, you know, done in a few hours.

DR. WEISS: But you would like, basically, both types of studies getting
a new cohort of patients with specular microscopy prior to the
procedure, and then following them through, as well as following these
patients?

DR. McCULLEY: No. No. So for the specular microscopy, I would go with
the existing group, because in a post‑market surveillance study that
I\'m more concerned about, I want to know about corneal graft. I want to
know about retinal detachment, because the absence of a control group
here is a major deficiency. And, you know, using control groups based on
other case series is inadequate, so I would like to know on a much
larger sample, with less defined testing, less onerous testing, about
major outcomes; cataract surgery, new treatment for glaucoma, retinal
detachment.

DR. WEISS: And how long out would you follow those patients?

DR. McCULLEY: Probably ‑‑ initially about probably 3 to 5 years.

DR. WEISS: Do you think for ‑‑ I mean, say those posterior keratotomy
took 20 years for them to get corneal edema, so will that ‑‑

DR. McCULLEY: Well, each one of these things is different, so ones that
occurred in my lifetime, professional lifetime. One example would be
extended wear contact lenses, approved for 30 days in 1981. They were
reduced in 1989, so about 8 years later, with a very, very inefficient
way of making that determination. Anterior chamber lenses was even more
inefficient. There was no surveillance mechanism. There was a lot of
controversy about what we\'re seeing. The literature is a very
inefficient way to do post‑ market surveillance. There are many, many
patients who have rigid anterior chamber lenses with no clinical
inclination that one could see as one followed them.

DR. WEISS: Well, we\'re going to make this efficient.

DR. McCULLEY: Right.

DR. WEISS: So for this particular efficient way of doing it, how long of
a follow‑up would you recommend? Would you still say 3 to 5 years?

DR. McCULLEY: Yes.

DR. WEISS: Okay. Dr. Mathers.

DR. MATHERS: In terms of modeling, addressing what Karen Bandeen‑Roche
said, I think we could reasonably have an objective as we model this,
that we would like to stay above. And I think from our various analyses
here, that it is reasonable to propose that at the end of the expected
use of the device, that we end up with an endothelial cell count of 1500
or greater, because this is still far less than the normal cell loss.

Normal cell loss is quoted here as being .6, but if you do the numbers
on the data from Dr. Grimmett, the normal is really like .4 percent per
year. And if we have a loss rate that you\'re calculating of 1, 1.1, we
are still like three times greater than the normal. So if we do our
projections and model this to keep above 1500 by the end of the device
use, I think we will be serving the public reasonably well. And it\'s
still a relatively conservative approach.

DR. WEISS: So are you saying take the original cohort and if the cell
count kept on dropping off, at what point, how many years they would
take ‑‑

DR. MATHERS: As this gets modeled and we have more data, the model is
going to get better. The projections are going to get better, and the
width of ‑‑ or the data is going to get more accurate. And as we can
determine this, when we know how accurate it is, if we set the parameter
to keep the end point at greater than 1500, which we will be able to do
as you continue to model it.

DR. WEISS: So you\'re basically saying to the FDA that statistically
they should try to predict into the future, and that will tell them how
long that they would be able to do the study. And if that\'s ‑‑ if I\'m
correct, I\'m being told at the same time that that can\'t be done.

DR. MATHERS: Well, as we get more data, we don\'t know how good the data
is going to be when it comes in, and it may be possible in a year or two
to determine what the rate of this loss is.

DR. WEISS: I think we probably have to tell them up front what we want,
as opposed to let this go on for as long as we see fit. Dr. Macsai.

DR. MACSAI: I\'m a little lost here in this conversation, and I just
want to ‑‑ reel me back in here. I\'m listening to what Dr. Schein is
saying, and I\'m in no way disagreeing with you, that it would be
interesting to know this information from a public health perspective.
I\'m not sure it\'s the Sponsor\'s responsibility to get that data. It
would require a National Registry akin to the Australian Graft Registry,
and I don\'t know that we have that set up in the United States.

I think it\'s a wonderful concept if we could do it. We have to register
every patient that has this device, and follow them forever, and I\'d
love to know. And I just don\'t know that it\'s reasonable to know. So
to the second thing, though ‑‑

DR. WEISS: Actually, he was saying 3 to 5 years.

DR. MACSAI: Well, we\'d look at them for 3 to 5 years.

DR. WEISS: Okay. So you would prefer not to have a new cohort ‑ ‑

DR. MACSAI: I know about the cataracts, and I know about the retinal
detachments. Okay. But I thought we were supposed to be talking about
the endothelium here. And I thought the question was how many patients
do we have to follow and for how long to establish stability of the
endothelial cell change, because we\'re all setting around not raising
our hands, because we don\'t know if the endothelial cells are
decreasing to a stable level, so the question is how many.

My answer to you in my review was, I am not a biostatistician. Dr. Gray
is a biostatistician. Dr. Edelhauser is an expert in endothelium, you
know. Put those two in a room, figure it out, tell us the answer, we\'re
done.

DR. WEISS: Dr. Edelhauser is about to tell us the answer. Sometimes you
get what you want.

DR. EYDELMAN: If you\'re not ready to give us the exact number, maybe
you can give us the parameters on which to base the calculation, so we
can certainly perform the calculations. But if you tell us the rate that
you\'d like to ascertain, and with which predictability, or with which
‑‑ what statistical parameters you want us to include, we can certainly
perform the calculations.

DR. WEISS: Well, let me just get one thing from the panel, just in terms
of following the initial cohort. Whether it\'s those 200 ‑ ‑ one
question for the panel. For this cohort that would be looked at with
specular microscopy, does the panel want these patients to have had
pre‑operative specular microscopy done? Those of you who would like to
have at least pre‑operative specular microscopy, could you raise your
hand.

(Vote taken.)

DR. WEISS: So I think there\'s ‑‑ Dr. McMahon. There\'s a majority that
would like pre‑operative specular microscopy. So from what I recall from
the FDA\'s presentation, there were 206 patients who had pre‑operative
specular microscopy, and at least two time points afterwards. Correct me
if I\'m wrong. So of those 206 patients, perhaps we\'re starting out
that with ‑‑ that\'s the maximum number. And then we could ‑‑ we\'ll
probably go down from that.

Does the panel think that 206 would, starting out, be too low? Would it
be feasible to tap into that population? Anyone have an opinion on that?
Dr. Macsai.

DR. MACSAI: I think that\'s the only population we have. I think we
expect a 10 percent loss to follow‑up. You know, unfortunately those 206
weren\'t told you\'ve got to come back every year for five years. So the
Sponsor, I\'m sure, will do their best to track them down and reel them
in, and look at their endothelium. And whether or not it\'s
statistically significant, Dr. Gray will tell us.

DR. WEISS: So then I would propose that that 206 could be at least the
cohort that we\'re looking at for a post‑market study. Then the second
question that the FDA has asked us and I will ask the panel, is there
guidance for number of years that you would like these people followed?
Dr. McCulley.

DR. McCULLEY: I think five is reasonable.

DR. WEISS: An additional five years?

DR. McCULLEY: No.

DR. WEISS: Total of five years.

DR. McCULLEY: Total of five years.

DR. WEISS: So that you want one more time line at one year down the
line.

DR. McCULLEY: No. What I want ‑‑ what I would ideally like to see,
again, I have a sense that all we\'ve done is shift the things to the
right or left, however you\'re looking at it. But I would like to see
yearly up to five years for as many years as possible. We\'ve already
missed some years for that cohort of 206.

DR. WEISS: Okay. Well, those ‑‑ okay. Dr. Sugar.

DR. SUGAR: I was going to say the same thing. The last patient ‑‑ the
first patient should reach the five year time window next month. And the
last patient would reach that time in December of 2007, so I think as
many patients as possible should get ‑‑ of those 306, not 206. There are
306 that had baseline specular microscopy. As many of those as possible
should get annual data for as long as ‑‑ up to as many ‑‑

DR. WEISS: Dr. Eydelman, would that answer 1(a)?

DR. EYDELMAN: So you want all eyes in the PMA cohort that had
pre‑operative endothelial cell counts to be followed for five years. Is
that correct?

DR. SUGAR: With specular microscopy.

DR. WEISS: Dr. Sugar, is that correct?

DR. SUGAR: That\'s what I\'m suggesting. Yes.

DR. WEISS: That\'s correct. Dr. McCulley, you concur?

DR. McCULLEY: I think that\'s reasonable, annually for five years.

DR. WEISS: Is that ‑‑ Dr. Rosenthal, is that burdensome?

DR. ROSENTHAL: No, but we need to know whether you want it done in the
pre‑market arena, or in the post‑market arena.

DR. McCULLEY: Post.

DR. WEISS: Post‑market arena is what Dr. McCulley.

DR. McCULLEY: It depends on whether you approve it now or not.

DR. WEISS: Dr. Sugar, post‑market arena?

DR. SUGAR: Yes. I mean ‑‑

DR. WEISS: Post‑market.

DR. SUGAR: That\'s assuming that we\'re going to approve the product
now, which I presume, and that we shouldn\'t ‑‑

DR. ROSENTHAL: No. We can\'t presume what we\'re going to do, because we
haven\'t voted it for it yet.

DR. SUGAR: No, but I can tell you what I presume. And my presumption is
that we will approve it, and that we should not hold up approval of the
product based on acquisition of this data.

DR. WEISS: Dr. McCulley, and then Dr. Macsai.

DR. McCULLEY: I would agree with Joel, but to put it back more broadly
for Ralph, I mean, if it\'s not approved, then we would request that ‑‑
or recommended for approvable, that they be followed annually. If we do
recommend approvable, which I too would ‑ not being a voting ‑ not going
to get to vote, but I would. And I would be comfortable with that, and I
would say then, I would prefer this ‑‑ as I said, I\'d be comfortable
with a recommendation for approvable with a post‑market surveillance
annually of that initial cohort. You had pre‑ops for a total of five
years.

DR. WEISS: Dr. Mathers.

DR. MATHERS: When you say \"approval\" there, you\'re talking about
three different groups here, and they are very different. You have
myopes for minus 3, myopes for 15 to 20.

DR. WEISS: We\'re going to get to that in a moment.

DR. MATHERS: Okay. But that\'s ‑‑ I mean ‑‑

DR. WEISS: We\'re just talking about the specular microscopy portion,
and then in terms of the different categories, we will be getting to
that. Have no fear.

DR. MATHERS: Okay.

DR. WEISS: Dr. Macsai. And I\'d sort of like to wrap‑up this. Dr.
Macsai, then Bandeen‑Roche, and then I\'d like to wrap‑up this
particular issue. Yes.

DR. MACSAI: I agree with Joel about post‑market surveillance. I would
add two comments. One, if approvable, it\'s got to be labeled that this
stability has not been documented, and it\'s got to be an education for
patients and physicians. And if data comes out later that shows there\'s
massive problems, the FDA has an obligation to take an action.

Number two, if perhaps we\'re all wrong, and we don\'t have to wait
until 2007, and at 2006 the biostatisticians, or 2005, the
biostatisticians say hey, this was much ado about nothing, then the
labeling be changed at that point, and we accept the statistician\'s
interpretation that it is, in fact, stable.

DR. WEISS: With that in mind, if you want to put in labeling that
stability of endothelial cell loss has not been documented, would you
want to put a warning in there that there could be risk of corneal edema
or no? Dr. McCulley.

DR. McCULLEY: I don\'t remember well enough. There are different
implications to these words, and I don\'t ‑‑

DR. WEISS: Dr. Rosenthal. Would it be fair, if we\'re going to be
putting in labeling that there is no documentation of a stabilization
point as far as endothelial cell loss by specular microscopy, would it
be fair to put in labeling there could be the risk, or the risk of
corneal edema is undefined. Or because it\'s undefined, we shouldn\'t
say it?

DR. ROSENTHAL: That\'s the panel\'s decision.

DR. WEISS: Dr. Macsai.

DR. MACSAI: I don\'t ‑‑ we don\'t have corneal edema. We don\'t have one
patient yet with corneal edema. What we have is ‑‑

DR. WEISS: Well, that\'s what we\'re talking about, isn\'t it?

DR. MACSAI: Right. But no ‑‑

DR. WEISS: That\'s what we\'re afraid of.

DR. MACSAI: No, what we\'re talking about is long‑term endothelial cell
loss. So what we say is that the data and the outcomes and long‑term
effects on the endothelium are unknown.

DR. WEISS: But for patient labeling, I think you\'d have to put that in
terms that it means something to someone, because endothelial cell loss
doesn\'t have any significance to a patient. And I would maybe defer
this one to Glenda Such.

MS. SUCH: Yes. I was just going to say, I don\'t know if this belongs in
the labeling section of our discussion or not, but I was going to say
there should be something at least at the bottom of the precautions that
says something about the fact that no information is known about this
beyond four years. Whether or not it\'s regarding this issue or any of
the issues.

DR. WEISS: So maybe we\'ll get back to that when we get back to
labeling. When we\'re talking about ‑‑ so we\'ve talked about, and I
think hopefully to your satisfaction, we\'ve talked about a post‑ market
study, and following the cohort. Does anyone want what\'s suggested,
taking another fresh cohort of patients who are having this done after,
if it gets approved, after approval, and following these patients. Does
anyone want that?

DR. SCHEIN: May I make another comment?

DR. WEISS: Dr. Schein.

DR. SCHEIN: What is the logic of having a post‑market surveillance study
for an extended wear contact lens where not a single ulcer is seen in a
pre‑market trial? The logic is that there\'s a concern about the
particular end‑point, which requires a different kind of study. And I
think the situation is exactly analogous. We have a new kind of device.
We don\'t have any historical data to rely on. The situation is
analogous to the way the rigid anterior chamber lenses were when
ophthalmologists were putting them in their mothers, which is just after
the pre‑market approval. There was a lot of excitement, so I think to
not set up some mechanism that\'s an early warning is completely
irresponsible on our part. And I do believe it\'s the industry\'s
responsibility, if they want to introduce these kinds of products.

The idea is not to stifle innovation. As you\'ll see, I\'m going to be
voting for approval. But the idea is to set up a mechanism that we can
trust to either restrict labeling in the future, pull back the product,
or to provide very sound information about its safety.

DR. WEISS: Well, in that case I think what we\'ll do is we\'ll confine
that one to labeling. If anyone else wants to comment on specifically a
labeling issue. Dr. Matoba.

DR. MATOBA: In the case of the contact lens issue, that we had an
indication from your study that there was a certain risk for microbial
keratitis, and here we don\'t have any information that there is that
type of calamitous outcome that could occur, so here you\'d be fishing.

DR. SCHEIN: The rate of retinal detachment is higher in this study is
higher than ulcerative keratitis was in any of the other studies. The
rate of cataract is higher, so it\'s not just corneal edema.

DR. WEISS: Dr. Bandeen‑Roche, then Dr. McCulley, then Dr. Mathers, then
Dr. Sugar. Not Dr. Sugar.

DR. BANDEEN‑ROCHE: If you want to defer this to the safety discussion,
that\'s fine. But I have to at least raise it now, which is that we saw
no hint of stabilization through three years. I mean, it was just, you
know, all of the year‑to‑year changes were pretty even. So suppose the
data come in, and my overly pessimistic tendencies for once, you know,
bear out, and we see exactly the same continuing rate of decline, once
all of the data are in. Would you then declare the product safe and go
ahead?

DR. WEISS: Dr. McCulley.

DR. McCULLEY: Yeah. Could we ask maybe the FDA to respond to that? And
could we also ask the FDA to respond to Oliver\'s suggestion for ‑‑ I
don\'t ever recall a discussion at a panel, at least that I\'ve been at,
where that kind of study post‑market surveillance, or whatever the term
would be for that particular one, would come up. I\'d like to hear what
the FDA says about both of those issues in terms of authority and
practicality.

DR. ROSENTHAL: We have a member of the staff from the Office of Science
and Biometrics who\'s ready to address this issue for you. Dr. Roselie
Bright.

DR. BRIGHT: One minute.

DR. ROSENTHAL: I still ‑‑ while Dr. Bright is getting ready, you still
have to decide whether you want this fourth and five year data on the
existing cohort before it goes to market, so you have assurance of ‑‑ a
reasonable assurance of safety and efficacy. Or do you have that
reasonable assurance of safety and efficacy now, and the follow‑up can
occur after it is put on the market. That is different than this type of
approach, which is in addition to the follow‑up of the endothelial cell.

DR. WEISS: So I think what Dr. Rosenthal is pointing out is we\'ve put
the cart before the horse.

DR. ROSENTHAL: A little bit.

DR. WEISS: And that if everyone is in agreement that we have no evidence
there\'s stabilization of endothelial cell loss, then is anyone in the
panel bothered by the potential of a continued cell loss rate of 2
percent per year in these patients. And if anyone in the panel is
bothered by that fact, how do you justify that, or explain that, or
accept that?

DR. McCULLEY: Jayne, I\'ve said it before and I\'ll say it again. We
don\'t have the solid data. We need more data. My sense of this, based
on everything including my broad clinical experience and past history
with things, is that I would be comfortable enough with this being
recommended for approvable. But to further give us assurance and comfort
that we follow it post‑market.

DR. WEISS: Then I would ask you, Dr. McCulley, can you explain to the
panel why you\'re comfortable with approval? What factors about this PMA
in the face of no documentation of stabilization of the cell loss make
you comfortable with approving this?

DR. McCULLEY: Okay. I don\'t think there\'s no documentation. I think
there\'s suggestion that there is, but I don\'t think there\'s proof.
And the suggestion to me is that we have stabilization in the cell size,
variability in shape, and that it does appear that with a limited number
of patients that the cell loss between years three and four is leveling
off. And I\'ve seen ‑‑ and in the absence of any apparent known reason
for continued endothelial cell loss, absence of any known mechanism to
support continued endothelial cell loss, those give me the degree of
comfort that I think this is reasonable. But do I think I have data that
would let me nail that down if I wanted to switch sides and argue it the
other way? No. But I think that it would be reasonable to try to gather
more data to give more comfort to everyone else, and to myself. I could
be wrong. I don\'t think I am, but I have reasonable comfort, but I
don\'t have as solid a data ‑‑ if I did, we wouldn\'t be having this
discussion.

DR. WEISS: But the question for the panel really now is whether there
should be pre‑market data or post‑market data, if there\'s ‑‑

DR. McCULLEY: And what I\'m saying is, I think we have sufficient
assurance now to recommend approvable with continued surveillance
post‑market.

DR. WEISS: Dr. Mathers, and then Dr. Macsai, and then Dr. McMahon.

DR. MATHERS: well, finish this discussion. That goes more to Oliver\'s
question.

DR. ROSENTHAL: Finish your discussion about this.

DR. WEISS: Finish our discussion, and then go forward.

DR. ROSENTHAL: And then we\'ll move on.

DR. MATHERS: It\'s a philosophic point. You\'re saying that we don\'t
know, so let\'s go ahead. I would say we don\'t know, so let\'s make
sure before we go ahead. And again I\'ll say that I don\'t think that
what we say about minus 10 to 15, or 15 to 20 applies to what we say
about the 3 to 10. But in the absence of some indication of safety in
this regard, I think going ahead is not the correct answer.

DR. WEISS: Dr. Macsai.

DR. MACSAI: If you look at my review, I didn\'t make a slide of this ‑
I\'m sorry. I did make a table of the rate of annual endothelial cell
loss, assuming a pre‑operative mean count of 2,657, which was the
pre‑operative mean endothelial cell count here. And if we take the
average loss, I\'m not going to argue with Mike or Bill Bourne, but if
you take the average loss at .6 percent by natural attrition, that would
mean you\'d lose 15.9 cells per year.

In that August \`02 panel meeting that Dr. Grimmett did his report on,
he said 1.5 percent would be okay. And that\'s 39.8 cells per year. This
PMA has 1.8 percent, which is 48 cells per year. And then the ANSI
Standard is set at 2 percent, which would be 53.1 cells per year, so
this PMA lies right smack dab in the middle between the recommendations
of the August \`02 panel meeting, and the ANSI ‑ which was 1.5 percent,
and the ANSI guidance document referred to, which was 2 percent. So at
1.8 percent, it ain\'t bad. I just don\'t know if it\'s going to be bad
in the future, so I think looking at these patients to five years is
prudent.

I guess my question to ‑‑ I have another question I just want to ask Dr.
Schein, since I can\'t ask him private, is ‑ what if you look at this
cohort for five years, this endothelial cell counted cohort for five
years to see about retinal detachments, and cataracts, and I forgot what
else you said. Would that answer your question? No?

DR. WEISS: Dr. Schein.

DR. SCHEIN: The reason it wouldn\'t answer the question is, one, sample
size; and two, representativeness, the latter being more important. So I
would want some sample of patients that are actually getting the device
post‑market, and some sample of surgeons that are doing it.

DR. MACSAI: Oh, to see who performs the same?

DR. SCHEIN: Absolutely. And also a larger number, but not for cell
counts. That\'s a different story. That\'s a longer term issue.

DR. WEISS: Dr. McMahon.

DR. McMAHON: This is to Ralph, and this is sort of a semantics question,
because we\'re dealing with a situation with regard to endothelial cell
loss, where we kind of don\'t know. And so the obligation of the panel
of voting on safety and efficacy, one can be that we have to have
reasonable assurances that the device is safe, versus reasonable
assurance that it\'s not unsafe.

DR. WEISS: Well, the way it reads is \"reasonable safety and efficacy\".

DR. McMAHON: Yeah, but I want to know the spirit of that view, because
it makes a difference on how I would vote.

DR. WEISS: Well, I\'ll call on our spiritual counselor, Dr. Rosenthal.

(Laughter.)

MS. THORNTON: Ralph, could you speak into the microphone, please. We
want to get this one.

MR. ROSENTHAL: The reasonable assurance of safety and efficacy.

DR. WEISS: Okay. So with this in mind, since it seems ‑‑ from what I
understood from the vote before, most of the panel members didn\'t feel
the stabilization was ‑‑ the data showed stabilization. Do most of the
panel, even with that fact, would most ‑‑ those panel members who would
feel that there is still ‑‑ this is still reasonably safe to have a
post‑market study, and go ahead with approval under any means, or we\'re
not talking about what type or whatever, in terms of labeling or other
issues. What number ‑‑ if you could raise your hands.

DR. ROSENTHAL: Excuse me, Dr. Weiss. It\'s a post‑market follow‑ up of
the existing IDE subjects.

DR. WEISS: Fine.

DR. ROSENTHAL: That\'s very different than a post‑market study of
another group of patients.

DR. WEISS: So we\'re talking post‑market study in order to get further
data, and approval with the information we have at the present. At the
present point, and we haven\'t gone through the other issues, the
members of the panel who would ‑‑ yes.

DR. BRIGHT: Well, I have a presentation that goes over what\'s
appropriate for pre‑market, what\'s appropriate after the device is
allowed on the market, what you can get in a pre‑market setting versus
condition of approval, versus post‑market. And that might short‑circuit
some of the questions.

DR. WEISS: Okay.

DR. McCULLEY: Jayne, can I say one thing, and I do want to hear what she
has to say.

DR. WEISS: Yes.

DR. McCULLEY: In response to Bill\'s philosophical question, the issue
is do we have reasonable assurance of safety and efficacy. I think we
do. I don\'t think we have absolute, and I would like to go ahead and
get the absolute. That\'s the reason for requesting additional
surveillance. I think we have reasonable, but it\'s not absolute.

DR. WEISS: Would I be able to ‑‑ just in the interest of time, would you
be able to show whatever that you have that speaks specifically to the
choice of studies the panel might have, as opposed to the background
information that you might have, that we could look at concrete stuff as
far as what our choice in terms of studies that we might recommend?

DR. BRIGHT: Well, I have two concrete choices, but I want to lead up why
I got there, if that\'s okay.

DR. WEISS: If you can make a quick lead‑up.

DR. BRIGHT: I\'m covering many slopes. Okay. Well, the disclaimer is
that just because I\'m presenting about those market studies, doesn\'t
mean that I think it\'s approvable right now, but it would apply even if
there was a later discussion about approvability.

The reasons for doing post‑market assurance would be that the study
population for the pivotal study is small, and not large enough to
detect the potentially serious adverse events. And the study population
for the pivotal study is highly selected. It doesn\'t include vulnerable
sub‑populations.

The study duration is typically shorter in real‑world exposure, so
we\'ve been talking about the 3 and 4 year effects, versus 30 and 40
years. And it can detect problems due to improper or unskilled use of
the device in the real‑world. And study centers ‑‑ but the study centers
that you already have the data from are typically highly skilled and
motivated.

And another general reason is to detect adverse events due to
drug‑device, or device‑device interactions that would not be detected in
controlled studies. So questions that might need to be addressed for
this particular device are the longer term decline in endothelial cell
count, long term development of cataract. Dr. Schein mentioned some
other outcomes.

Some issues for phakic IOLs is the prior history in the 1980s with an
implantable lens that was associated with safety concerns after 10 years
of use, so we would want ‑‑ might want an earlier warning system. And
PIOLs could be implanted in a large number of young adults with moderate
vision problems. And, therefore, in the worst case scenario, there\'s a
potential for a large number of middle aged to elderly adults needing
corneal transplants.

So what are the three authorities we have for requiring studies? We have
the pre‑market authority, the study has to be done in order for the
device to get to market. But the disadvantage is a small sample size and
short follow‑up time. The condition of approval study is one where the
approval is conditional until the results of that study are
satisfactory, but you have to order it before the device even gets the
conditional approval. And the post‑market surveillance study, we can
order that study any time, but patient and physician approval is the
most difficult during that time because the device is freely available.

So in considering the type of conditional approval study, it has to be
least burdensome. We can consider any appropriate study design, and it
does not need to be simply an extension of the pre‑ market study. The
sponsor could be asked to report progress and results to the panel each
year if the panel desires, and the sponsor can use the results to change
the labeling and marketing.

So there are two main types of observational study designs. There\'s
case control and follow‑up. The advantage of the case control study is
you can be more efficient with a smaller sample size, but in this
instance, I think it\'s impractical because I think the use of this
device is likely to be relatively uncommon. And you also have to decide
in advance what outcomes you\'re going to look for.

But in the follow‑up study, you can enroll patients as they get the
PIOL, so if it\'s vastly popular, you get your cohort up and running
very quickly. If it takes longer, then it takes longer to accrue, but
that\'s fine because it\'s affecting a smaller portion of the population
anyway. You get flexible follow‑up time, and you can discover new
outcomes that weren\'t anticipated. But the disadvantage is are that you
need to minimize the drop‑out rate, and you need a large number of
patients.

We worked out two options. There\'s nothing required about any of these,
but they\'re basically discussion and talking points. The first option
was called registry, so you could ask patients at less than one year
intervals whether they had an ophthalmic visit for a problem. And we
said less than a year because if we use the mail system, which is
considered least burdensome of different kinds of ways you could contact
patients, they\'re forwarding interval is one year. And you could ask a
very simple question, did you have to go to the ophthalmologist. And
then if they say yes, ask for the details for getting their records. And
you could follow as many patients as possible for a decade or more,
whatever time period the panel is interested in.

The advantages are, you can readily describe and identify the population
of users in the event that some kind of regulatory intervention is
needed. And it\'s a relatively inexpensive study. The disadvantage is
that there\'s no early warning of impending problems. You get the
warning when somebody has the problem that\'s bad enough to go to the
ophthalmologist.

The other option that could be considered is something called a nested
cohort, where you could build on the existing clinical trial population,
and then sample some new patients, collect cell counts at baseline and
regular intervals. And have all of the specular microscopy results
assessed at a central location for the sake of comparability of results.

You\'d want the sample to reflect the diversity of patients and
implanting physicians so that you can get at the real‑world aspects, and
follow as many sample patients as possible for 30 years, or whatever
time is deemed proper.

And the advantages of doing this would be that the follow‑up would be
concentrated at expert centers, and there would be central reading of
the counts. There would be early warning of cell count decline, and it
could be used to detect other adverse events, such as cataract or the
other outcomes.

Disadvantages are you need aggressive persuasion of the sample patients
to come in for their visits, and it would be more expensive. Is there
any questions?

DR. WEISS: Okay. Thank you. What I\'d like to do is sort of cut to the
chase, because I feel we\'re ‑‑ the reason we\'re raising this question,
and I couldn\'t delay it as long as I wanted to, to get to other issues,
was because I feared we were going to go around in circles, and that\'s
what\'s begun to happen. So what I\'d like to do is just address
ourselves to the issues of safety to sort of hone down on what our
concerns are, as bespeaks the endothelial cell count.

What I\'d like is, those who are concerned that any of these patients,
even if they didn\'t have any other surgery, could develop corneal
decompensation, corneal edema from this procedure, I\'d like a show of
hands for those members of the panel who are concerned that from the
data they\'ve seen, these patients could develop corneal edema, at any
point down the line. Are you concerned that that could happen?

(Vote taken.)

DR. McCULLEY: That\'s an open‑ended question.

DR. WEISS: That is an open‑ended question. So that\'s true, it is an
open‑ended question, Jim. Then the second question I have for those of
you who have that concern, do you think a large percentage of patients
‑‑ are you concerned that a large percentage of patients could develop
corneal edema from just the implantation of this device?

(Vote taken.)

DR. WEISS: So you have ‑‑ no one has any ideas on ‑‑ so is that what the
safety concern is here? Because if that\'s what the safety concern is,
then I think we\'re talking about specifically the loss of endothelial
cells, and we should address ourselves to doing a study that addresses
that particular concern, which is the loss of endothelial cells. Is that
the concern on the panel, is the loss of corneal endothelial cells?

DR. MATHERS: That\'s one concern.

DR. WEISS: That\'s one concern. Okay. So let\'s address ourselves to
that concern. What ‑‑ is there any problem ‑‑ why ‑‑ would not following
the cohort of 306 patients for up to a five year period of time to see
if there was stabilization with an additional year, address the concern
of loss of endothelial cell count, or why would that not address that
concern? Dr. Mathers.

DR. MATHERS: It might or might not, depending on how the data came out.
It would certainly help.

DR. WEISS: Dr. Bradley.

DR. BRADLEY: It seems we\'ve had a discussion of do the data stabilize
or do they not stabilize. And I wonder whether that\'s the appropriate
question we should be challenging the Sponsor and the FDA with, in terms
of this post ‑‑ possible post‑approval analysis. Mike Grimmett a couple
of years ago suggested 1.5 percent per year loss was okay. The current
data is 1.8 percent, I believe. Is that what Marian said? A simple
statistical question is whether or not the data show a significantly
greater decline than the decline that is considered safe. If the decline
is concerned safe as 1.5 percent per year, it becomes a statistical
question to analyze the data. And it may take five years to do that, to
show whether or not the data are declining not significantly more than
this supposedly safe decline rate of 1.5 percent. So the issue of
stabilization versus not, doesn\'t seem to be the issue here. It seems
to be whether or not the decline is greater than what is considered
safe. And that becomes a very straightforward statistical question,
which surely the Sponsor and the FDA could sort out.

DR. WEISS: Dr. Bandeen‑Roche.

DR. BANDEEN‑ROCHE: More from a public health point of view, you could
state it the other way. Right? In other words, you might want to
demonstrate that it\'s at least that safe, you know, that it\'s no
greater than 1.5, rather than just that it\'s not statistically
different than 1.5.

DR. BRADLEY: I think that surely that\'s all one is able to do, to say
whether it\'s statistically different or not.

DR. BANDEEN‑ROCHE: Right, but you might want to reverse the Type 1 and
Type 2 error, and require evidence that the rate is lower than 1.5,
rather than just saying it\'s not statistically greater.

DR. WEISS: Dr. Rosenthal, could we have some help, because I could see
we\'re getting nowhere here. And we\'re taking a long time to get
nowhere. Do you have any suggestions for the panel?

DR. ROSENTHAL: The panel has to decide whether they want follow‑ up of
these patients before they give an approvable. They can give approvable
with conditions, and the conditions can be follow‑up of the patients
before it goes on the market, or after it goes on the market. And give
not‑approvable because then that ‑‑ with the same ‑‑ of course, in the
not‑approvable situation, it would be because they don\'t have the data
before they give the approvable.

DR. WEISS: At the present time, as concerns the issue of endothelial
cell loss, can the panel members who feel there is not enough
information right now to make a decision on safety before this is
released into the market, could raise their hands. Dr. Matoba.

DR. MATOBA: What about if we vote on whether panel members would be
satisfied if Sponsors were to follow for an additional amount of time,
the patients for whom they have pre‑op endothelial or specular
microscopy, and then vote on whether it should be four years or five
years.

DR. WEISS: Well, the first question that we need to answer, and which
the FDA is bringing forth to us, is if we don\'t have that data, I\'m
getting ‑‑ I\'m not getting a sense from the panel whether that data can
be given after this is released into market, or it\'s a condition for ‑‑

DR. MATOBA: But I think we can agree on whether we want ‑‑

DR. McCULLEY: Vote on it.

DR. MATOBA: I think we can agree on whether we want the data or not. And
then we can decide whether we would be willing to approve or not
approve.

DR. WEISS: Fine.

DR. McCULLEY: We want the data.

DR. MACSAI: We want the data.

DR. WEISS: Everyone ‑‑

DR. MATOBA: Okay. So but then do we agree that if they follow those
patients who had pre‑operative specular microscopy that\'s adequate, or
are we going to ask for something ‑‑

DR. WEISS: Well, why don\'t we just break this down into simple points.
Is everyone in agreement that we would want to get at least five year
data for the patients who\'ve had pre‑operative specular microscopy?
Those who are in agreement with that, could you raise your hand?

(Vote taken.)

DR. WEISS: Does anyone want longer than five year specular microscopy or
would like the FDA to determine the length of the study depending on
what the results of five year microscopy? Depending on the results of
the five year microscopy, that would determine the length of that
particular study.

DR. MACSAI: Jayne, we can request that that be brought back to panel,
that five year data for review, or the FDA can review it.

DR. WEISS: Well, I think FDA will look at it. I don\'t think that has to
be ‑‑ if we\'re ‑‑ well, whether or not it got brought back to panel
depends on whether this gets approved with conditions or not, so that\'s
‑‑ am I correct, Ralph, on that?

DR. ROSENTHAL: Yes.

DR. WEISS: Yeah. Okay, so we ‑‑ I think ‑‑

DR. ROSENTHAL: It\'s whether you do not approve it.

DR. WEISS: Then it would come back for another go around. So the panel
is in agreement that they would like the cohort that\'s had
pre‑operative specular microscopy, have another specular microscopy done
at five years time, and then ‑‑

SPEAKER: Annually until five.

DR. WEISS: Annually until five years, and then have the FDA determine
how long after, in terms of those results. Now on that basis, what I
need to find out from panel is, would that be information that is needed
before this gets approved? And how many of you would require that
information before you would feel comfortable voting for saying that
this is a safe device?

DR. GRIMMETT: Jayne, there\'s two issues there. How many would feel
comfortable just having year four, or needing both, so there\'s two
parts to that.

DR. WEISS: No, I don\'t want to break it down any further. We\'re
splicing ‑‑ I\'m stating the question. Actually ‑‑ okay. I don\'t ‑ ‑ if
we keep on deviating, we\'re going to be here until tomorrow, which I
don\'t ‑‑ I\'d just like to hone in on this particular question. We\'ve
talked about up to five years. We want specular microscopy. We\'ve
talked about perhaps extending that, depending on what that data shows.
What I just want is a show of hands from the panel, is this needed to
vote for approval? Would you need this data before you would feel that
this is approvable, with or without conditions?

DR. GRIMMETT: All the way to five, inclusive of everything, needing
five.

DR. WEISS: So, Mike, you would need five ‑‑ you would need an additional
year data before you would approve this?

DR. GRIMMETT: No. I would need four year data as a condition of
approval, in order to approve it.

DR. WEISS: Okay.

DR. GRIMMETT: With five year being a post‑market surveillance.

DR. WEISS: Fine.

DR. GRIMMETT: That\'s my position.

DR. WEISS: Fine. Does anyone have a position different than what Dr.
Grimmett said? Dr. Sugar.

DR. SUGAR: I would suggest conditional approval with continued
acquisition of that data up to five years; that is, this would be a
marketable device once the agency approves it, while we\'re still
acquiring that data.

DR. GRIMMETT: When they see four year data, ‑‑ just as a clarification,
Dr. Sugar, when the FDA sees four year data, and feels that it shows a
reasonable level of stability, then it can be approved.

DR. SUGAR: Well, no. It would still ‑‑ it would be conditionally
approved, so it would be marketed now.

DR. GRIMMETT: Oh, so your\'s are all post‑market. Year four and year
five are post‑market.

DR. SUGAR: Unless I misinterpreted Dr. Bright\'s statement, that we
could conditionally approve it, and it could be marketed with the
condition that that data continued to be acquired; that is, this is a
marketed device ‑‑

DR. GRIMMETT: Isn\'t that post‑market surveillance?

DR. ROSENTHAL: You can do it two ways. You can require the data to be
submitted to us before it can go to market, four years, five years, four
years only, four and five years, or you can say it can go out right now,
but once it\'s out in the marketplace, we have to get the data at four
and five years.

DR. SUGAR: The latter is ‑‑

SPEAKER: You want post‑market surveillance. You are in agreement on
that.

DR. SUGAR: Post‑market acquisition of data through five years, with it
being conditionally approved.

DR. WEISS: So I\'m getting a sense from the panel right now, there are
these two different choices. But from what I\'m hearing from the panel,
they would feel comfortable with the post‑market surveillance,
post‑market ‑‑

DR. McCULLEY: Get a vote on the two.

DR. WEISS: Dr. Bandeen ‑‑

DR. GRIMMETT: Four years before it gets out with continued post‑ market
to five. That\'s choice one. Choice two is, let it go now and do
post‑market surveillance on four and five when it\'s already out in the
market. That\'s choice two. Vote for one or two.

DR. WEISS: Dr. Bandeen‑Roche.

DR. BANDEEN‑ROCHE: Am I correct in presuming that by the time the four
year follow‑up is complete, there will be some five year data?

DR. WEISS: Yes.

DR. BANDEEN‑ROCHE: So that\'s another ‑‑

DR. WEISS: So why don\'t you state the first choice, and we can have
panel ‑‑

DR. GRIMMETT: Let\'s state the second. How many would vote for approval
now with the current existing data, with post‑market surveillance of
endothelial data at four years and five years?

(Vote taken.)

DR. GRIMMETT: That was your choice, if I stated correctly. That\'s
enough.

DR. ROSENTHAL: How many were there?

DR. WEISS: And how many would vote for ‑‑ restate the first one.

DR. GRIMMETT: For gathering the four year data now as a condition of
approval, and if satisfactory by review of the FDA, then approve it, and
then continue post‑market surveillance out to year five.

(Vote taken.)

MS. THORNTON: It was six to five.

DR. GRIMMETT: You want to take it again?

DR. ROSENTHAL: Yeah, could we.

DR. GRIMMETT: Take it again.

MS. THORNTON: It was six to five.

DR. GRIMMETT: Which way?

DR. ROSENTHAL: Could we have the other first?

DR. WEISS: Now I just want to clarify the four year data that we\'re
trying to get, you have a continual number of patients who are getting
four year data, so when will you get this four year data? At what time
point would you ‑‑

DR. ROSENTHAL: We need you to tell us.

DR. WEISS: I know it\'s ongoing, so if the ‑‑ so you would ‑‑ so the
panel ‑‑

DR. ROSENTHAL: Ten more eyes, 20 more eyes?

DR. WEISS: How many ‑‑

DR. ROSENTHAL: All the eyes. It\'s up to you.

DR. WEISS: Okay. So then I would ‑‑ I\'d like the panel to understand
that if they went with, I believe it\'s the first option, it\'s
undefined when that condition would be met. Am I correct?

DR. ROSENTHAL: Do you want to explain?

DR. WEISS: When would that condition that all the four year data for all
these patients would be met? Because we also have to realize that they
only have four year data on 57 patients at the present time, so how many
more patients would they be able to get four year data on?

MS. LOCHNER: At the present time, they obviously have more than that
number. That cut‑off on the database happened a couple of months ago, so
as we speak, more and more people are reaching four years. I think the
Sponsor can address, you know, the issue is when was the last patient
enrolled. When will the last patient be out to four years in that
cohort, and so they\'ll know exactly when they\'ll have the complete
group.

DR. MACSAI: It\'s December of 2006.

DR. WEISS: What I would like to know from ‑‑

MS. LOCHNER: No.

DR. WEISS: Yeah. I\'d like to know from Dr. Gray statistically what
number would you need, or what number of patients would you need to have
four year data before you feel that you could make a ‑ ‑ Dr. Gray, do
you have any comment on finding four year data for all the remaining
patients helpful?

DR. GRAY: Helpful?

DR. ROSENTHAL: Oh, no. He\'s not to give you any ‑‑

DR. GRAY: I can\'t answer that kind of a question without a lot more
information. I mean, that\'s a difficult ‑‑

DR. WEISS: How many ‑‑

DR. GRAY: I can\'t do it off the top of my head. I\'m sorry.

DR. WEISS: From the FDA, how many ‑‑ the last four year data would be
coming back when? When would be the ‑‑ Sponsor, please.

DR. LAMIELLE: Helene Lamielle. December, 2006.

SPEAKER: What did she say?

DR. WEISS: December, 2006. Dr. Macsai.

DR. MACSAI: Dr. Lamielle, is that ‑‑ because I ‑‑ that\'s what I thought
too, but now I\'m rethinking it. Is that the last person enrolled, or is
that the last person with specular microscopy? I don\'t get that clear.

DR. LAMIELLE: That\'s the last person on the whole.

DR. MACSAI: But when was the enrollment of the 306 specular microscopy
patients completed?

DR. LAMIELLE: We have to look at the data, when the last microscopic
specular patient was enrolled.

DR. MACSAI: Okay.

DR. LAMIELLE: But the specular microscopy data have been done all along
the study, so there is no reason ‑‑ it\'s earlier than the rest of the
cohort.

DR. WEISS: So I would just like clarification from the panel members who
would require this data that perhaps may go out to approximately two
years from now in order to release this into the market. I would presume
that you would want to delay approval of this for two years, or more
than two years, because you have concerns about safety because of the
specular microscopy data. Am I correct ‑‑ for those of you who voted for
Option 1, am I correct on assuming that\'s the cause of the vote in that
direction? Dr. Mathers?

DR. MATHERS: Concerns about the endothelial issues ‑ I\'m sorry.

DR. WEISS: Yes, because you would be delaying the vote, or it would have
to come back to ‑‑ you\'d be delaying this for more than two years,
because you have concerns about safety as regards to the issue of the
findings on the specular microscopy.

DR. MATHERS: That is precisely the problem, and I think that it is a
very significant issue, and we should know more before we get approval.
That\'s why I voted for conditional approval, that we need to know this
before we approve it.

DR. WEISS: Yeah, Donna.

MS. LOCHNER: I was just going to say, it is possible that as the Sponsor
theorized that the rate is essentially going, you know, dramatically
down at four years, that the data will have sufficient power before the
last of the patients are enrolled. So if what they\'re theorizing is
true, they may not have to wait as long as you\'re saying to have
sufficient power to show that the loss is decreased from the three year
point.

However, in a worst case situation, maybe they\'ll need all their data,
and have to wait that long. But if their theory is true, one would
expect that they would be able to have sufficient power much earlier
than that.

DR. WEISS: So the panel could say that they would want acquisition of
four year data until ‑‑ for the number, until which point the FDA deems
that they can determine with certainty that the data shows stability, at
which point then that would be the condition that would be met for it to
be released into market.

MS. LOCHNER: Certainly. And no matter what the panel or FDA says, the
sponsor will push that point in any case, so you don\'t have to worry ‑‑

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

DR. MATHERS: I would like the condition to be achieved, such that at the
end of the lifetime of the device, that the patient would still have
1500 cell count.

MS. LOCHNER: Right. And if you just use the data the sponsor has, you
can do that calculation and see where they are.

DR. MATHERS: That\'s correct. It is a lower rate than 1.5 percent per
year.

MS. LOCHNER: We understand.

DR. WEISS: Dr. Bradley.

DR. BRADLEY: Again, just to clarify, the stabilization, absolute
stabilization is not the gold standard here. It is the rate which is ‑‑
rate of decline which deemed safe. And we\'ve got a 1.5 is okay, and a
1.5 is not okay. so there is some debate about what the rate actually
is.

DR. WEISS: Dr. Grimmett.

DR. GRIMMETT: Let me clarify. That 1.5, the figure came about at last
year\'s meeting due to the fact that in looking at what would be a
sample size needed to show a specific rate of cell loss. And if we set
the bar too low, the sample sizes would have to be enormous. It wasn\'t
that 1.5 was deemed a safe level. It was that 1.5, if you wanted to
screen that they were under that, your sample sizes could be reasonably
sized so it wouldn\'t be onerous. That\'s where it came up.

DR. WEISS: Dr. Bandeen‑Roche.

DR. BANDEEN‑ROCHE: I just wanted to say that I agree with this
discussion that\'s been happening in the last couple of minutes and, you
know, just so long as we also keep in mind representation, as well as
just power. You know, that we\'re not ‑‑ we don\'t have an overly
selective group, both sufficient numbers, and decently representative of
the whole cohort.

DR. WEISS: Dr. Macsai.

DR. MACSAI: I\'d like to speak in favor of my disagreement with the
majority of the panel. We had a presentation by Dr. Edelhauser who\'s
deemed internationally as an expert in the field of endothelial cell
data of all sorts, and we\'ve seen that the pleomorphism and
polymegathism are pretty darned good here, and they\'re stabilizing. And
then we looked at that they counted 90 cells, but probably 100 to 150
cells would have been better. And there\'s a lot of room for error in
the 90 cell count, and now we\'re arguing about 1.8 versus 1.5, versus 2
percent. Where, if you looked at the confidence interval of those
numbers, and then took a confidence interval of those counts, and then,
you know, multiplied it by all those factors out, I think you\'d wash
this whole thing away.

You know, I\'m concerned as everyone, and I started out my whole review
as saying that this ‑‑ we don\'t want to create ORC ‑ I can\'t ‑ a
situation with a lens ‑ excuse me ‑ take that from the thing ‑ a lens
that might cause endothelial cell decompensation, but we have a device
that\'s really effective, probably more effective than what\'s out
there. And I know safety is really important, and you\'re talking to
Mikey who doesn\'t like anything here, but I mean, do we really want to
wait until 2006?

We approved these contact lenses when we already had your study saying,
you know, they\'re dangerous. Okay?

DR. WEISS: I think at this point we have the data, and everyone, I
think, has their opinions or has quite a few opinions. And at some
point, this may come to a very close vote. But I think the information
is out there, and we all have our perspective on, and we still have a
couple of questions. And I don\'t want to tell you how many hours behind
we are, so we\'re going to ‑‑ I think we have the information on
endothelial cells. We\'re going to end up putting it to a vote, and when
it gets put to a vote, and what I\'d like to do is go on to a
non‑controversial topic, like cataracts. I bet the Sponsor didn\'t think
that was going to be the non‑ controversial portion.

DR. EYDELMAN: Question 2(a) ‑ \"Do you believe that the three year
follow‑up is sufficient to establish a lens pacification profile
associated with this device? If not, what is your recommendation?\"

DR. WEISS: Dr. Macsai.

DR. MACSAI: It\'s sufficient.

DR. WEISS: I think the panel has gotten beaten into submission.

DR. SUGAR: I think we should ask for post‑marketing acquisition of data
on cataracts that accrue in this five year period while we\'re looking
at their endothelium.

DR. WEISS: Sounds good. Dr. Schein.

DR. SCHEIN: As I said before, I\'m more concerned about cataract and
retinal detachment, than I am about the cornea. Because although it is
uncertain on endothelium, there has not been progression to any clinical
disease, while there has been, in a relatively short time period. I
frankly don\'t believe most of the cataract rating. I don\'t disbelieve
it because I think investigators are dishonest, but I know, and it\'s
well‑published, that using clinical grades, whether it\'s the LOC system
or the Wisconsin system, is incredibly unreliable. You need a
photographic standard to really believe it, and that may be why there\'s
such variation between Canada, these investigators, site‑ to‑site, and
Dominican Republic, and maybe more than just position skill. So I think
this is a real issue. People who get cataract surgery, their myopes.
They\'re going to have the eye entered twice, retinal detachment rate
will behave accordingly, so I don\'t think this is adequate information
to establish a lens opacification profile. You need a larger sample and
representative surgeons.

DR. WEISS: Well, certainly I would think it would be not difficult if
we\'re going to be getting data at four years, five years, to include
cataracts in that.

DR. SCHEIN: It\'s not a large sample, and it\'s not a representative
group of surgeons.

DR. WEISS: Dr. Sugar had mentioned considering IOL removal if there\'s
progression of cataract formation. Did anyone want to put that in the
labeling, as well? And that goes later on, but I have it.

DR. SUGAR: I don\'t think it\'s ‑‑

DR. WEISS: Is that what you said, Joel, or is ‑‑

DR. SUGAR: No. I expressed lack of information ‑‑

DR. WEISS: Lack of data.

DR. SUGAR: ‑‑ on what the toxicity of the removal event is, in terms of,
do cataracts get worse after you take the lens out? I don\'t know.

DR. WEISS: So you ‑‑

DR. SUGAR: And I don\'t think the Sponsor has sufficient numbers within
this cohort to give us an answer that would satisfy me.

DR. WEISS: So you\'re not going to ask the Sponsor for an answer ‑‑
it\'s a question that remains and will stay unanswered. Or would you
like to ask the Sponsor ‑‑

DR. SUGAR: Again, if the Sponsor has data on ‑‑ you know, certainly if
they find that removing the IOL is cataractogenic, obviously, they need
to let us know that. And I assume that they\'re mandated to let us ‑‑ to
let the FDA know that as an adverse event.

DR. WEISS: As part of the ‑‑ Dr. Rosenthal.

DR. ROSENTHAL: Unfortunately, the adverse event issue, if they\'re
informed of it, they are mandated to let us know. But if they are not
informed of it, unless the physician reports it through the MDR system,
we will never know about it.

DR. WEISS: Well, we can ask them at this point if they have the
information to let the FDA know. Is that correct?

DR. ROSENTHAL: Well, at this point you have the information because it
was submitted in the PMA.

DR. SUGAR: No. We don\'t have information on whether removing the lens
halts progression or induces progression of whatever opacities were
there.

DR. ROSENTHAL: No, you don\'t have that.

DR. WEISS: So we can ask them for that information, and that\'s ‑ ‑ if
they have it.

DR. ROSENTHAL: When? When do you want them to give it to us?

DR. WEISS: If it was ‑‑ if the panel wanted, that could be a
conditional, could it not?

DR. EYDELMAN: I just want to make it clear.

DR. WEISS: Yes.

DR. EYDELMAN: Are you trying ‑‑ there\'s no data from the PMA cohort
that you\'re discussing obtaining the data from post‑market, or what
exactly ‑‑

DR. WEISS: I think Dr. Sugar is talking about the patients who\'ve
already had this done. Am I correct?

DR. SUGAR: Well, then the number is too low.

DR. EYDELMAN: Yes.

DR. WEISS: Okay. So then do you have ‑‑ is there a statement you want to
make, or is that just sort of a wish list that\'s not going to get
answered?

DR. SUGAR: I guess I don\'t know how to make the statement about the
statement, but yes.

DR. WEISS: Dr. Eydelman, do you have a suggestion on how to make a
statement about a statement?

DR. EYDELMAN: If you want to find out the specific rate, you need to
collect data. If you want to have a general warning, a precaution about
lack of data, you can do that in labeling. Those are the two options.

DR. SUGAR: I guess both is what I would like, which is to find out if ‑‑
and I don\'t know how you find this out. Assuming, as I think we are,
that this is a low frequency event, it\'s going to be hard to acquire
that data in any very short period of time. It would be nice to know
what appropriate recommendations are for dealing with lens opacification
in these patients that is not visually significant. Does removing the
implant cause progression or halt progression?

DR. ROSENTHAL: Ralph Rosenthal. I think at this point in time, all we
can do is put a warning in saying that you do not know what the effect
would be on the cataract that develops following implantation when you
explant it.

DR. SUGAR: Then I think the labeling should reflect there is a lack of
data on the impact of removing and/or replacing the lens on the
endothelium and on the lens.

DR. WEISS: Fine. Dr. Matoba.

DR. MATOBA: Well, okay. I hate to ask this question because of labeling
conditions, but is someone keeping track of all the labeling questions?

DR. WEISS: I am, as well as Dr. Mathers, I hope. Any other issues about
cataract?

DR. SUGAR: I guess I raise the other one, the axial length measurement.
Is axial length measurement accurate with the lens in place? And I
don\'t know how to deal with that in this.

DR. EYDELMAN: That is actually something we can ask the Sponsor, and
work out the proper ‑‑ that is the easiest of the issues. We have not
heard the answer to Question 2(a).

DR. WEISS: So the question ‑‑ Question 2(a) is ‑ \"Do you believe a
three year follow‑up is sufficient to establish a lens opacification
profile associated with this device\"? All of those who feel that it is,
and would like to answer yes, please raise your hand.

(Vote taken.)

MS. THORNTON: We have eight.

DR. WEISS: So it\'s a majority, not unanimous, but a majority. And
we\'ll go with the majority. B. Question B is ‑‑

DR. EYDELMAN: \"In light of the findings, they believe surgeon
experience to have be an important factor in ASC development secondary
to surgical trauma. If yes, they believe that future users of this lens
should be required to undergo special training.\"

DR. WEISS: So I think that there was a consensus that there should be
special training. Would the FDA need to know from us what type of
special training, or you can determine that with the Sponsor? Dr. Macsai
had mentioned ‑‑ Dr. Sugar and Dr. Macsai, I think both had mentioned
mandate ‑ perhaps proctor for early cases, but that\'s something that
you all can determine with the Sponsor, so we do not have to get
involved in that.

DR. ROSENTHAL: I think I should clarify. We can mandate training. We
generally do not mandate what type of training.

DR. WEISS: So would it be acceptable to the panel that training or some
sort be mandated?

(Vote taken.)

DR. WEISS: Fine. Dr. Macsai had brought up tracking and recalling. If
there were multiple surgical problems with a physician, I would assume
that would be too burdensome and beyond the usual scope that we advise.
Am I correct on that?

DR. EYDELMAN: Yes.

DR. ROSENTHAL: I\'ve never heard it recommended before. If the sense of
the panel is that that\'s what they feel is reasonable, we can ask the
agency ‑‑ well, we are the agency. We can ask higher up in the agency
what their feeling is about the recommendation. We may not take it, and
we may take it.

DR. MACSAI: Jayne, can I clarify?

DR. WEISS: Dr. Macsai, yeah.

DR. MACSAI: The recommendation really wasn\'t to the agency, it was to
the Sponsor. The recommendation was simply to the Sponsor, that if
there\'s a disproportionate number, I assume these are not ‑ ‑ these are
going to be consignment lenses, and if somebody, you know, keeps
ordering new ones, and keeps sending back ones they implanted wrong, or
they tore upon implanting because they can\'t manage to get them through
the shooter, red flag. Go retrain that person. Rescind their
certification. As simple as that.

DR. WEISS: So the agency can take that under advisement. Okay. The
Sponsor. C.

DR. EYDELMAN: Has to do with recommendation for replacement of ICL.

SPEAKER: I think we dealt with that at one point.

DR. EYDELMAN: Yes, we did.

DR. WEISS: WE did this one. Okay. What was the answer?

SPEAKER: We don\'t know.

DR. WEISS: We don\'t know. Always nice to have definitive answers for
the agency. Question 5, \"Do the safety and efficacy outcomes support
approval of the STAAR ICL for the eyes with the following pre‑operative
manifest. (A) is minus 3 to minus 7.\" Now one thing I will point out,
obviously, the results in these patients were much better. But then
again, you might ‑‑ the panel might determine the risk benefit ratio is
also a little bit different because there are effective treatments in
these patients. A minus 3 has a whole choice of treatments, where a
minus 15 does not. But having added that introduction, I\'d like a vote.
For those who agree that the safety and efficacy outcomes, safety and
efficacy support approval for eyes with minus 3 to minus 7 ‑ if you
agree, vote with your hand in the affirmative.

(Vote taken.)

MS. THORNTON: I\'ve got one, two, three, four.

DR. ROSENTHAL: No, there are five.

MS. THORNTON: Five. Where\'s the other one? Tim, keep your hand up.

DR. ROSENTHAL: There\'s one, two, three, four, five.

DR. WEISS: Okay. Five out of 11.

DR. ROSENTHAL: No. You have to vote.

DR. WEISS: Why don\'t we have ‑‑

DR. ROSENTHAL: There has to be another vote.

DR. WEISS: Five people are voting in the affirmative. For those who
disagree that safety and/or efficacy do not support approval for minus 3
to minus 7, can you vote? They disagree.

DR. ROSENTHAL: Please vote. You can abstain. Please vote either yes, no,
or abstain.

DR. MACSAI: Minus 3 to minus 7.

DR. ROSENTHAL: There\'s four against.

DR. WEISS: This is a no vote. Dr. Bandeen‑Roche.

DR. BANDEEN‑ROCHE: We\'re taking everything into account, including the
discussion on ‑‑

DR. WEISS: Every single thing.

DR. BANDEEN‑ROCHE: ‑‑ endothelial cell count. Right?

DR. WEISS: Everything. Safety and efficacy.

DR. EYDELMAN: Well, you\'re voting both ways.

DR. WEISS: Okay. What are we voting now? Okay. Let\'s have a vote again.
Those who agree that safety and efficacy outcome support approval for
minus 3 to minus 7 ‑ those who ‑‑

DR. GRIMMETT: With or without the prior endothelial concerns. Are you
separating that out? Are you concluding it, the endothelial safety
issue?

DR. WEISS: Yes.

DR. GRIMMETT: We already went over, or are you separating it out?

DR. SUGAR: With the condition, I assume.

DR. GRIMMETT: Point of clarification.

DR. WEISS: Well, with the conditions of ‑‑ let\'s ‑‑ if you want to
break it out, let\'s break it out into needing the four year data as a
condition of approval. And then we\'ll have a vote for not needing the
four year data, but as a condition of approval having it ‑‑

DR. SUGAR: We just did that. We voted that way.

DR. WEISS: So let me ‑‑ I\'m going to defer to FDA. Since we\'ve done,
how do you want this phrased at this point to give you any information?

DR. EYDELMAN: Okay. I will assume that you\'re not expecting to stratify
the four year data by preoperative refractive bins, because then we\'ll
never have enough. So, therefore, you have to take into consideration
then endothelial cell data as you know currently. And assuming that
overall four year data will be looked upon until this device is
marketed, do you consider that safety and efficacy ‑‑ do they support
approval for minus 3 to minus 7?

DR. WEISS: So for those of you who require that four year data before as
a condition of approval, four year data on the rest of the cohort as a
condition of approval, do you believe it\'s efficacious for minus 3 to
minus 7?

DR. COLEMAN: Excuse me, Jayne. Can I have safe and efficacious.

DR. WEISS: Safe and ‑‑ is that ‑‑

DR. GRIMMETT: For everything else but the endothelium.

DR. WEISS: No. Once you have your four year data, you\'re going to have
your four year data as a condition of approval.

MS. LOCHNER: Can I say something?

DR. ROSENTHAL: Can I clarify?

DR. WEISS: Yes, please clarify.

DR. ROSENTHAL: Are you ‑‑ do you want ‑‑ what ‑‑ do you want to limit
the power ‑‑ the refractive error for which this device should be used
or do you not?

MS. LOCHNER: And to say that another way, I think the panel already
voted on the endothelial cell issue. And the motion seemed to carry that
the four year data would be obtained pre‑marketly.

DR. ROSENTHAL: That was a straw vote, and ‑‑

MS. THORNTON: Would you please use the microphone.

DR. WEISS: It would be a straw vote. I\'m sorry. Maybe it wasn\'t in the
‑‑

DR. ROSENTHAL: It was a straw vote, and you still don\'t know what the
ultimate vote will be, and what the conditions will be.

MS. LOCHNER: But I think we want you to set aside the endothelial cell
issue at this time, and speak to the refractive ranges.

DR. WEISS: So we\'re speaking now basically of efficacy. If we\'re
speaking about ‑‑

MS. LOCHNER: No, safety and any other ‑‑

DR. WEISS: Safety and endothelial cell data, and efficacy. We\'re trying
to get at whether, setting aside the endothelial cell issue, which we
already had a straw vote on, and we assume that that issue wouldn\'t
change based on the refractive ranges. Setting that aside, are there
additional concerns that might make you vote differently by the
different refractive ranges? Dr. Coleman.

DR. COLEMAN: Yeah, but one of my issues that hasn\'t been addressed,
because we\'ve been voting on safety based on corneal endothelium, is
the safety related to glaucoma, and also the lack of gonioscopic data.
And one of the things that I need in terms of for my feeling, the safety
of this procedure is having post‑ operative gonioscopic evaluations on
the cohort in this PMA. And that information is not available.

DR. WEISS: Okay. I would like to ‑‑ I\'m getting disturbed how the
proceedings are going. I would like to emphasize, this is reasonable
safety and efficacy. I mean, there ‑‑ I think it would be nice to have
gonioscopy, and I think there were other parts that could have been
included in the study. But with all fairness to the sponsor, at the
point that this study was approved, it was approved with the input of
the agency, so we can\'t hold them up to a higher requirement, which
would be nice, but it\'s not fair for information that we\'ve
subsequently gathered.

With the data that we have, and that the agency required from them, and
that they performed, do we have reasonable safety and efficacy? I would
be disturbed if at this point this was ‑‑ it was not approved on the
basis they didn\'t have post‑operative gonioscopy because that was not a
requirement that the agency made, and there is nothing in particular ‑‑

SPEAKER: That was a requirement that the panel ‑‑

DR. WEISS: Well, the panel made that, but that was not a binding
requirement. I mean, can the agency comment if I\'m out of line here?

DR. COLEMAN: It\'s not in the study, but the thing is that they could ‑‑
this is Dr. Coleman again ‑ excuse me. I thought that you could when
you\'re doing the four year reviews or the five year reviews of these
individuals, same with conditional approval, but they could also have
gonioscopy by the surgeons to see how the angles were doing, whether
there\'s pigment deposition ‑‑

DR. WEISS: No, I think that ‑‑

DR. COLEMAN: So it\'s definitely doable, even now in this current
cohort. It\'s just that information hasn\'t been obtained. And you have
an increased rate of interocular pressures of about ‑‑ in three years in
this cohort about 6.8 percent of the cohort has a pressure elevation of
more than 5 millimeters of mercury from baseline. If you believe the
ocular hypertensive treatment study, that\'s associated with a 50
percent increased risk of glaucoma in these young individuals. And so
specular microscopy

DR. WEISS: What percent of higher myopes would be expected to get
glaucoma?

DR. COLEMAN: That issue is debatable. The investigators went ‑‑ the
Sponsors went over it, but one of the issues is, is it\'s still
considered debatable whether or not high myopia is associated with an
increased risk of glaucoma.

DR. WEISS: Okay. So you would like to put as ‑‑ if data is gone that
four years of specular microscopy, you would like gonioscopy to be done
at four years, as well.

DR. COLEMAN: To looking at pigment deposition and increased peripheral
anterior synechiae, because those references that Dr. Grimmett found did
show that in those eyes that had elevated pressures that were having
problems, they did have increased pigment deposition, and also
peripheral anterior synechiae. Glaucoma is a long‑term risk for these
individuals. I mean, I think that it\'s something they\'re going to be
living with for a lifetime if they do have an increased risk of
glaucoma, because a 40 year old\'s prevalence of glaucoma is about .18
percent when you look at the Baltimore Eye Survey in Caucasians. And if
you do some extrapolations, this could be actually increasing and
doubling that prevalence in this age group.

DR. WEISS: Dr. Grimmett.

DR. GRIMMETT: Michael Grimmett. I\'m certainly in favor of warning
clinicians in the labeling about our concerns about pigment deposition
and need for gonioscopy, so that clinicians go ahead and do the correct
thing, but the study was approved without gonioscopy. And while I think
it\'s regrettable, I am not in favor of mandating the Sponsor to gather
further gonioscopy data. I don\'t think that would be fair.

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

DR. MATOBA: Okay. I want to ask Dr. Eydelman, when the FDA put this
question together, did you want us to just address safety efficacy for
each of these refractory subsets, or do you want us to also take into
consideration philosophical ideas, such as whether we think that an
interocular procedure is justified in a patient who is minus 3?

DR. EYDELMAN: As I tried to explain in my presentation, what I was
hoping that the panel will do is look at each of the refractive ranges,
and look at the risk benefit analysis for this device, and for other
alternative devices for each of these refractive ranges, and make a
decision upon that.

DR. WEISS: So with that in mind, let\'s talk about minus 7 to minus 10.

DR. SCHEIN: So to clarify that, because that is my question.

DR. WEISS: Yeah.

DR. SCHEIN: So the answer is, compared to what? And so the comparison
here is not spectacles or contact lenses, it\'s compared to other
refractive ‑‑

DR. WEISS: Dr. Rosenthal.

DR. ROSENTHAL: You\'re not meant to compare it to anything.

DR. SCHEIN: Well, that\'s not what you said.

MR. ROSENTHAL: You\'re meant to take the risk benefit ratio of this
device.

DR. WEISS: We have the safety and efficacy minus the endothelial cell
data for each of these refractive ranges, irregardless of what else is
out there. That\'s what we have to look at. So I\'m going to ask ‑‑

DR. SCHEIN: That makes no sense whatsoever, does it?

DR. WEISS: But is that what the agency is asking?

DR. SCHEIN: I mean, what ‑‑ obviously, it\'s inappropriate to ‑‑

DR. ROSENTHAL: We\'re asking do you feel a patient with a minus 3
diopter myopia have a interocular lens put in their eye to treat their
minus 3 diopter myopia.

DR. MATOBA: That\'s not the way the question is worded. I thought
that\'s what you were getting at, but that\'s not the way the question
is worded.

DR. ROSENTHAL: And minus 4, and minus 5, and minus 6. So I think maybe
we should look at it ‑ is there a range at which you would feel
comfortable subjecting a patient with myopia to an interocular procedure
in which this device is implanted?

DR. SCHEIN: Okay. So in other words, it is in comparison to other data
that ‑‑

SPEAKER: No.

MR. ROSENTHAL: Not comparison.

DR. SCHEIN: Not in a quantitative way, but it\'s ‑‑

DR. WEISS: Okay. Dr. Bradley has suggested the following wording, which
I think is good wording. If the Sponsor can establish that the
endothelial cell count is not declining at dangerous levels, depending
on how you want to classify that word, does the panel consider this
device safe and efficacious for the following ranges. So let\'s first
talk about minus 7 to minus 10. If there was no issues with the
endothelial cell count data, I\'d like a raise ‑‑ a show of hands ‑‑ Dr.
Matoba.

DR. MATOBA: I think risk benefit is different from what you\'re saying,
because safety is never absolute. It\'s all relative. And so the benefit
for a minus 3 is different from a benefit for minus 12 ‑‑

DR. WEISS: That\'s why I\'m talking about minus 7 to minus 10 first.

DR. MATOBA: You can\'t take that phrase out of the question, I don\'t
think.

DR. WEISS: But that\'s why I\'m speaking about minus 7 to minus 10
first. I\'d like to clear up those, and then obviously, when we get into
the minus 3s, it sounds like it\'s going to get more contentious. Minus
7 to minus 10, are there any issues that the panel has with safety and
efficacy, regardless of ‑‑

DR. ROSENTHAL: Excuse me.

DR. WEISS: Yes, Dr. Rosenthal.

DR. ROSENTHAL: I just want to clarify what I was ‑‑ a risk benefit
analysis, Mrs. Lochner has told me, does take into account other
options. But you are not to compare the option. You are to use a
clinical judgment to say whether or not you feel that a certain range
would be appropriate for this device.

DR. WEISS: Minus 7 to minus 10, can we have a vote for those who would
feel that this is safe and efficacious if the endothelial cell data
shows such for minus 7 to minus 10.

(Vote taken.)

DR. WEISS: So we have a majority of the panel who feels it would safe
and efficacious for minus 7 to minus 10. Minus 10 to minus 15, can we
have a similar vote, with some prompting by Dr. Macsai. That\'s all
right. We\'ll use you for other votes here, Marian. I\'m enlisting you.

(Vote taken.)

DR. WEISS: This is in favor of. So minus 7 to minus 10, and minus 10 to
minus 15, it is safe and efficacious. How about minus 6?

SPEAKER: What?

DR. WEISS: I know who I\'m dealing with here.

SPEAKER: Excuse me.

DR. WEISS: Minus 6, how many of you ‑‑ I\'m not going to go the minus 3
to minus 7 range, because there\'s going to be possibly a breakdown, so
I avoid breakdowns.

SPEAKER: Call a vote.

DR. MACSAI: Can I ‑‑

DR. WEISS: Yes, Dr. Macsai.

DR. MACSAI: If we\'re looking at efficacy and safety, and we have a
guidance document that exists for minus 3 to minus 7 for safety and
efficacy, and we look at this group, which is how we\'ve broken out
minus 3 to minus 7 or 6.9 ‑ I don\'t remember ‑ compared to the guidance
document, okay. You can eliminate the endothelial issue. It meets the
criteria, safe and effective.

DR. WEISS: So you would ‑‑ you feel for minus 3 to minus 15, it\'s safe
and efficacious. So we can go to minus 3‑minus 7. Let\'s go to minus 3‑
minus 7. Minus 3‑minus 7, can we have a vote by hands for those who feel
that this is safe and efficacious.

MS. THORNTON: One, two, three, four, five, six.

DR. WEISS: Hey, it\'s a good day.

DR. MACSAI: You may not put it in your eye, but it meets the guidance.

DR. BANDEEN‑ROCHE: May I just say something for the record?

DR. WEISS: Dr. Bandeen‑Roche.

DR. BANDEEN‑ROCHE: I just want to make clear that I was abstaining
because I don\'t feel like I have the clinical expertise to make the
complicated risk benefit decision that you seem to be asking for.

MS. THORNTON: Yeah. Then I\'d like to have a negative vote, are there
any other abstenders?

DR. WEISS: We\'re going to have a vote for minus 3 to minus 7, those who
did not feel it had evidence of safety and efficacy. Dr. Schein, Dr.
Matoba, Dr. Mathers and Dr. Coleman. And then we had one abstention by
Dr. Bandeen‑Roche.

MS. THORNTON: Okay. I\'ve got it. That\'s minus 3 to minus 15.

DR. WEISS: Minus 3 to minus 15 at this point. Are we finished with that
question, Question 5. So we\'re going to go to Question 7 ‑ additional
labeling recommendations. What I will do is, interest of time, is
mention some of those that have been brought up already, and see if
there\'s consensus or disagreement. There was one comment about adding
in the labeling that the stability of the endothelial cell count has not
been documented. That might be a moot point if a condition for approval
is getting the four year data.

DR. SCHEIN: It\'s not moot.

DR. MACSAI: It\'s not moot at all.

DR. SCHEIN: There\'s still going to be labeling of whatever goes out
there. If we approve it with condition of acquiring that data
post‑approval, then that would have to be in there.

DR. WEISS: Fine. So we\'ll include that. Dr. Grimmett had indicated
white‑to‑white is not sufficient to determine the lens size. I don\'t
know that that would go into labeling. Dr. Macsai wanted non‑Caucasian
eyes from the Dominican Republic included. Dr. Coleman.

DR. COLEMAN: Yeah. I wanted to include that long‑term risk for glaucoma
are unknown, and then to also in the table that they have on page 20 of
25, they have glaucoma there too. And I would change that to elevated
interocular pressure, ocular hypertension, whatever definition they use.
And also, for the interocular pressure greater than 25 or greater than
10 ‑‑

DR. WEISS: Can you ‑‑

DR. COLEMAN: Slow down.

DR. WEISS: Slow down a little.

DR. COLEMAN: I have one, and I think that that\'s misleading because
they had five patients that had pressures of greater than 25, or greater
than 10 millimeter increase during baseline to 36 months. And so I think
it\'s misleading just to use that last visit, because pressure does
vary, and we don\'t just use one ‑‑

DR. WEISS: So tell me what you want.

DR. COLEMAN: So I want IOP greater than 25, or greater than 10 increased
from pre‑op. And I want the exact number, which is 5, instead of 1. And
so that would be a percentage of 1.4 percent instead of 0.2 percent.
This is in table ‑‑

DR. WEISS: I\'m going to actually need you to write this down, because
it\'s going too quick for me.

DR. COLEMAN: Okay.

DR. WEISS: Dr. Macsai had included data about halos and wanted to
include data about patients having complaints of halos and glare.

DR. MACSAI: Can I elaborate?

DR. WEISS: Okay. Yes, Dr. Macsai.

DR. MACSAI: I also wanted to include limbal pathology as an exclusion
criterion. I mean, the same as a pterygium, you can\'t measure
white‑to‑white.

DR. WEISS: I\'m just wondering if the Sponsor had any patients with
pterygias or things along ‑‑

DR. EDYLMAN: I think in general, most of those ociopathology was
excluded.

DR. WEISS: Okay. So that\'s fine. Dr. Grimmett had suggested having
something in labeling about a learning curve, that there\'s a learning
curve of the surgeon with a higher rate of upside down lenses and
cataracts, and surgeons with less experience.

Dr. Macsai had also requested, and I don\'t know ‑‑ this may not go on
labeling, but had requested that the 65 excluded eyes was ‑‑ if you
could elaborate on that.

DR. MACSAI: Sixty‑five eyes with pre‑existing conditions were included
in the study. It would be nice to know what were the pre‑ existing
conditions, what happened to those patients. It would give the
implanting surgeon and patient tremendous information, so let us know
what happened. What were the pre‑existing conditions, and what happened
to those patients?

DR. EYDELMAN: There was actually a section in the PMA that talked about
that.

DR. MACSAI: Oh, I missed it. Sorry. We\'ll include it then.

DR. WEISS: So we don\'t have to get involved in that then.

MS. THORNTON: You want that included in the labeling?

DR. MACSAI: Yeah, in the surgeon\'s information.

MS. THORNTON: Okay.

DR. WEISS: Dr. Schein, Dr. Matoba, and then Dr. Bradley.

DR. SCHEIN: I would like to see the more severe complication rates
reported on a per‑patient basis, rather than on a per‑eye basis.

DR. MATOBA: Under patient precautions, pigment dispersion should be
listed.

DR. MACSAI: Can you talk a little louder?

DR. MATOBA: Yes. Under patient precautions or relative ‑‑ yeah, under
patient precautions, I would like pigment dispersion to be listed. I
don\'t think it is right now. And on page ‑ let\'s see ‑ L‑36, which is
the beginning of the patient information draft, the third paragraph
where they mentioned the term \"phakic interocular lens surgery\", I
don\'t think that the average patient knows what phakic means. That term
should be explained. It never comes up again as you go on reading it. It
should be explained, and I think there should be a clearer discussion of
the alternative treatments for myopia.

And then lastly, on page L‑43, \"List of Adverse Events and
Complications\", I think they should ‑‑ even though it was not observed
in the study, I think they should mention the possibility of
endophthalmitis and loss of the eye, even though it\'s very rare, but
that\'s risk with interocular surgery.

DR. WEISS: Dr. Ho, and then Dr. McMahon.

DR. HO: Allen Ho. I would propose that the labeling include the
increased risk of vision loss from retinal detachment remains unknown.

DR. WEISS: Well, the risk, not the increased risk.

DR. HO: Yes, I\'m sorry. The risk.

DR. WEISS: Dr. Bradley, then Dr. Sugar, then Dr. Bandeen‑Roche.

DR. MACSAI: You missed McMahon.

DR. WEISS: Dr. McMahon. Excuse me.

DR. McMAHON: I\'d like to bring up a completely new issue, and that is,
I have a problem with the name of this device. This device has nothing
to do with a contact lens, and I think it is a disservice to the public
by using this term. I think it\'s a Euthanism probably from the
marketing department gone hog wild. And I would like to see all mention
to this in the device and labeling removed.

DR. MACSAI: What?

DR. McMAHON: The word \"contact lens\" I want removed from the name and
all labeling.

DR. WEISS: Doctor ‑‑ Sally. Sorry.

MS. THORNTON: I\'m Dr. Sally.

(Laughter.)

DR. WEISS: AT this point, I\'ll give out free M.D.s just ‑‑

MS. THORNTON: It sounded like part with Dr. Phil and Dr. Ruth.

DR. WEISS: Your book comes out soon.

MS. THORNTON: I also think we need to get some comments on the labeling
from the consumer representative.

MS. SUCH: Now?

DR. WEISS: Now is as good a time as any.

MS. SUCH: Okay.

MS. THORNTON: Before we leave this subject.

MS. SUCH: Good. Glenda Such. A couple of things. One is, I could ask a
question first and that is, precautions ‑‑ excuse me. On the precautions
versus the contraindications, there\'s a mention about ‑‑ we have just
brought up also about retinal detachment. And I wonder if there
shouldn\'t be something in the contraindications about retinal
detachment. How long after retinal detachment should you not have this
process? That actually should be in there.

Also ‑ I just went blank.

DR. WEISS: I believe it was an absolute contraindication for inclusion
into the study, so we don\'t ‑‑ we won\'t change that. And that would be
up to an individual physician if they intended to use this in ‑‑

DR. MACSAI: It\'s not a contraindication.

DR. WEISS: A retinal detachment is not a contraindication?

DR. MACSAI: No.

DR. HO: Correct. The definition was stable retinal exam, so that ‑‑ you
can have a very stable retinal exam post retinal detachment, and in
fact, after a retinal detachment surgery, you may be at less risk for a
problem, i.e., retinal detachment if you have it, so I\'m comfortable
with that. To answer your question, Glenda, I would say ‑‑ I would leave
that to surgeon discretion really.

MS. SUCH: And not have it in the patient ‑‑

DR. HO: Not have a specific time frame.

MS. SUCH: Okay. I was just concerned about that. The other is something
that\'s very small housecleaning part. It\'s on the same issue as the
phakic, and that is talking about in the very beginning of the patient
brochure, they talk about that it\'s 3‑D to 20‑D before they get into
what a diopter is. And let me tell you, most people wouldn\'t know a
diopter from a hole in the wall, so that should be spot up right away.
And even though there\'s a mention about that there\'s a glossary, most
patients won\'t look at the glossary unless they really, really a very,
very academic minded, so anywhere you can, to write out the actual
words, even though I know it\'s going to add to printing cost to
actually write out the words. That\'s the majority I have right now,
this very moment.

DR. WEISS: Just in terms of the patient information, I had ‑‑ looking at
the labeling, I think it should be listed in patient information that
the higher myopes should not expect the same results as low myopes,
because this reduces, does not correct myopia. I\'d like long term
effect on the endothelium is not known. And in mentioning ‑ sort of
following up on Dr. McMahon\'s comment ‑ in the glossary, there\'s a
definition, Collamer ICL is a collagen‑ based contact lens. I have to
say, that\'s the name of this device, but if I ‑‑ I think the average
person, if they see Collagen‑based contact lens, that certainly invokes
something different than an interocular lens, which we\'re discussing.
I\'m not sure how to address that issue, but Dr. Bradley will tell me.

DR. BRADLEY: Yeah, two points. One, on the issue of naming, I agree with
Dr. McMahon. I think calling this a contact lens will be grossly
misleading to the public. They already have a sense of what a contact
lens is. It\'s well‑defined. This is not a contact lens. It never will
be a contact lens, and to tell the public that it is, I think is
misleading. So perhaps we could take a vote on that, if there\'s some
contention over that.

Second issue, in spite of what Dr. Schallhorn assured us this morning,
the issue of pupil size still concerns me with this product. I mean, it
has a small optical zone. An optical zone size that would not be
considered safe for standard refractive surgery. And even with the
larger optical zones used in current LASIK, we\'re still concerned that
the procedure might not be appropriate for people with very large
pupils. And I wonder if some labeling for this particular device should
also warn the physician and the patient that if they happen to have
large pupils, this device may cause them problems at night.

DR. WEISS: Well, I think what would be more accurate to say is the
effect of pupil size is not known, because we have no evidence that it
does or doesn\'t. Sally has pointed out to me, I could see the National
Enquirer headline saying I got endophthalmitis from my contact lens.
Those weren\'t her exact words, but distancing herself from my comments
already, didn\'t take long. Dr. Coleman, Dr. Grimmett.

DR. COLEMAN: So for patient labeling issues, I also wanted to recommend,
concerning putting in that they may need to use medications chronically
to control eye pressure, because a lot of the patients had ‑‑ they had
like ‑‑ they have so far two patients that have needed to use topical
beta blockers chronically for their ocular hypertension.

DR. WEISS: Well, wouldn\'t it be more fair to say glaucoma is a risk,
than to tell you what the treatment is going to be?

DR. COLEMAN: They haven\'t shown that you\'ve gotten glaucoma. They\'re
just describing that you\'ve gotten high eye pressures. And according to
them, they didn\'t have glaucoma. They just ‑‑ that\'s why I wanted to
change that labeling, because the risk of glaucoma is unknown. They
weren\'t really ‑‑ they aren\'t doing visual fields, and you don\'t see
anything about the optic nerve. And so you really can\'t say anything
about glaucoma. They aren\'t doing angle evaluations. I mean, they
aren\'t doing a glaucoma evaluation, so they really ‑‑

DR. WEISS: Okay. The agency will describe it.

DR. COLEMAN: Yeah.

DR. WEISS: Okay. Any other ‑‑ yes. Go ahead.

MR. CROMPTON: Just a little fair balance from the industry rep on
labeling, is FDA really does work closely with the Sponsors on labeling.
And a lot of the comments that I\'m hearing, these kind of generic
comments that aren\'t specific to the study here, really can be
addressed in precautions, black box warnings, things like that. And I
know that all companies want to represent the product correctly.

When we get into trade names of products, that is a matter of some
concern to companies and the agency. And I think the agency guides that,
rather than the panels. So trade names get into patent issues,
copyright, all that sort of stuff. As long as claims are not being
misrepresented, I think that is a key thing.

DR. WEISS: The only problem is that contact lens is ‑‑

MR. CROMPTON: I understand the issue.

DR. WEISS: I would say that\'s somewhat deceptive.

MR. CROMPTON: I understand the issue, and I think FDA has a lot of
practice dealing with companies in terms of how they name their
products.

DR. WEISS: Ralph, do we need ‑‑ does the panel need to get involved in
this issue, or does not?

DR. ROSENTHAL: (Nodding head no.)

DR. WEISS: Fine. I had two things on the physician labeling. Is on page
6, there\'s a discussion of calculation of lens power. I\'d ask the
panel and the agency, should they be specifying the two formulas that
they specifically used in this study, or just say calculation of lens
power? Do you think it would be helpful to specify the formulas that
they used, or not really? Anyone. Dr. Sugar. No, just leave it as is.

Page 14, they indicate the post‑op regime should be Ocuflox and
Tobradex. I don\'t think that it has to be specifically ‑‑ there\'s no
reason why they have to use those particular drugs. And I think that
could read that the post‑op regime used in the PMA were those drugs.
Does anyone disagree with that? No? Any other labeling?

DR. GRIMMETT: I have a question.

DR. WEISS: Yes, Dr. Grimmett.

DR. GRIMMETT: Is the agency going to obtain stratified data by lens
optic size on the symptom data, the halos and stuff? Yes. Okay. Moot
point.

DR. MACSAI: That\'s what I asked for.

DR. GRIMMETT: I just want to make sure it\'s stratified.

DR. WEISS: Does anyone want to have any warning in there that 20 percent
of patients fell out of the usual endothelial cell loss, and had a
higher rate of endothelial cell loss? Dr. Schein.

DR. SCHEIN: I think the most direct thing to do is simply to show some
data at a level that the people reading this would understand. Maybe a
histogram of cell counts at baseline and at 3 or 4 years.

DR. WEISS: Dr. McMahon has pointed out to me that there\'s a ‑‑ I have
one list of questions, and he has another. And on his other, a very
important question that has been not handled by panel at this point, so
I\'m going to jump around. It is, do the safety and efficacy data for
eyes with pre‑operative myopia of greater than 15 to 20 support approval
in this refractive range? We\'ve gone up to 15.

MS. THORNTON: We voted on that.

DR. ROSENTHAL: You just did efficacy. I would like to hear your
discussion on safety issues, other than endothelial cell counts, which
you\'re addressing globally.

DR. WEISS: Above 15. We\'ve gone up to 15, but we omitted above 15 to
20. Those had a higher rate of loss of best corrected vision. I think we
‑‑ we did talk ‑‑ what do you specifically want us to address, because I
have highlighted that the panel did say it was efficacious for reduction
of myopia over minus 15.

DR. ROSENTHAL: The other safety issues.

DR. WEISS: The other safety ‑‑ is the panel satisfied with the safety
profile, aside from endothelial cell counts, in this group of higher
myopes? Dr. McMahon.

DR. McMAHON: I have some concerns in that in almost all categories,
there\'s a higher incidence of troubles, if you\'re looking at the
troublesome categories, and the numbers are relatively small. I think it
was 57 eyes, and so I have my concerns about that. And actually would
like to see either more data to expand the range to 15 to 20 that
demonstrates an acceptable safety profile, or to exclude it.

DR. WEISS: Does anyone else have any concerns? Dr. Mathers, then Dr.
Coleman.

DR. MATHERS: But I think in this particular group, this device has a
very, very strong appeal, because there is nothing else that can help
these people besides a contact lens, so in the risk benefit ratio, I
think that this is ‑‑ it\'s my own opinion that this actually has the
best risk benefit ratio of any of the other degrees of myopia, because
nothing else is available.

DR. WEISS: I apologize. As I recall, I think 100 percent of people in
that group would have it done again, so even though the satisfaction
wasn\'t the highest, they had the highest rate of deciding they made the
proper decision, probably particularly for the reason that you
mentioned, that if you have a majority of those people ending up 20/40,
that\'s probably a miraculous result for them.

DR. MATHERS: The alternative treatment is clear lens extraction, and
this is preferable.

DR. WEISS: Dr. Coleman, then Dr. Ho, then Dr. Bradley.

DR. COLEMAN: Yeah. I just wanted to point out that in this group, the
incidence of pressures greater than 10 millimeters of mercury over from
baseline was greater. It\'s about 4 percent versus the 1.4 percent.

DR. WEISS: So, I mean, that could be ‑‑ and this is separate, and I
apologize for digressing, but it probably ‑‑ I mentioned putting in the
patient information that the high myopes didn\'t have the same level of
efficacy, and we should also probably indicate they had a higher level
of risk at the same time. Dr. Ho.

DR. HO: Yeah. Dr. Mathers makes a very good point. The issue here for
those 28 eyes that were over 15 diopters is ‑‑ I\'m, you know, very
concerned about the possibility of retinal detachment with any kind of
procedure in those large myopic eyes. But if you look at those that are
willing to do it again, it\'s very telling. I think it was, as you
mentioned, zero out of 28 were not willing to do it again. And the point
of the other procedure being clear lens extraction, I think potentially
could be fraught with more risk. And that\'s why I\'m supportive for
this group.

DR. SCHEIN: Jayne.

DR. WEISS: Dr. Schein.

DR. SCHEIN: This could be dealt with in labeling by simply saying this
is the highest risk group. Notice, one of the people that wanted to have
it again had a macular detachment, isn\'t seeing very well. Now how do
you interpret that?

DR. WEISS: Hope springs eternal. Dr. Bradley.

DR. BRADLEY: Just to clarify a point Dr. Mathers made. I think you
perhaps meant to say these people have no other surgical options. They
clearly have other options.

DR. MATHERS: Contact lens, and spectacles.

DR. WEISS: You get terrible vision though. DR. BRADLEY: They don\'t work
very well.

DR. MATHERS: But yes, it\'s something.

DR. WEISS: Dr. Bandeen‑Roche.

DR. BANDEEN‑ROCHE: Would someone briefly speak to the clinical
significance of the trace anterior subcapsular, so in other words,
between those and the nuclear cataracts, there were 13.5 percent in this
group who had a cataract of some type. And is that an acceptable
trade‑off?

DR. WEISS: Dr. Eydelman, can you speak to that?

DR. EYDELMAN: The slide is up.

DR. WEISS: Okay. Great. Well, you know, we are speaking though a very
small number of eyes.

DR. EYDELMAN: Thirty‑one.

SPEAKER: They\'re at risk for cataract in any case.

DR. WEISS: I\'m not sure what conclusions can be reached on that small
number.

DR. MACSAI: They\'re at a greater risk for nuclear sclerotic cataract.

DR. WEISS: Dr. Macsai.

DR. MACSAI: Oh, sorry. Dr. Macsai. These patients are at greater risk
for nuclear sclerotic cataracts at an earlier age, whether or not they
have this implant ‑‑ this device implanted.

DR. WEISS: So I would suggest that this could be handled in ‑‑ the
sentiment I\'m getting is that there aren\'t a lot of good options, that
even though the safety and efficacy were not as good as other ranges,
this could be addressed in labeling to let the patients know that their
expectations should be less. I see some nodding by the panel, so that
will be good enough for me.

And we already indicated that we wanted this to be listed as reduction
of myopia, as opposed to correction. Dr. Sugar had mentioned a couple of
other things. There is something in patient and physician labeling,
indicating that this device improves the quality of vision. I think you
mentioned reduction as opposed to correction, if we\'re talking about
contrast sensitivity or rather than just saying the quality of vision.
Am I correct on that, Joel?

DR. SUGAR: Well, I can\'t speak to why the Sponsor put it in there, but
they did, I think, ask the patients about their quality of vision. I
don\'t think that\'s sufficient. I think you could say it may improve
the quality of vision, but then they should put the data in.

DR. WEISS: And then you wanted a brochure with a picture of the device
and the positioning. Anything else in the labeling? I think we answered
above 15 to 20. Dr. Grimmett.

DR. GRIMMETT: Let\'s take a vote on it.

DR. WEISS: I don\'t ‑‑ I mean, unless you want to vote, Ralph? Fine.
Above minus 15 to minus 20, excluding endothelial cell data, who would
agree that this shows safety and efficacy?

(Vote taken.)

MS. THORNTON: Six for.

DR. WEISS: Six for, and who would ‑‑

DR. ROSENTHAL: Four there, three there ‑ that is seven.

MS. THORNTON: Well, why don\'t you count. I can ‑‑ one, two, three,
four, five, six, seven. You\'re right. Seven for.

DR. WEISS: And those would disagree with safety and efficacy, please
raise your hand.

MS. THORNTON: Two against.

DR. SCHEIN: There\'s this problem that I would vote for approval, but I
don\'t think it\'s particularly safe.

DR. WEISS: Well, it\'s both. It\'s a marriage, safe and efficacious.

DR. SCHEIN: Yeah, that\'s the problem.

DR. WEISS: So life is full of ‑‑ so would you vote for ‑‑ with those
two, safe and efficacious, would you vote for approval or not?

DR. SCHEIN: Presuming all the information is in the labeling, I would
vote for approval.

DR. WEISS: Okay. Fine. Eight‑one. Any other labeling issues? Okay.
Seeing no other labeling issues, does the FDA have any other questions
that they want the panel to address?

MS. THORNTON: Last chance.

DR. WEISS: Last chance. Okay. Seeing no other questions, then we are
going to go to our open public hearing. And seeing no one for the open
public hearing, we will now move on from that. I hear applause, so that
might have been the correct decision. FDA closing comments. No closing
comments. I think everyone has been beaten into submission. Sponsor
closing comments. Ah, FDA closing comments.

DR. CALOGERO: Yes. Hi there, Don Calogero. I\'d like to clarify
something. I think there\'s a little sort of confusion here in terms of
these rates. And we were throwing out rates, Dr. Macsai threw out rates,
1.8 percent, ANSI is 2 percent, the panel gave a rate of 1.5 percent,
all in the same ball park. But the rate that you threw out, 1.8 percent
and Gerry calculated 2 percent, those are mean rates. The rates from
ANSI and the rates from that panel discussion are the upper 90 percent
confidence intervals. So in terms of ANSI and that discussion, the upper
90 percent confidence interval needs to be below that point.

If you look at the upper 90 percent confidence interval of the data out
to three years, it\'s actually about 3‑1/2 percent. So you\'re saying
3‑1/2 percent, then is acceptable. If you look at the Sponsor\'s data,
from year 3 to year 4, at the upper 90 percent confidence interval, they
have met that criteria of 1.5. It\'s 1.42 or something.

The only problem that I hear from the discussion about that data is, it
may ‑‑ that group may not be representative of the entire population.
You may sort of a sampling bias or something, so I just want to point
out that there\'s sort of a little miscommunication here, or confusion.
The actual rates that the Sponsor has from year ‑‑ three months to three
years are very different than the levels that ANSI has, and ISO has, and
was recommended previously by the panel, so I just wanted to clear that
up.

DR. GRIMMETT: Thank you.

DR. WEISS: Sponsor closing comments.

DR. SLADE: The battery on our laptop is not up to the length of your
discussion.

DR. WEISS: That comforts me, Dr. Slade.

MS. THORNTON: Do you want the projector on?

DR. SLADE: Yes. We would like the projector on. I really appreciate you
all staying to listen to my talk. Okay. There. Okay. And what I would
like to do is give you our closing comments from the Sponsor. Excuse me
just a minute. This is not actually my computer. Is the toggle F10? F8.
Okay. Super.

Let\'s just go right to the chase to our comments. What do we know, and
what do we not know about this PMA and this device? What are the current
standards of requirements for safety of the corneal endothelium for any
device? And what do we know about endothelial safety for this particular
device? What information do we have to support a determination of
reasonable assurance with post‑market labeling and follow‑up, a
reasonable assurance of safety today, and how do we best add to the
evolving knowledge‑base in this area over time, a needed area, a needed
area for our patients.

We\'ve looked at the standards for endothelial cell safety. The ANSI
standards of 1‑1/2 percent. You add the .6 percent, somewhere around 2
percent, and we don\'t have any targets for hexagonality, or coefficient
of variation, although we\'ve seen that those can be the most sensitive
indicators of endothelial stress. That\'s what we know is the standard.

Endothelial safety with the ICL, we have a cumulative total mean loss of
8.4 to 9.7 percent. We do have suggestion of endothelial cell
stabilization, or a leveling of cell loss between 3 to 4 years. We have
it with two different cohorts, the 57 eye cohort, and the 37. While
those aren\'t our largest numbers, those are our best models. The 37,
for example, are the people who made every single visit, so it\'s the
best models, and we can certainly post‑ marketly follow that particular
cohort up.

And then in addition to that, in addition to that, we have the percent
hexagonality and the coefficient of variation data, which easily
supports the absence of chronic endothelial stress. This is that 37 eye
cohort I just mentioned. And if anything, it\'s trending to a
leveling‑out, or certainly no farther down.

It\'s important to look at these again. This is the percent of hexagonal
cells. Anything over 45 percent is a winner, and this is clearly,
throughout the entire follow‑up, over that, and it\'s stable. It\'s not
dancing around.

The coefficient of variation is the same thing. Anything that is not
above 45 is, again, a winner. And this does fit into that to the
adequate confidence intervals, and it\'s stable. It\'s stable over time,
just like the visual acuity results, just like the refractive stability
that I showed you.

Further, if you\'re trying to figure out the safety of this lens, I
would challenge you to postulate a clear mechanism for chronic
endothelial cell loss due to the clinical procedure, which is cataract
surgery with a lot of the steps left out, or the ICL, the material
itself, which is a proven approved material behind the iris. We have no
evidence of inflammation over time when assessed with the most sensitive
methods we have today. Don Sanders, I think, made that point clear. And
we have no evidence of corneal stress or instability based upon the most
sensitive measures of morphology by I think who we ‑‑ the person, Henry
Edelhauser, who we all respect, over time. Again, you\'ve seen the
morphology of endothelial cells. If we look at the cell flare study, at
no point in time did we ever get the cohort outside the normal range.
That\'s significant.

Further, I think we should stress again what Hank Edelhauser presented
to us. There\'s a change. We\'re learning about our understanding of the
corneal endothelium. There does appear to be a reservoir of endothelial
cells in the corneal periphery, based upon his lab, and earlier
confirmatory studies. There\'s even the good evidence for peripheral
corneal endothelial stem cells, even in adult corneal tissue. And again,
Dr. Edelhauser, I think, has well‑documented this, just the simple
references, the fact of increasing cells. And then when we make our
incision into the cornea, we\'re not even approaching where we have most
of these safety cells, which is superior.

Further, our understanding of the corneal endothelium, I think we\'ve
all struggled today. And if anything, it\'s proven that a linear
modeling of endothelial cell loss over time is difficult based upon our
current knowledge‑base. The non‑homogenate endothelial cell density, the
presence of an endothelial cell reserve in the periphery, including the
stem cells, and the potential for these cells to migrate from the higher
density periphery to the lower density central endothelium further
supports reasonable safety for this device.

From Dr. Edelhauser, the higher endothelial cell density found in the
paracentral and peripheral cornea affords an additional reassurance of
safety beyond the morphology for the endothelium in patients implanted
with the ICL. The surgical incision for the ICL is corneal, and
temporal, and it\'s at a distance, and it\'s only a couple of clock
hours away from the largest endothelial reserves which reside in the
superior corneal.

So to finish this out, what do we know today? And we actually know, I
think, a fairly good deal. Well, we realized, and we continue to realize
the need for additional options, additional good clinical options in
refractive surgery. And one note about this ‑ the beauty of this is
it\'s a non‑dose dependent procedure. LASIK, the more LASIK you do, the
more trouble you run into. This is the same procedure, the same lens,
whether it\'s a minus 3 or minus 15, or a minus 20.

Endothelial morphology represents a highly sensitive measure or
indicator of corneal endothelial stability, and I think we\'ve seen the
results, seen the studies that back that up. And in the ICL population,
I don\'t know how the results could be any better. It clearly indicates
a stable endothelium without stress by morphology.

We believe the stabilization of endothelial cell loss occurs between
three to four years. We have the absence of any cases of corneal
decompensation in ten years of history greater than 30,000 implants
internationally. Again, as I mentioned, I don\'t know if we got all of
the data from those patients, but I do believe that the first person
that had a corneal decompensation would be quite ‑ ‑ we\'d know about
that.

There is a iron‑clad Sponsor commitment to continued specular microscopy
data. I don\'t have a financial interest in STAAR. I wasn\'t an
investigator in this study. I am a paid consultant, but I can assure you
of their commitment to continue the collection of specular microscopy
data post‑market approval, in all study patients through five years or
beyond with the same rigor of analysis, the same lab, the same Dr.
Edelhauser looking at the specular microscopy images.

So a long‑term commitment to surveillance of study patients for all
safety findings. A well‑developed training program. Now we\'ve had the
‑‑ you know, is this something that only the creme de la creme surgeons
can do? Well, remember when LASIK came along and everybody would say
well gee, that\'s pretty crazy. You know, only corneal surgeons should
be doing that. And it just didn\'t pan out that way.

I would submit to you that that was a procedure where surgeons had to
learn new steps. This, they don\'t. It\'s all cataract steps. I do
believe strongly, having been involved in directing the LASIK courses,
that the training program will be excellent and superlative beyond what
we\'ve had before. And finally, the Sponsor is totally committed to
labeling to encompass your recommendations, no matter how many volumes,
or how the package insert becomes. And that to the panel and the FDA, to
provide further assurance of safe use of the ICL.

I submit to you that the clinical data presented in the PMA does
establish the effectiveness of the myopic ICL for the correction or
reduction, as labeling ‑‑ as we are dictated to by you for labeling,
between minus 3 and minus 20. And I submit to you that the clinical
outcomes presented in this PMA provide a reasonable assurance of safety
of the myopic ICL in this patient population, this study designed for
moderate to high myopia. Thank you very much.

DR. WEISS: Thank you very much, Dr. Slade. I would like to thank the
Sponsor for an excellent presentation, the primary reviewers, and the
member of the panel, as well as the agency for the usual detailed
evaluation of the data, and now we will move to the voting options,
which will be read by Sally Thornton.

MS. THORNTON: \"The Medical Device Amendments to the Federal Food, Drug
and Cosmetic Act as amended by the Safe Medical Devices Act of 1990
allows the Food and Drug Administration to obtain a recommendation from
an expert advisory panel on designated medical device pre‑market
approval applications that are filed with the agency. The PMA must stand
on its own merits, and your recommendation must be supported by safety
and effectiveness data in the application, or by applicable publicly
available information.

Safety is defined in the Act as reasonable assurance based on valid
scientific evidence that the probable benefits to health under
conditions on intended use outweigh any probable risk. Effectiveness is
defined as reasonable assurance that in a significant portion of the
population, the use of the device for its intended use is in conditions
of approval when labeled will provide clinically significant results.

Your recommendation options for the vote are as follows. Number one,
approval, if there are no conditions attached. Number two, approvable
with conditions. The panel may recommend that the PMA be found
approvable, subject to specified conditions, such as position or patient
education, labeling changes or a further analysis of existing data.
Prior to voting, all of the conditions should be discussed by the panel.
Not‑approvable. The panel may recommend that the PMA is not approvable
if the data do not provide a reasonable assurance that the device is
safe, or if a reasonable assurance has not been given, that the device
is effective under the conditions of use prescribed, recommended, or
suggested in the proposed labeling.

Following the voting, the Chair will ask each panel member to present a
brief statement outlining the reasons for their vote.\" Thank you.
Jayne.

DR. WEISS: Thank you. I\'d like to have someone make a motion. Dr.
Sugar.

DR. SUGAR: I\'d like to move approval with conditions with the volumes
of conditions that Steve Slade mentioned.

DR. WEISS: Well, one of the ‑‑

MS. THORNTON: Well, you can\'t do that.

DR. SUGAR: I know, but Jayne has them all listed on her computer, and
she can give us the words.

DR. WEISS: Okay. Do we have a second for approval with conditions? Dr.
Mathers and Dr. Macsai second it. There were two conditions, there was a
choice of one condition that I think we do need to have the panel list.
We will, of course, vote on the secondary motions, the conditions,
before we vote on the primary motion. But the secondary motion, as far
as data to be included for specular microscopy and when that would be
needed ‑ I need someone to phrase that for me, because there was a
disagreement among the panel, and I need that to be included here.

MS. THORNTON: Are you calling for a condition now?

DR. SUGAR: Yes.

DR. WEISS: What is your ‑‑

DR. SUGAR: With the condition that after approval, data continue to be
acquired on endothelial cell density on an annual basis, up to a minimum
of five years.

MS. THORNTON: Is there a second?

(Seconded.)

DR. WEISS: So there\'s a second for the ‑‑ and can you repeat that
condition, Dr. Sugar, because what ‑‑ if it\'s all right with agency,
before we go on with additional ‑‑

MS. THORNTON: We can discuss it after the second.

DR. WEISS: Okay. Can you repeat what that motion is and then we\'re
going to have discussion of that. And the a vote of that condition.

DR. SUGAR: Approvable with conditions. One of the conditions being that
data continue to be acquired on an annual basis on endothelial cell
density to at least five years.

DR. WEISS: Can you ‑‑

DR. GRIMMETT: For clarification, he\'s recommending approval now,
post‑market later.

DR. ROSENTHAL: Approval now, and the endothelial cell data will be
collected after the approval ‑‑

DR. SUGAR: Correct.

DR. ROSENTHAL: ‑‑ for four and five years. And longer, if need be.

DR. WEISS: Okay. So approval now, and I would like the panel to be
extremely clear when they vote on this. This is approval now, and then
the endothelial cell count data will be collected afterwards, after
approval. We will have a discussion, and Dr. Bradley will have the first
point. After we have discussion of this secondary motion, we will vote
on the secondary motion before we go on to other labeling. Dr. Bradley.

DR. BRADLEY: I thought in our earlier discussions that approval was
going to be conditional upon the four year data convincing us that, in
fact, endothelial count decline was not at a dangerous level.

DR. GRIMMETT: Then vote against this motion.

DR. WEISS: This is why I wanted a particular motion put forward for a
vote. If you disagree with this, as Dr. Grimmett so kindly pointed out,
then you vote that you disagree. And if you agree with it, then you vote
that you agree. Is there any discussion, aside from when you disagree
you vote no, and when you agree you vote yes. I assume not, so Dr. Ho.

DR. HO: Allen Ho. I would like to add to that, as part of discussion,
that the annualized rates of retinal detachment be included.

DR. WEISS: This is separate. That\'s a separate condition. This is not,
as Dr. Slade indicated, we will have a volume coming up. But hopefully,
it will be done shortly enough. This is just this particular point. Dr.
Bradley.

DR. BRADLEY: A question ‑‑ the motion is that the data be collected post
approval.

DR. SUGAR: That\'s correct.

DR. BRADLEY: Do you have any desire that something specific be done with
the data once collected, or is that irrelevant to your motion?

DR. SUGAR: It\'s certainly not irrelevant. I don\'t know how specific we
need to be with that, but the data be reviewed by the agency and apropos
of our discussion, if the endothelial cell density continues to decline
at the same rate, that the issue be represented either to the panel, or
that there be some further discussion about whether approval should be
continued.

DR. WEISS: Just for clarification, Ralph, what would the ‑‑ aside from
the statement that Dr. Sugar just made as far as collecting the data, do
you need any further clarification at this point from the panel what we
mean by collecting the data, what we want you to do with the data, or
that would be sufficient for you at this point?

DR. ROSENTHAL: I think we understand the mood of the motion.

DR. WEISS: Okay. The mood ‑‑

DR. ROSENTHAL: The question is, and I\'m not sure I can give you an
answer, is if the endothelial cell count continued to drop at 4 and 5
years, I\'m not sure what our options would be. And that is something we
would have to take up with higher order people in the agency.\*\*

DR. SUGAR: Well, could not rescind approval?

DR. MACSAI: Recall? I mean, is that not an option? You\'ve done it
before.

DR. ROSENTHAL: Everything you\'ve said are options.

DR. WEISS: Would we need to ‑‑ would Dr. Sugar need to amend his motion
to include what his desire for ‑‑ he would not. Dr. Sugar, is there
anything else you wanted to add to that motion? Are you satisfied ‑‑

DR. ROSENTHAL: I just wanted to add, that I\'ve just been informed that
a PMA has never been withdrawn from ‑‑

DR. SUGAR: You mean approval has never been withdrawn.

DR. ROSENTHAL: Approval has never been withdrawn. There could be the
issue of generalized recall. I\'m not sure how that would work. I\'ve
never had it. Oh, I have had one. It\'s not easy, based on endothelial
cell counts. And on 4 and 5 year data when you\'re looking at data,
possibly 20 years down the line.

DR. WEISS: I assume the intent of Dr. Sugar\'s motion was to ‑‑ because
he believes there\'s reasonable safety and efficacy, but he would like
to be assured of that. And if there was any evidence to the contrary,
that the agency could act on that evidence to the contrary. What I\'m
hearing from you now is that the agency would have difficulty acting on
that evidence.

DR. ROSENTHAL: We would have difficulty withdrawing the PMA. It\'s never
been done, and you can ‑‑ I think you can probably sense the problems we
would have in dealing with a company that has four and five year data
that shows a 1.9 percent drop in endothelial cell counts, with no
corneal edema, and no problems. And we\'re saying well, it should be
recalled because 20 years from now, patients could get in trouble. I
mean, I just don\'t know where that argument could go, and I\'m sure it
would not stop at me.

DR. WEISS: Is there any way that the motion could be amended to have the
end result that Dr. Sugar is looking for, in that if there is a concern
about safety, then there could be a recall?

DR. ROSENTHAL: No.

DR. WEISS: So then from what you\'re telling me, it\'s pointless to get
any data afterwards, since there\'s nothing you can do about it.

DR. SCHEIN: How about labeling changing?

DR. WEISS: Dr. Matoba.

DR. MATOBA: Dr. Schein said a labeling change could be made.

DR. WEISS: So a labeling change could be made, but the device would
still be on the market. Dr. Mathers, and then Mr. Crompton.

DR. MATHERS: The collection of this data is important clinically. I
mean, just because the device is out there, doesn\'t mean that surgeons
have to put it in. If they have a clear and overwhelming indication of a
risk, then it ‑‑ and that data is collected because we are telling them
to do it, so then it will help the public to know that.

DR. WEISS: And I would be ‑‑ I would assume this data is not
confidential. Is this data confidential? This data is not confidential,
so it would be released for public information?

DR. ROSENTHAL: Once the PMA is approved, the data that comes in
subsequently would become part of the new ‑‑ I mean, it would come in as
an amendment, and we would amend the safety ‑‑ the summary of safety and
effectiveness. And we would amend the labeling.

DR. WEISS: So it is not confidential. It would go into labeling. The
lens ‑‑ if there were any issues, the lens would not get recalled. PMA
would not be rescinded, but that it would go into labeling, and it would
be out there for the public. Yes.

MS. LOCHNER: Yeah. And just for the record, I want to make clear, the
FDA does have the authority to withdraw approval of the PMA. However, we
do want to caution you that this is an extremely high regulatory burden
to meet. And, in fact, it has never been done in the device center
because of that high legal and regulatory burden that we have to meet to
withdraw the approval. And I think, frankly, it would be very, very
difficult for an ophthalmic device. So what we can do is other things,
such as push for a mandatory recall of the product, or other
authorities. Ask the company to voluntarily withdraw the PMA.

There are other things we can do, but ‑‑ and certainly, things like
mandatory recall, that assumes a certain acceptance by the company and
agreement that there is a problem, so I just don\'t want the record to
reflect that there\'s nothing FDA can do once a PMA is approved. We can
withdraw approval of the PMA. It\'s an extremely high legal and
regulatory burden, however.

DR. WEISS: Mr. Crompton.

MR. CROMPTON: And I would thank FDA for that comment. FDA has a variety
of enforcement tools, as we know. And companies are not in the business
of putting unsafe products on the market. There\'s no vested interest
for a company to put on a product that is showing a safety profile that
is not being reflected in terms of accurate labeling and communication
to potential surgeons that are using the device.

I would comment though, that this is in the danger of statistics and
extrapolation, that this is a challenge, I recognize. We had a
recognized expert here today who could not tell us what the rate of
endothelial cell loss is. To hold a Sponsor to that standard is almost
unprecedented for a device, for them to do that sort of basic research.
Unusual for me to see that the panel is unanimous saying that we have an
effective treatment here, and frankly, a reasonable safety profile for
this device. That word \"reasonable\" means something, and Dr. Rosenthal
gave an excellent, excellent definition of what the Act requires for
reasonable evidence of safety.

I think the Sponsor demonstrated that today. The post‑market scenario is
real. This company is committed to doing that. FDA will look at that
data on an annual basis. And believe me, if the safety profile isn\'t
there, there will be a discussion with the company. We just know that in
the industry. So I can\'t advocate on the part of the company, but in
terms of the industry position, we cannot be put on to answer these
basic scientific questions when we bring new devices to the market.

We deal with protocols that were actually blessed by the agency over
five years ago, and now other things are coming up as we gain experience
with these devices and with new treatments. A factor, unfortunately,
that you cannot consider in your deliberations, but needs to be put up
there, because it\'s been put up four times today. You\'ve got over
30,000 implants in Europe with a 10 year history. If there was a problem
with corneal edema, I think the company might know about that.

DR. WEISS: I don\'t think ‑‑ actually, from what I hear from the panel,
no one is really worried about corneal edema. As Dr. Mathers has
indicated, he just wants people to have 1500 cells at the time of their
demise. A good goal for all of us, I will mention.

Any other comments on this motion? Otherwise, we\'ll put it to a vote.
If there are no other comments, I just want to clarify what\'s been
said, is that this data would be obtained after this device is released
to be used. It would be difficult, although not impossible, for the FDA
to act on any adverse information coming in from that data. Am I ‑‑ Dr.
Rosenthal, anything else you\'d want to add for my interpretation? If
not, if everyone understands this motion, then I would like those in
favor of the motion ‑‑ perhaps, Dr. Sugar, could you just restate the
motion, and then I\'ll ‑‑ you can\'t restate it. Okay. In that case, no
restatement of the motion. We\'ll just have a vote on it from your
memory.

MS. THORNTON: Would you please try to state it.

DR. WEISS: Okay. I ‑‑ would I try to state it? I\'ve stated it enough.
Joel, please, have some pity.

DR. SUGAR: Yeah. I don\'t think this motion will pass, but I\'d like to
move for ‑‑

DR. WEISS: I\'d move to strike that one from the record.

DR. SUGAR: One of the conditions being that with ‑‑ that post‑ approval
data be acquired on endothelial cell density on an annual basis up to at
least five years.

DR. WEISS: Fine. All of those in favor of the motion, please signify by
raising your hand.

(Vote taken.)

DR. WEISS: All of those who are against, signify by raising your hands.

(Vote taken.)

DR. WEISS: Any abstentions on this? So the motion passed 6‑5. Dr. Sugar.

DR. SUGAR: I\'m surprised.

DR. WEISS: So we will now go on to other motions, and then on to
labeling. Do I have any other motions?

DR. SCHEIN: Yes, I have a motion.

DR. WEISS: Yeah.

DR. SCHEIN: I\'d like to propose as a condition that a post‑ marketing
surveillance study involving the collection of new data of content and
scope to be determined by the FDA and the Sponsor be required.

DR. WEISS: I think that was what was just ‑‑

DR. SCHEIN: No, no. It is a very important distinction. That was
follow‑up data of the pre‑market endothelial cells. I\'m referring to
post‑market surveillance study, as we got a little lecture on from the
FDA. And I don\'t want to spend time, details of the content and scope,
that would be worked out between the Sponsor and the FDA.

DR. MATOBA: This is a registry type of ‑‑

DR. SCHEIN: I think of half a dozen different ‑‑

DR. WEISS: Okay. So we have a motion for something separate than the
previous motion, which is a post‑market study, and that could be
clarified at another time, I assume.

DR. SCHEIN: The purpose is to look for rates of cataract, retinal
detachment, treatment for elevated eye pressure, and any other
conditions felt appropriate by the FDA.

DR. WEISS: And this ‑‑ to clarify for the panel, this would be a new
cohort of patients who began enrollment after this was into the
marketplace.

DR. SCHEIN: After it\'s approved, yes.

DR. COLEMAN: I second it.

DR. WEISS: We have a second by Dr. Coleman. Does the agency need any
clarification of that before we have a vote? There\'s a proposal ‑‑ a
motion ‑‑

DR. ROSENTHAL: The agency only ‑‑ no, we understand the motion quite
clearly. The agency would like to know if there are any specific issues
‑‑

DR. SCHEIN: He said cataract, retinal ‑‑

DR. ROSENTHAL: Oh, did he? I\'m sorry.

DR. SCHEIN: Cataract, retinal detachment.

SPEAKER: Elevated interocular pressure.

DR. SCHEIN: Elevated interocular pressure.

DR. WEISS: Is there any discussion ‑‑

DR. ROSENTHAL: And you\'re happy for us to work it out with the company
and our post‑market surveillance people.

DR. SCHEIN: Yes.

DR. ROSENTHAL: And possibly members of this panel as homework
assignments.

DR. SCHEIN: Yes.

DR. ROSENTHAL: Thank you.

DR. WEISS: Does the panel ‑‑ Dr. Macsai.

DR. MACSAI: As a friendly amendment, Dr. Schein, could we add glaucoma
to not just elevated interocular pressure?

DR. SCHEIN: Yes.

DR. MACSAI: And is the purpose of this ‑‑ clarify for me, because I
still got a little confused there earlier. The purpose of this is to see
how the device performs out in the general world?

DR. SCHEIN: Yes. In patient populations that are not strictly selected
based on inclusion criteria for a study amongst surgeons‑ at‑large who
receive training, to see what the risk profile is.

DR. MACSAI: So this would be surgeons who aren\'t investigators.

DR. SCHEIN: This would be the actual use of the product after it is
approved.

DR. MACSAI: Okay.

DR. WEISS: I just have a question to the agency. Does this meet least
burdensome provisions in terms of what you heard?

DR. ROSENTHAL: I think you can recommend what you want to recommend. I
would like to get some sense of time though, Dr. Schein.

DR. SCHEIN: Well ‑‑

DR. ROSENTHAL: You know, you can do a post‑market study for a day, a
month, a year, 25 years.

DR. SCHEIN: As some people in the audience know, there was a requirement
for those who received approval for silicone hydrogel extended wear
contact lenses to estimate a rate of ulcerative keratitis. That\'s a
different issue, because the time duration is not as important there,
but a greater sample size is important, so that study is in 5,000
individuals for a year. I would surmise ‑‑ without doing some
calculations, I don\'t want to just make things up off the cuff, that
the sample size would be smaller, but the duration a little longer. So I
would think in the two to three year range, but with a smaller sample
size. There are techniques for working these things out, which are
well‑known.

DR. ROSENTHAL: Thank you.

DR. WEISS: So we have a second. Is there any other discussion?
Otherwise, we\'ll put it to a vote. All those in favor signify by
raising your hand.

(Vote taken.)

MS. THORNTON: Dr. Sugar for, Dr. Bandeen‑Roche for, Dr. Schein for, Dr.
McMahon for, Matoba for, Bradley for, Mathers for, Ho for, Macsai for,
Coleman for.

DR. WEISS: All those who are against, signify by raising your hands.

(Vote taken.)

MS. THORNTON: Grimmett against.

DR. WEISS: Any abstentions? No abstentions. Any other motions? So the
motion is passed, 10‑1. Any other motions? Dr. Macsai.

DR. MACSAI: As a point of clarification, Dr. Weiss, we talked about all
kinds of other things earlier.

DR. WEISS: Yes.

DR. MACSAI: Anterior chamber depth, preoperative endothelial cell count,
labeling issues. Am I to assume that all those are in the yea, or do we
vote on each one of those?

DR. WEISS: We won\'t vote on each of them, but what I wanted the panel
to do is to bring up any other motion ‑‑ any other conditions, and if
there are no others, then I will just read from what I scribed, and I
would ask Dr. Mathers to fill in anything that I might have missed.

DR. MACSAI: Why don\'t you read them, and then we\'ll see if you missed
anything.

DR. WEISS: Okay.

DR. MACSAI: May save time.

DR. WEISS: Okay. So under ‑‑ this is going to be a grab‑bag because I
listed it in each of the ‑‑ underneath each of the questions that were
posed by FDA. There was the desire for indicating that patients should
have a preoperative endothelial cell count prior to having this
procedure, demonstrating normal endothelium for age. There was a
consideration of serial endothelial cell counts postoperatively. There
was no determination made on that particular one, so we might want to
put that was a separate condition and have a vote on that.

Preoperative endothelial cell count with normal endothelium for age, I
think we can list in the grab‑bag with everything else that there was
fairly uniform agreement on. I would ‑‑ if you would like, Dr. Macsai,
because I think you had brought this up, is consideration of serial
endothelial cell counts postoperatively. Did you want to raise that as a
motion to be voted on or not?

DR. MACSAI: I think I was voted down.

DR. WEISS: Well, you don\'t ‑‑ it\'s not a vote until we do it now. So
do you want to put it forward as a vote, or leave it be as a condition
to be voted on, or would you rather it not?

DR. MACSAI: No. I\'m comfortable with the preoperative endothelial cell
count.

DR. WEISS: There was indication of not implanting in anterior chamber
cell depths less than three.

DR. MACSAI: That\'s correct.

DR. WEISS: That\'s correct. In terms of with the post‑market
information, and I will presume that would refer to Dr. Sugar\'s motion,
as well as Dr. Schein\'s motion, information on the cataract, as well as
the specular microscopy. Information indicating that we don\'t know
whether removing or exchanging the lens causes more complications.
Information or requesting the Sponsor to give us information whether the
axial length measurement is accurate if an IOL is in place. Mandating
training. Indication that this is efficacious for reduction, not
correction, of myopia over minus 15. Indication that the IOP may
increase if the viscoelastic is not rinsed out. Recommendation that the
IOP checked in 4 to 6 hours, and 24 hours. For this particular one,
check in 4 to 6 hours and 24 hours. If there\'s a question on this, we
can keep that as a separate motion and vote on that. Was there agreement
on that particular one? Dr. Coleman.

DR. COLEMAN: I thought there was only agreement on within 24 hours.

DR. WEISS: So we can take out the 4 to 6 hours. Fine. Dr. Macsai.

DR. MACSAI: I would like to see that 4 to 6 hour recommendation be left
in.

DR. WEISS: So if you\'d like to see that left in, why don\'t you put it
forward as a separate motion from the grab‑bag of motion that everyone
is agreeing to and have a vote on it.

DR. MACSAI: Can we?

DR. WEISS: Yes, you can.

DR. MACSAI: Okay. I move that we recommend that in the labeling, we
recommend to the surgeons they check the patient\'s pressure 4 hours
post‑op. And I think that that might have been followed by most of those
investigators on this study. And the label ‑‑ if the Sponsors would like
to clarify that, I know that they\'re not allowed, but I think that\'s a
really good idea.

DR. WEISS: So we have a motion. Check the pressure 4 to 6 hours. Do we
have a second of that motion?

DR. COLEMAN: I second it.

DR. WEISS: Can we have a vote. All in favor say aye or raise your hands
aye.

(Vote taken.)

DR. WEISS: We have Dr. Macsai, Dr. Coleman, Dr. Grimmett for. All of
those against.

(Vote taken.)

DR. WEISS: Dr. Sugar, Dr. Schein, Dr. McMahon, Dr. Matoba, Dr. Ho, Dr.
Mathers. All of those abstaining?

(Vote taken.)

DR. WEISS: Dr. Bandeen‑Roche and Dr. Bradley. The motion does not pass,
so we\'re going to include it in the grab‑bag. Check IOP in 24 hours.
We\'re going to ask the Sponsor to provide information. Was there ‑‑
gonioscopy will be performed at four years, as part of these studies
that have been mentioned by Dr. Sugar and Dr. Schein. Dr. Coleman. Well,
I\'m talking about as part of the post‑market studies, you want
gonioscopy to be performed, or is this gonioscopy that was already
performed that you want the results?

DR. ROSENTHAL: Dr. Weiss, you\'re talking about post‑market evaluation
on the IDE cohort. Is that what you\'re talking about now?

DR. WEISS: I\'m bringing up both factors of Dr. Sugar\'s ‑‑ Dr. Coleman
had brought up the interest in getting gonioscopy at four years, and I
would like to clarify for the agency whether we\'re talking about
gonioscopy for the cohort that was studied, or whether gonioscopy would
be done ‑‑ Dr. Schein is nodding, so this is from the cohort that was
originally studied. That would be satisfactory?

DR. COLEMAN: Yeah. This is for the cohort that was originally studied,
but I thought that that ‑‑ that was based on the four years data
pre‑approval. And we\'ve already passed a condition for ‑‑

DR. WEISS: So you\'re no longer interested in that?

DR. COLEMAN: No. I am interested in it, but I don\'t see ‑‑ you know,
it\'s not a condition, I guess, because it would be approved ‑ ‑ I mean,
you\'re talking if they would do ‑‑

DR. WEISS: Well, we\'re just talking about information gathering as part
of the four year specular microscopy. Do you still want gonioscopy? If
you don\'t, we can ‑‑

DR. COLEMAN: No, I do.

DR. WEISS: You do. Okay. So we\'ll include it. It\'s not a condition ‑‑

SPEAKER: It\'s not for approval.

DR. WEISS: It\'s not a condition.

DR. COLEMAN: It\'s not a condition. Okay.

DR. WEISS: We\'re going to label the ‑‑ for labeling ‑‑ yes, Sally.

MS. THORNTON: This list that you just gave, is this ‑‑ this is to be
collected under one condition called \"Additional Information Needed
from the Sponsor\"?

DR. WEISS: I think it depends on each of ‑‑ no. The answer is no.

MS. THORNTON: Well, what is this?

DR. WEISS: I think if you ‑‑

DR. MACSAI: These are conditions.

DR. WEISS: It doesn\'t fulfill one ‑‑ these are all separate conditions
that there was essentially unanimous agreement on, and they would
ordinarily be voted on separately, but in interest of time and because
we\'ve discussed them already, they\'re going to be listed together.
Although, the only thing they have in common is the unanimity of the
panel\'s agreement to include these as either labeling or information
that\'s required from the Sponsor, or ‑‑ for example, we have something
here, \"Do Not Implant In Anterior Chamber Depth Less Than 3\", and
advice to put this in in someone with a normal preoperative endothelial
cell count, and these are ‑‑ there\'s all variation here.

MS. THORNTON: Okay. Could we, for the ‑‑ in the interest of trying to
track this complete motion, could you please ‑‑ you\'re saying some of
them are for this group, some of them for that group. Could you vote on
the ones that are for the Sponsor to gain additional information, I
think for clarity. And then you can say the group of labeling so that
it\'s all ‑‑ it\'s separated. So you can vote on additional information,
then vote on labeling issues. Those are separate motions.

DR. MATHERS: This is all the original cohort that we\'ve been deciding
now.

DR. WEISS: Yes.

DR. MATHERS: Not the labeling. I\'m not sure that we have to go through
all these.

DR. WEISS: Well, let\'s go through each of the ‑‑ no, we won\'t discuss
them individually, but ‑‑

DR. ROSENTHAL: We need to know what you want done on the original cohort
when they come back.

DR. WEISS: Why don\'t we just handle that then. If you\'re talking ‑‑

DR. ROSENTHAL: We understand the endothelial cell counts at four and
five years. We need to know, is there another part of the examination.
Do you want gonioscopy performed, do you want pupil size, and some
evaluation of glare issues? Those are things which you can have done on
your fourth year visit.

DR. WEISS: From what I understand ‑‑

DR. ROSENTHAL: Or fifth year visit.

DR. WEISS: From the panel, for the original cohort, the main interest
was yearly specular microscopy until which point the agency feels that
stabilization has been met. And Dr. Coleman wanted gonioscopy,
particularly at four years.

DR. COLEMAN: And peripheral anterior synechiae and pigment deposition.

DR. WEISS: Can you repeat that?

DR. COLEMAN: Peripheral anterior synechiae and pigment deposition.

DR. WEISS: Did you want that yearly, or you wanted that just ‑‑

DR. COLEMAN: No, just at four years, or at some time point.

DR. WEISS: So we ‑‑ the panel was only looking for two things, specular
microscopy in the original cohort, and gonioscopy. Was there anything
else? Dr. Macsai.

DR. MACSAI: Yes. We discussed also when they came back for their four
and five year visit, looking at the lens. Dr. Sugar recommended that.

DR. WEISS: Yes, you\'re right. So specular microscopy and examination of
the lens yearly. Is there anything else? Does that satisfy what we\'re
looking at for the cohort?

DR. MACSAI: Yes.

DR. WEISS: Do you need us to vote on that? So can someone put that
forward as a motion.

DR. MACSAI: I move that at the four and five year checkup of these
patients when we\'re measuring endothelial cell density, we also ask the
Sponsor to perform gonioscopy and examination of the lens, report the
data to the FDA for their analysis, and this be done for a minimum of
five years to attempt to further establish safety parameters for the
device.

DR. WEISS: Do we have a second of that? Dr. Matoba seconds. Can we have
a vote. All those in favor, raise your hand, signify agreement.

(Vote taken.)

MS. THORNTON: Sugar for, Bandeen‑Roche for, Schein for, McMahon for,
Matoba for, Bradley for, Mathers for, Ho for, Grimmett for, Macsai for,
and Coleman for, unanimous.

DR. WEISS: So now with the cohort being handled, we\'re going to go to
labeling issues. One of the labeling issues was to label the stability
of the endothelial cell loss as not been documented yet, that long‑term
information about development of glaucoma is not known. Dr. Coleman had
a list since ‑‑ I\'m going to ‑‑ can you read that list for me, Dr.
Mathers? Would you be so kind?

DR. MATHERS: Risks greater than ‑‑ pressure greater than 25 or increased
more than 10 millimeters. And we were going to ask you for clarification
on that, but it was ‑‑

DR. COLEMAN: Can I look at it?

DR. ROSENTHAL: While you\'re doing that, can I be sure that you\'ve done
the issue of anterior chamber cell ‑‑ anterior chamber depth?

DR. WEISS: We listed that.

DR. ROSENTHAL: Okay. So it\'ll be contraindicated in anterior chambers
less than 3 millimeters.

DR. WEISS: Yes.

DR. ROSENTHAL: And you also said an endothelial cell count?

DR. WEISS: Yes, we did. That\'s endothelial cell count must be normal
for age before starting.

DR. ROSENTHAL: Okay. That\'s all been approved by the panel.

DR. WEISS: Yes.

DR. ROSENTHAL: Thank you.

DR. COLEMAN: There was a precaution that the long‑term risk of glaucoma,
peripheral anterior synechiae and pigment dispersion are unknown. On
page 20 and 18, to change their use of the term \"glaucoma\" to ocular
hypertension and give a definition of what they called ocular
hypertension, their pressure levels, whatever it was. On page 20 and 18
of the labeling, to place it that it was 5 individuals that had pressure
greater than 25 or more than a 10 millimeter mercury increase from
pre‑op. And that\'s about a 1.4 percent incidence. And on page 14, to
change the wording in the second line to talking about flushing out the
viscoelastic, that using the cannula through the wound, you may flush
viscoelastic from the eye, and this may or may not be adequate for
decreasing the risk of elevated eye pressures immediately
postoperatively. And then the recommendation, interocular pressure
measurements within 24 hours post‑op, but that\'s been covered.

DR. WEISS: Also, Dr. Macsai had mentioned including limbal pathology
which prevents you from getting measurements as an exclusion criteria,
that data about the incidence of halos, glare be included, that there\'s
also mentioned by others, that there\'s a learning curve with higher
upside down lens rate and cataracts formation in surgeons with less
experience. This is more complications on a per‑patient than a per‑eye
basis was mentioned by Dr. Schein, that this be listed that way. That
under \"Patient Precautions\", pigment dispersion be listed.

Dr. Macsai wanted information about the 65 excluded eyes be included,
that the risk of retinal detachment remains unknown, that Dr. Sugar had
wanted removal of the phrase indicating that this improves the quality
of vision, and having specification as far as what is meant by this,
that the brochure have a picture of the device and the positioning.

We have already indicated that the labeling will indicate that there\'s
correction of myopia up to minus 15, and it\'s for reduction of myopia
over minus 15.

Under M.D. labeling, post‑op regime using the PMA with Ocuflox and
Tobradex, rather than recommending that this must be used in all
patients. Indicate that higher myopes had worse results with lower
efficacy and higher risk, and the long‑term effect on the endothelium is
not known for all patients.

It was suggested that under the patient book, explain what a diopter is.
Don\'t use abbreviations. Also, the affect of the pupil size for this
device is not known, and increased IOP may be associated. I think
that\'s already been handled by Dr. Coleman\'s comments.

Were there any other labeling issues that ‑‑ Dr. Matoba.

DR. MATOBA: Well, I previously mentioned that I think risk of
endophthalmitis, and possible loss of the eye should be mentioned under
possible adverse events. And the term \"phakic IOL\", or interocular
lens was used in the patient information sheet, and that should be
clarified. And alternative treatment should be listed more specifically.
It\'s sort of mentioned in passing in the introduction, but it should be
listed specifically.

DR. BRADLEY: Also, Jayne, the suggestion was made that implantable
contact lens be ‑‑ that name be changed presumably in the device.

DR. WEISS: Well, I understood from the agency that that\'s not something
that we would get involved in. Ralph, are we getting involved in names?
I guess we\'re not getting involved in names.

DR. ROSENTHAL: You can recommend whatever you\'d like to recommend, and
we will ‑‑

DR. WEISS: So what ‑‑ is that ‑‑

DR. ROSENTHAL: ‑‑ act accordingly if we feel that ‑‑

DR. WEISS: What would you like to say specifically as far as that goes?

DR. BRADLEY: I think it should be described to the patient in an
accurate way, and if the FDA deems that contact lens is misleading,
which some of us on the panel believe, then that should be changed.

DR. WEISS: So we could have a better description of what is meant in
this case of a contact lens in the labeling. I don\'t know if we list
it, but we should list that the effect of pupil size is not known. I
think I mentioned that. I did mention that. Dr. McMahon.

DR. McMAHON: I think the intent of the comment was, is not to explain
what a contact lens is, but that the word \"contact lens\" is
misrepresentative of what this device is. And the panel recommends that
that term be eliminated from the title of the device, and from labeling.

DR. WEISS: I think the ‑‑ does the panel sort of ‑‑ is there consensus
on that statement? I see head nods which will ‑‑ so there\'s consensus
that this ‑‑ that wording is deceptive, and we would leave it up to the
FDA to come up with better wording. What was that?

DR. MATHERS: Explain possible need for chronic pressure medications.

DR. WEISS: Was that included in your list of things?

DR. MATHERS: You mentioned it later.

DR. COLEMAN: That\'s for the patient labeling.

DR. MATHERS: Yeah.

DR. COLEMAN: That was for patient labeling, just so they would be aware
that they might need medications to control the interocular pressure.

DR. WEISS: Dr. Macsai.

DR. MACSAI: I\'d like to make a motion that we approve the inclusion of
all the labeling issues, for the patient booklet, for the surgeon
booklet, all the training issues, all the restrictions, all the caveats
that Dr. Weiss has gone through over the past 15 minutes, as part of our
conditions of approval.

DR. WEISS: Do I have a second for that?

DR. BRADLEY: Second.

DR. WEISS: So we will then put that to a vote. All of those in favor
raise your hand.

(Vote taken.)

MS. THORNTON: Dr. Sugar for, Dr. Bandeen‑Roche for, Dr. Schein for, Dr.
McMahon for, Matoba for, Bradley for, Mathers for, Ho for, Grimmett for,
Macsai for. That\'s it, 10 for.

DR. WEISS: So we have ‑‑ the motion has passed so ‑‑

MS. THORNTON: No, then there is the vote for against. One against.

DR. WEISS: Sorry. One against. Dr. Coleman against. Sorry. And any
abstentions?

MS. THORNTON: We have 11 votes.

DR. WEISS: So the motion passes. That\'s the labeling motion. So at this
point, we will then go ‑‑ are there any other motions? Otherwise, we
will vote on ‑‑ any other conditions? Otherwise, we\'ll vote on the main
motion.

SPEAKER: We did. That was the main motion, wasn\'t it?

DR. WEISS: No, those were the ‑‑ that was labeling.

DR. COLEMAN: Can I change my vote then? I voted for the labeling. Sorry.

DR. WEISS: The transcript can reflect that Dr. Coleman would like to
change her vote on labeling. Now that we\'ve reflected that, we\'ll go
on. Are there any other conditions? If there are no other conditions,
then we will vote on the main motion, which was put forward initially,
the very first thing that was put forward.

MS. THORNTON: Approvable with conditions.

DR. WEISS: Which is approvable of this PMA with conditions, which were
already voted on. So all of those in favor ‑‑ Dr. Mathers, are you ‑‑

DR. MATHERS: This is approval ‑‑ this is not a conditional approval.
This is approval with conditions.

DR. WEISS: We vote on the ‑‑ what we do is we make the main motion, and
then we list all the conditions, vote on the conditions, and we then go
back to the main motion which has included all these conditions. So we
know what the conditions are because we voted on them. Now we\'re going
back to the main motion, which will be the last vote, I hope. Having
said that, we\'re going to vote on the main motion. Can we have a vote.
All of those in favor, can you raise your hand.

(Vote taken.)

DR. WEISS: Dr. Sugar is in favor, Dr. Schein, Dr. McMahon, Dr. Matoba,
Dr. Bradley, Dr. Ho, Dr. Grimmett, Dr. Macsai are in favor of the
motion. Those who are opposed to the motion. Dr. Bandeen‑ Roche and Dr.
Mathers, and Dr. Coleman are opposed to the motion. And those ‑‑ anyone
abstaining? The motion has passed, and ‑‑

MS. THORNTON: Eight to three.

DR. WEISS: And this PMA is approved ‑‑

MS. THORNTON: Approvable with conditions.

DR. WEISS: Approvable with conditions. And then I\'d like to poll the
panel members as to why they had the vote they did. Dr. Coleman.

DR. COLEMAN: I voted against the motion because I felt although there is
reasonable assurance of efficacy, I was not comfortable with the
reasonable assurance of safety based on glaucoma and angle morphology.

DR. WEISS: Dr. Macsai.

DR. MACSAI: I voted in favor of approval with conditions due to the fact
that I felt the efficacy of this device was significantly proven by the
sponsors. This device appeared to have a lower incidence of higher order
aberrations, and complications involved in operating on the cornea and
the visual axis. This device is removable. I do, however, caution that
despite the percent hexagonality, and coefficient of variation of the
endothelial cell counts appearing to be acceptable, the percent of
endothelial cell loss, which would establish safety, is not determined
for this device; and, therefore, post‑market surveillance will be
required.

DR. WEISS: Dr. Grimmett.

DR. GRIMMETT: Dr. Grimmett voted approval with conditions for similar
reasons to Dr. Macsai.

DR. HO: Allen Ho. I voted approvable with conditions. I think the data
presented clearly show efficacy and reasonable safety. I\'m struck by
the lack of visually significant complications in 500 surgeries in this
group of at‑risk eyes, but I do believe that there is a small chance of
a worst case scenario that is below the detection of the design of this
current study. And, therefore, I support the surveillance.

DR. WEISS: Dr. Mathers.

DR. MATHERS: I voted against the motion. I believe the device
demonstrates excellent efficacy, and in the short term, reasonable
safety. But I believe that the data does not support the use of this
device in the patient population so described, because of long‑term
risks of corneal decompensation.

DR. BRADLEY: Dr. Bradley. Yeah, I voted for this motion. I think the
device established itself as effective. The concerns about safety raised
by the panel, I think will probably best be answered by this potentially
larger and post‑market study that we\'ve suggested. And I think if the
concerns of the panel regarding safety are shown to be true in that
post‑market study, I think the product will probably be removed from the
market.

DR. WEISS: Dr. Matoba.

DR. MATOBA: I voted that the ‑‑ in favor of approvable with conditions,
because I believe the device has been shown to be reasonably safe and
efficacious. However, I am philosophically opposed to the concept of
interocular procedures for patients in the range of myopia minus 3 to 4
or 5.

DR. WEISS: Dr. McMahon.

DR. McMAHON: Dr. McMahon. I\'d like to congratulate the Sponsor on a
well done study for ‑‑ a well done presentation of both the data and the
presentation today for what otherwise is a very complicated project, and
you\'re to be congratulated. I\'ve waffled through the day with regard
to my vote for approvability, approvable. And I think with the
reassurances that the Sponsor will look at the follow‑up data in a
responsible manner, I voted that way. And hopefully, this will turn out
for the best for all of us.

DR. WEISS: Dr. Schein.

DR. SCHEIN: I voted for approvable with conditions, feeling that the
data was sound for efficacy. I voiced my concerns about safety. The
nature of the device and its intention does not allow safety to be
evaluated in a pre‑market setting, and if we were to deny this kind of
study, it would stifle all innovation. And I think the post‑market
surveillance gives us adequate comfort.

The last comment I\'d like to make is to encourage the FDA to request
control groups for these studies. They do not need to perform a
randomized clinical trial, but it\'s not difficult to get control groups
matched to age and for Dr. Barrett to look for some of these outcomes.

DR. WEISS: Dr. Bandeen‑Roche.

DR. BANDEEN‑ROCHE: I voted against the motion because to vote for it, I
would have had to conclude that the data set before us gave me a
reasonable assurance of safety and efficacy. While I was reasonably
convinced of efficacy for reasons I\'ve already described, the data did
not meet my threshold for reasonable assurance of safety; that is, I
agree with the Sponsor that there is a suggestion of stability, but not
yet a reasonable assurance interim. My clinical colleagues indicated to
me that without stability, there would be a safety concern. And finally,
I would conclude for a reasonable assurance of safety with further data
of the sort that we\'ve talked about, panning out in the way everyone
would hope.

DR. WEISS: Dr. Sugar.

DR. SUGAR: I voted for approval of the motion. I feel that the efficacy
has been well demonstrated, the safety remains a concern, and
longer‑term data will help assure that. I think at the present time, it
is ‑‑ appears to be reasonably safe and, therefore, approvable.

DR. WEISS: Mr. Crompton.

MR. CROMPTON: I\'d just like to congratulate the Sponsor on an excellent
presentation, and it was a long day, tough day. And the panel, for your
very, very thorough deliberations today. It really does help industry,
and the FDA, of course. And Sally, great job. Thank you.

DR. WEISS: Sally Thornton has a few additional comments before we
adjourn.

MS. THORNTON: Just to let you all know that the November 7th panel
meeting that was tentatively scheduled, has been cancelled. And shortly,
I hope the schedule for the next meetings will be up on the web for
2004. They will be on the hotline very shortly too. I want to thank the
panel ‑‑

DR. ROSENTHAL: May I just make one comment, that the cancellation of the
November whatever day it was, 7th panel.

MS. THORNTON: Yes.

DR. ROSENTHAL: Was made with the agreement of the FDA and the Sponsor.

DR. WEISS: Okay.

MS. THORNTON: I just wanted to thank the panel for their perseverance
through a very difficult and complicated application. I appreciate their
cooperation to stay and work with us all the way through passed our
time. Thank you. And that\'s all I have.

DR. WEISS: Thank you. The meeting is adjourned.

(Whereupon, the proceedings in the above‑entitled matter went off the
record at 5:58 p.m)