FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

OPHTHALMIC DEVICES PANEL

Friday,

August 2, 2002

Salons A-C

Hilton Hotel Gaithersburg

620 Perry Parkway

Gaithersburg, Maryland

IN ATTENDANCE:

Jayne S. Weiss, M.D., Chair

Arthur Bradley, Ph.D., Voting Member

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

Alice Y. Matoba, M.D., Voting Member

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

Stephen A. Burns, Ph.D., Consultant

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

Consultant, deputized to vote

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

William D. Mathers, M.D., Consultant

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

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

Glenda V. Such, M.Ed., Consumer Representative

Ronald E. McCarley, Industry Representative

[C O N T E N T S]{.underline}

PAGE

Call to Order

Jayne S. Weiss, M.D.

Chair 5

Introductory Remarks and Conflict of

Interest Statement

Sara M. Thornton

Executive Secretary 5

Open Public Hearing

John A. Vukich, M.D.

University of Wisconsin 9

Questions for Public Speaker 17

Open Committee Session

Jayne S. Weiss, M.D. 25

General Issues Discussion on Design Elements

for Clinical Studies of Phakic Intraocular

Lenses (IOLs)

FDA Presentation

Donna R. Lochner

Chief, Intraocular and Corneal Implants Branch 25

Guest Speaker Presentations

Specular Microscopy (Endothelial Cell Counts)

Bernard E. McCarey, Ph.D.

Emory University 28

Henry F. Edelhauser, Ph.D.

Emory University 42

Questions for the Speakers 55

[C O N T E N T S]{.underline}

PAGE

Guest Speaker Presentation

Lens Opacity

Liliana Werner, M.D., Ph.D.

Storm Eye Institute 84

Questions for the Speaker 104

Panel Deliberations and Questions for Panel Discussion

Introduction of Questions

Donna R. Lochner 111, 149, 161

Question 1

Michael R. Grimmett, M.D.

Discussion Leader 115

Discussion 137

Question 2

William D. Mathers, M.D.

Discussion Leader 151

Discussion 156

Question 3

Mark A. Bullimore, MCOptom, Ph.D.

Discussion Leader 163, 185, 186, 188

Discussion 165, 186, 187, 189

Discussion on Remaining Issues 190

Closing Comments

Jayne S. Weiss, M.D. 231

Sara M. Thornton 232

[P R O C E E D I N G S]{.underline} (8:30 a.m.)

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

MS. THORNTON: Good morning and welcome to the 104th meeting of the
Ophthalmic Devices Panel. Before we proceed with the agenda, I do have a
few short announcements to make.

I\'d like to remind everyone who is new to the sessions today to sign in
on the attendance sheet in the registration area. I\'d actually like
everyone to sign in, but I know some of you have heard this announcement
before. But please do sign in right outside on the registration table.

All handouts for the meeting are available out there on the table, and
we\'d like, if you have messages for the panel members, the FDA
participants, if you need information or have special needs, they should
be directed to Ms. Annmarie Williams, who\'s over here by the door, and
Ms. Jennifer Weber. They\'re both available also at the registration
area.

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

Lastly, will all meeting participants please into the microphone,
directly into the microphone, less than four inches away, according to
my instructions, and give your name clearly, so that the transcriber
will have an accurate recording of your comments and others will be able
to hear you.

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

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

I\'d like now to read the conflict of interest statement for this
session of the 104th meeting. \"The following announcement addresses
conflict of interest issues associated with this meeting and is made
part of the record to preclude even the appearance of an impropriety.

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

\"Therefore, waivers have been granted to Drs. Mark Bullimore and
Stephen Burns for their interests in firms that could potentially be
affected by the panel\'s recommendations. The waivers allow these
individuals to participate fully in today\'s deliberations. Copies of
these waivers may be obtained from the agency\'s Freedom of Information
Office, Room 12A-15 of the Parklawn Building.

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

\"Lastly, we would like to note for the record that Drs. Henry
Edelhauser, Bernard McCarey, and Liliana Werner, all invited guest
speakers today, reported interests with firms at issue. Dr. Edelhauser
reported a personal financial interest, a consulting relationship, and a
professional relationship in the form of contracts and research grants.
Drs. McCarey and Werner reported professional relationships in the form
of contracts, grants, or research.

\"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 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, Dr. Weiss.

DR. WEISS: Thank you, Sally.

We\'re going to have some comments at this point by Mr. David Whipple.

MR. WHIPPLE: Thank you.

I only had one comment that I wanted to make this morning. I wanted to
thank this panel for yesterday\'s discussion of the labeling for the
wavefront technology LASIK device. I know it was long and difficult, but
a very important discussion for us in the agency. Not only will we use
your comments and recommendations as guidance in a framework for
building labeling for devices of this type, but we will also use it for
monitoring the promotion and advertising when they go to market their
products as well. So thank you for that discussion yesterday.

DR. WEISS: Thank you very much.

We\'re going to proceed to the open committee session and start with the
FDA presentation. Excuse me. I\'m out of order. We\'re going to start
with the open public hearing session and Dr. John Vukich of the
University of Wisconsin is going to make his presentation.

DR. VUKICH: Thank you and good morning.

DR. WEISS: Would you be able to start by ‑‑ just start by identifying
yourself and your conflicts, if any. Thank you.

DR. VUKICH: Okay. Thank you.

My name is John Vukich. I am an associate professor at the University of
Wisconsin in the Department of Ophthalmology. I\'m an investigator and
medical monitor for Staar Surgical, and it is from this experience that
I draw the information from which I form my opinions that I will be
presenting this morning.

My testimony today, however, is as an private citizen. I have not
received support or reimbursement for my visit today, but I\'m here to
speak on behalf of phakic IOLs as a segment of the refractive industry
and as an option for the correction of myopia.

Right now, LASIK is gold standard by which we need to compare all future
refractive technologies. We\'re clearly trying to improve the outcomes
of LASIK, and I believe the decision yesterday to allow custom ablations
is a step in that direction. Any new technology that comes along
certainly is going to be compared to LASIK, and what I\'d like to do is
present some information on the comparison of LASIK and phakic IOLs.

We have looked at this in my practice. I am primary a refractive
surgeon. Most of my practice revolves around this. We looked at 198
phakic IOLs with a mean myopia of -10. We compared this to a similar
number, 219 LASIK patients similarly high myopia of between -9.5 to 12.
The mean was -9.5. Predominately female and younger patients in their
mid-30s.

When we looked at the percent of patients who achieved 20/20 or greater,
again, in this relatively highly myopic group of patients, we found that
about 32 percent of patients on their treatment achieved 20/20 or better
with LASIK ‑‑ again, with a mean correction of close to -10 ‑‑ and close
to 50, or 48.5 percent, were able to achieve 20/20 or better with phakic
IOLs, and this was statistically significant. The curve did fall off
towards the end and this was due to an early in the clinical trial
difference in the nomograms, and this curve has in fact stayed the same
all the way out and has remained consistent for this difference.

So we believe that phakic IOLs, at least as a single procedure, offer an
alternative to LASIK in the quality of vision that a patient might
expect in the higher ranges.

We know that recovery of visual acuity is an important issue.
Ultimately, patients need to retain their visual acuity, but the
rapidity of recovery is also an issue, and the length of disability is
an important issue, of course.

When we look at lines lost or gained early in the recovery at one week,
we see that with LASIK, again in the higher ranges, it is not uncommon
‑‑ almost 28 percent of patients lost two lines or more of acuity early
on, and we can explain this because of epithelial irregularities,
surface irregularities, or edema in the early postoperative period. We
contrast that with phakic IOLs, in which not a single patient in this
clinical trial lost two lines or more of visual acuity at week.

When we look at six months out, of course, we would expect the
epithelial changes to have recovered, and in fact that is the case.
However, there still were 6 percent of LASIK patients who had lost two
lines or more. This predominately fell from 20/15 to 20/25.
Nevertheless, this is a demonstrable loss of quality of vision that has
persisted through six months. Again, contrasting with phakic IOLs, in
which there was not a single patient who had lost two lines of visual
acuity. So in terms of preservation of acuity, we believe that phakic
IOLs offer a good alternative, and perhaps superior, to corneal ablative
procedures.

We have anecdotal reports that patients prefer the quality of vision
with phakic IOLs. There have been a limited number of patients who have
had a phakic IOL in one eye and LASIK in the other, and we have heard in
fact that at least one clinical trial from a prominent researcher in
Greece was discontinued because of the strong preference of the phakic
IOL eye and it was felt that continuing on that did not make sense for
them.

So based on this, we felt that perhaps maybe there was something we
could do to demonstrate a difference, and what we have done is we have
looked at wavefront analysis as an objective assessment of optical
quality, and have now looked at comparison of the induced aberrations in
patients who have either received a phakic IOL or LASIK.

These were 10 patients, 20 eyes, two eyes in each patient. The mean
myopia in the phakic IOL group was -12 ranging to -15. The LASIK group
ranged up to -10.5 with a mean myopia of 8.75 or a few diopters less.

When we looked at coma group means square values, for phakic IOLs the
average value was .22 or less than half of the amount of coma observed
in LASIK patients postoperatively, and this was highly significant at
the .001 level.

We can do image convolutions to demonstrate this difference looking at
the standard Snellen chart. This is what a patient might expect to see
in simulation with this much induced coma in LASIK, and this is what
they might expect to see with this much induced coma from a phakic IOL.

We can do the same image convolution with a photograph. Again, with
LASIK and with the phakic IOL, and we believe that there\'s a
demonstrable difference in the quality of the images that the patients
see and what we can demonstrate mathematically.

We looked at spherical aberration as well as an isolated fourth-order
higher term, and we see that there were three times as much induced, or
at least three times as much observed, RMS of spherical aberration in
the LASIK compared to the phakic IOL. Again, significant at the .001
level.

When we look at the image convolutions of this, we see the LASIK image
compared to the phakic IOL image, and again we can look at photographic
convolutions with LASIK and with the phakic IOL.

All of these images again demonstrate what we have heard anecdotally,
and that is that the patients with phakic IOLs seem to be very pleased
with the quality of the image that they receive.

These images or these RMS values do combine and it would probably make
more sense to look at the combination of terms. When we look at
spherical and coma RMS combined, we see LASIK versus phakic IOL, and
once again the image with phakic IOL.

Well, custom corneal ablation is not ideal option for high myopia. The
approval up to -7 yesterday I believe is a step forward in our ability
to correct myopia, but one of the issues that I think will limit this
application is the fact that it can remove up to 20 microns of tissue
per diopter with larger ablation zones and with a custom application. I
believe this will ultimately limit custom ablations to ranges that are
already approved, at least from one manufacturer, but in fact the simple
physics and the simple anatomy may eliminate this as a possibility for
higher corrections. So it would certainly be beneficial to have a
noncorneal alternative.

There is in fact a limit to how much corneal tissue can be removed. This
is a macroscopic view of a cadaver eye that has had corneal tissue
removed down to a level of 100 microns. This is clearly thinner than
what we would do clinically, but it does demonstrate grossly the elastic
character of the posterior surface of the cornea and again is consistent
with what we can observe with advanced imaging technologies.

Corneal ablation is certainly not appropriate for some patients no
matter what the correction achieved. Patients with keratoconus, as
demonstrated here, clearly would not be suitable for corneal reshaping,
but there are certainly many more patients who have subtle changes that
come to our attention when we screen them for refractive surgery,
changes of mild elevation, changes on the posterior surface elevation,
or keratometric changes that are subtle variants of what we would
consider an abnormal corneal topography or corneal anatomy, and in fact
a noncorneal alternative may be a superior alternative for these
patients as well.

The fact remains that there are few options available to patients who
have high myopia. This has led to some options being employed that are
not approved and in fact may pose dangerous situations for patients. We
have certainly seen clear lens extraction as an unapproved use of an
approved IOL for cataract surgery, but again used in a refractive
manner. This is controversial. However, it is being done.

With one anecdotal report from a clinical trial center in the United
States of a refractive-based practice, we looked at the incidence of
clear lens extraction before, during, and after the availability of
phakic IOLs in this individual practice. The white bar beneath
represents the time during which enrollment was available for phakic
IOLs, and we can see that there was a significant decrease in the total
number of clear lens extractions performed as a refractive procedure. At
the conclusion of enrollment, there was an over doubling of the number
of clear lens extractions.

Again, this is consistent with the researcher\'s or with the
investigator\'s observation that given an alternative, this particular
researcher would shy away from clear lens extractions, and we believe
that this is a better alternative and perhaps something that I think
would offer our patients perhaps a better, or we hope safer,
alternative.

In conclusion, I would like to suggest that corneal refractive surgery
is an excellent opportunity for patients. Many of them enjoy ‑‑ most all
enjoy ‑‑ the benefits of this, but I believe that a noncorneal
alternative is an important step forward. I believe that the safety and
efficacy of phakic IOLs needs to be demonstrated, but certainly the
opportunity to provide quality of vision seems to be quite high.

DR. WEISS: Thank you.

Do any of the members of the panel have any questions for Dr. Vukich? I
would actually start off with one question myself, which is how would
you weigh the potential risks of intraocular surgery ‑‑ namely,
endophthalmitis, albeit rare, and corneal edema ‑‑ against the benefits
of the visual recovery and quality of vision?

DR. VUKICH: Well, certainly, any time we go inside the eye, we have to
hold a different standard than we would on the surface. We know that
infection is an option, or at least is a problem, with LASIK, albeit
rare, but it\'s somewhat devastating when it does occur. It is something
that needs to be looked at very carefully in terms of the real
incidence.

I think the bigger issue in my opinion is the potential for removability
of these devices, and that is that there is an alternative to restore
the eye perhaps not exactly to what it was preoperatively, but to remove
whatever the patient may not have liked about the quality of vision. If
there is edge glare or halos or night vision problems or decentrations
with LASIK, the remedies are typically not satisfactory, and in fact
with the phakic IOL, at least the opportunity to reverse that or remove
the offending treatment certainly I believe offers a significant
advantage.

DR. WEISS: Depending on if the offense is irreversible endothelial cell
loss or infectious organisms or cataract formation.

DR. VUKICH: Very clearly, those are things that have to be looked at.
Endothelial cell counts are a critical issue, as are the potential for
infection.

DR. WEISS: I think Dr. Bradley had a question, and Dr. Bullimore as
well. Let\'s start with Dr. Bradley. Dr. Bradley, Dr. Bullimore, and
then Dr. Mathers.

DR. BRADLEY: I was just looking at your slide where you showed visual
acuity as a function of time after the procedure, and I didn\'t quite
follow your explanation of why the phakic IOL percent of patients
achieving 20/20 fell off at 12 months. You sort of ran through some sort
of excuse it sounded like.

DR. VUKICH: I\'d like to think of it as the reason. The early nomograms
for calculation of power will be represented at the last data point
collected as time goes on. So the first several phakic IOLs that were
implanted in this clinical trial systematically undercorrected all the
patients, and mid-course adjustment or early-course adjustment and the
attempted correction versus achieved correction became substantially
better. So that dip between six months and 12 months, which was the two
data points at six months and 12 months and there was no in-between
visit, remains something that between 12 months and two years we have
seen that seem dip, and now between two years and three years we see
that same dip. It is just simply the leading edge representing the
earliest patients who were enrolled, but the remainder of the line stays
as it has been with the improved nomogram.

DR. BRADLEY: Thank you.

DR. WEISS: Dr. Bullimore?

DR. BULLIMORE: Yes, this is Mark Bullimore. If my memory serves me
correct, one of the issues discussed by the panel at previous visits to
this phakic IOL guidance document was whether these devices should be
held to the same standard as LASIK. What\'s your impression?

DR. VUKICH: To the same standard in what regard?

DR. BULLIMORE: In terms of, say, vision.

DR. VUKICH: In terms of quality of vision?

DR. BULLIMORE: Yes.

DR. VUKICH: I believe that that is both appropriate ‑‑ I don\'t know
that we would want to see a step backward in the evolution of any
technology, and so holding to the same standard I believe makes sense.

DR. BULLIMORE: So in the absence of any other information, you would
argue that we should use the same criteria for uncorrected visual acuity
and corrected visual acuity and loss of visual acuity that is currently
used for refractive lasers?

DR. VUKICH: I think that makes sense. I think that it would also make
sense to stratify the data into the various ranges of power that you\'re
looking at, knowing that the standard for LASIK at -12 diopters should
be different than the standard at -1 or -2, and that the outcome at that
level could be a different expectation.

DR. BULLIMORE: You mean in terms of safety or efficacy or both?

DR. VUKICH: Both.

DR. BULLIMORE: So you would expect your LASIK patients in your -10 group
to be not doing as well as patients with lower degrees of myopia?

DR. VUKICH: I would expect higher enhancement rates. I would expect
potentially higher levels of reported edge effect, glare, and those sort
of symptoms in the higher ranges. We might also anticipate that the
higher ranges of LASIK may in fact become lower as we implement custom
corneal ablations limited by the tissue effect that needs to be removed.
We simply don\'t do -12 LASIKs anymore. At least, I don\'t, and many
reputable surgeons or high-volume surgeons have lowered the upper limit
at which they will perform LASIK, and that number I believe is still
going down.

DR. BULLIMORE: But clearly there are some less than reputable people
doing a lot of clear lens exchange.

DR. VUKICH: Again, I can\'t speak to the decisions that other surgeons
make.

DR. BULLIMORE: Okay. That\'s fine.

DR. VUKICH: In the face of not having an alternative, it seems to be
happening.

DR. BULLIMORE: Yes. And one final question. I mean, you presented data
on 200 patients who had phakic IOLs and LASIK. Were they all from your
practice?

DR. VUKICH: Yes.

DR. BULLIMORE: And where these people who had the phakic IOLs, were they
single device?

DR. VUKICH: Excuse me. The phakic IOLs were part of the multicenter
trial. Excuse me. All the LASIK patients were from my practice.

DR. BULLIMORE: Okay. Thanks very much.

DR. WEISS: Dr. Mathers?

DR. MATHERS: Do you have any information about observation of cataract
formation that might have occurred later? I mean, these lenses have been
implanted for some time now, but we don\'t see any data on three years,
four years, or whatever, and certainly something was implanted a little
bit longer than we have seen data for.

DR. VUKICH: Yes, and we are collecting data and do have a substantial
amount. In fact, all of the patients in at least one of the clinical
trials is submitted. Not submitted, but is through the two-year point,
and we\'re about halfway through the three-year collection of data. So
yes, that data does exist on the formation of cataracts in all of the
safety and efficacy parameters that were approved in the protocol
that\'s been undertaken. Again, I am not prepared to do a thorough
disclosure or presentation of that information, other than to say it is
going to be submitted and we believe represents a standard that we
believe is acceptable.

DR. WEISS: Dr. Huang?

DR. HUANG: Given the known potential complications of cataract,
glaucoma, and retinal detachment, are you implying that this phakic IOL
device should be limited to the higher myopias?

DR. VUKICH: Ultimately, the complication rate is something that is going
to determine whether or not phakic IOLs will be appropriate. The quality
of the optics and the ability to correct a refractive error I believe is
intuitive and has been demonstrated and will be demonstrated.
Ultimately, how safe they are is going to be the issue as to where they
should be used.

If a product can be demonstrated to be safe at any range, I see no
reason that it should be limited only to the higher myopic patients. I
believe initially it would make sense to offer this as an alternative
for higher myopic patients in which we know LASIK has limitations or may
not even be appropriate.

DR. WEISS: Dr. Grimmett?

DR. GRIMMETT: Dr. Michael Grimmett. Is your experience with phakic IOLs
mostly of the posterior chamber type? You don\'t have any other
experience or data otherwise regarding anterior chamber, either
angle-supported or iris clip? Is that correct?

DR. VUKICH: All of my personal experience has been with posterior
chamber phakic IOLs.

DR. GRIMMETT: Okay. Thank you.

DR. WEISS: Just one follow-up question in terms of the standards that
the IOL should held to visually. In a LASIK patient who has higher
myopic error, we can easily lift up the flap and enhance, but with a
phakic IOL, the risk of entering the eye again is higher than a flap
relift. With that in mind, would you still hold them to the same visual
results postoperatively?

DR. VUKICH: I think comparisons would need to be made based on a one- or
two-procedure comparison. I believe that all of the trials for LASIK
have been as a single procedure without enhancement, and I think the
ability to enhance we understand is real and people can do that, but I
believe that all the submissions have been on primary treatment, not
enhanced data.

Now, the ability to do a minor ‑‑ or not minor. To do a corneal
treatment on top of a phakic IOL certainly exists, although the answer
to question is yes. Going back in for a small refractive error probably
could easily be done on the corneal level, perhaps more appropriately so
than exchanging the implant.

DR. WEISS: Any other questions from the panel?

(No response.)

DR. WEISS: If not, thank you very much for your presentation.

DR. VUKICH: Thank you.

DR. WEISS: Are there any other comments from anyone else for the open
public hearing session?

(No response.)

DR. WEISS: If not, we will now ‑‑ obviously, I was anxious for the FDA
presentation. So now, we will have it.

MS. LOCHNER: I\'m just going to make a few introductory comments before
we actually present the questions to the panel.

Today we plan to discuss with the panel clinical study design for phakic
intraocular lenses. We have prepared for your review a document entitled
\"Phakic Intraocular Lenses: Clinical Guidance for Ophthalmic Devices
Panel Discussion, August 2, 2002,\" which is a compilation of several
activities in which the FDA participates. It generally represents a
composite of the American National Standards Institute standard, the
International Organization for Standardization standard, and the FDA\'s
guidance document for phakic IOLs.

We last received the panel\'s recommendations for phakic IOL studies in
1998 and so we thought it important to receive updated recommendations
from the panel. We will then compile your recommendations and present to
the ANSI and ISO Standards Committees and update FDA\'s guidance
document accordingly. By having this discussion today, we believe
sponsors of these studies will gain valuable information to successfully
prepare investigational device exemption and premarket approval
applications for their phakic IOLs.

We will begin this morning with presentations from our invited speakers
on two topics. First, Drs. Henry Edelhauser and Bernard McCarey from
Emory University will discuss methodology and analysis for endothelial
cell density specular microscopy measurements. Next, Dr. Liliana Werner
from Storm Eye Institute will provide background for the measurement and
analysis of lens opacity.

Following the invited speakers\' presentation, we will focus the
panel\'s discussion on three areas. First, the endothelial cell density
study with Dr. Michael Grimmett as the primary reviewer; second,
measurement of lens opacity with Dr. William Mathers as the primary
reviewer; and third, contrast sensitivity with Dr. Mark Bullimore as the
primary reviewer.

Questions have been provided to each of these panel members for these
topics to help to generate discussion. However, we hope the panel will
allow the discussion to move to any area of significance to them. We
hope to step through each of the three areas ‑‑ endothelial cell counts,
lens opacity, and contrast sensitivity ‑‑ one by one, opening each topic
to full panel deliberations after each of the primary reviewers\'
comments. After these three primary areas have been discussed, Dr. Weiss
will open the discussion to comments on any section of the clinical
study guidance.

Unless there are any questions about the agenda, I would like to move on
to the invited speakers. First, I\'d like to express my gratitude to
Drs. Henry Edelhauser, Bernard McCarey, and Liliana Werner for taking
time from their schedules to present to us today. We are honored to have
people of their caliber providing their insights to these important
topics.

I would like to introduce the first two invited speakers. Dr. Henry
Edelhauser is professor of ophthalmology and director of ophthalmic
research at Emory University University School of Medicine in Atlanta.
He received his Ph.D. from Michigan State University and joined the
faculty of the Medical College of Wisconsin. In 1989, he became the
Ferst Professor of Ophthalmology and director of ophthalmic research at
Emory. He has served as president of ARVO and has received the Honor and
Senior Achievement Award from the American Academy of Ophthalmology. He
also has received the Castroviejo Medal and the Alcon Research Award. He
presented a keynote lecture at the 55th Congress of Clinical
Ophthalmology in Japan entitled \"Cataract and Refractive Surgery: The
Effect on the Corneal Endothelium.\" His research interests include
surgical pharmacology, corneal physiology, drug delivery, and ocular
toxicology.

And Dr. Bernard McCarey is professor of ophthalmology at Emory
University School of Medicine and affiliate scientist at Yerkes Regional
Primate Center at Emory. He received a Ph.D. from Marquette University
and joined the Department of Ophthalmology at the University of Florida
College of Medicine. He joined Emory in 1979 and has served as chairman
of their Institutional Animal Care and Use Committee. He has received
the American Academy of Ophthalmology Section Honor Award, the Barraquer
Award, the Alcon Research Award, the CIBA Vision Research Excellence
Award, and Everett Kinsey Lecture Award at CLAO. His research interests
include corneal physiology, refractive surgery procedures, ocular
toxicology, and contact lenses.

And so, without further ado, I\'ll turn it over to Drs. McCarey and
Edelhauser.

DR. McCAREY: Thank you.

My name is Bernard McCarey. As you\'ve been told, I\'m at Emory
University. I have been interested in specular microscopy as a
laboratory science and also as a clinical science. At present, I am a
reading center for Medennium.

What I\'d like to discuss today with you is ‑‑ whoops. We\'re not moving
forward. It\'s hooked up, but it doesn\'t move.

DR. WEISS: I\'d just mention at this point, after all the speakers give
their presentation, they can actually sit at this table over here with
your names there, so the panel has an opportunity to ask you questions.

DR. McCAREY: Now we\'re moving. Thank you.

There are several specular microscopy units on the market presently and
they break into two categories, contact and non-contact. I present this
as a list for your handout. You can look at it later, but what I would
really like to do is to express to you the major differences between the
contact and non-contact.

Obviously, contact means you have to use an anesthetic. You have to
applanate the surface of the eye, but you also are flattening the
surface of the eye, and when you do this, you generally can look at a
larger field. So generally, the contact units are considered large-field
specular microscopy. The non-contact has a smaller field.

You can see on the very bottom of your slide we\'re talking about 700 or
800 cells can be visualized with a contact unit, whereas only 160 or so
for the non-contact, and this has to do with the height of the slit. If
we had time, we\'d go into specular glare, but basically the slit in
both of these instruments is the same width. It\'s just a different
height.

We are going to be collecting data about the cell morphology, cell area,
cell density, polymegethism, which is an order of variation in size, and
pleomorphism, which tells you about how many sides there are on a cell.

I add this slide just for your notes. It expresses the calculation for
cell density and coefficient of variation.

I also add this for groundwork. It gives you a feeling as to what people
would say at middle-age the number of cells would be on a corneal
endothelium, and it varies with age. This is well-known in the
literature and we can find many references in the literature towards
these numbers.

But what I\'d really like to show you is that these numbers are from
linear regression lines. They are not a number. A person doesn\'t have a
2,700 cell density because they\'re the age of 50. Rather, there\'s
quite a wide spread, as illustrated from this data from Dr. Edelhauser
in 1985. You can see a person of age 50 can have anything from 2,200 on
up to 3,300. So there is quite a spread.

We also have a convention, an issue, that I\'d like to mention. That is,
polymegethism is often referred to in the literature as a value like .27
for a normal young adult, but you can also see 27. Don\'t be confused.
It\'s just a literature convention.

The spread in coefficient of variation is sometimes even larger in the
normal population, as illustrated here. So please don\'t expect to find
one number.

The major question that we\'re going to have here is if you do a
surgical trauma or something else to the eye, how representative is a
central endothelial cell density to the information of what happened to
that tissue? If you cause local damage in one area of the cornea, how
fast does it affect another area, what does that time duration spell,
and can you really look at central endothelium and get a feeling for
what trauma occurred?

I reached back in the literature back to \'79, and I use this not as an
example of what a surgical technique may do to the tissue, but rather as
an example of how the tissue responds to a surgical event.

In this case, there was phacoemulsification and extracataract
extraction, and what the person did was they\'re obviously making an
incision in the superior area, going into the eye, potentially damaging
endothelium in the superior zone, and if we look at the control tissue,
we can inferior, central, and superior clustered together. After the
surgery, we see superior has dropped considerably, central has less, and
inferior less.

So the question is will this spread of damage rapidly congeal to one
point again? And if you look at this data, for 24 months there was only
slight difference, and it took on up to five years or more before all
three zones expressed themselves with the same value. So these things go
slowly.

DR. BULLIMORE: Before we move on, am I correct in assuming there\'s only
three people in that last data point?

DR. McCAREY: I\'m glad you mention it. No. There are three people, but
what this data did was he collected the data at one time point. So he
had 28 patients and some of them were out five years and some were out
four years or whatever, and he just collected the data in that manner.
Yes, there are very few data points in each one of these, but I show
this as an illustration as to what can occur.

As another example, we\'re looking at data from intracapsular cataract
extraction, and if I point just to mean cell area, you look at rapid
changes going on for the first four months and then some kind of a
linear response. Now, this is characteristic, if we looked at
keratoplasty, where you\'ll see much the same kind of event, rapid
changes ‑‑ in this case, six months ‑‑ and then a progressive change. So
this gives you a feeling as to when you might want to collect data
because of the kind of tissue response.

If we reach back into the literature from Dr. Bourne, we can see that he
chose to follow patients for 10 years after cataract extraction. It
doesn\'t matter if it\'s with or without an implant. The point is that
he followed the patients for 10 years and he saw a rather in form cell
loss of 2.5 percent per year.

We often are referring to what a normal patient would lose as far as
endothelial cell density over time simply because of aging, and we can
refer to a paper by Bourne. He says he followed them up for 10 years and
he has .6 percent, plus or minus 5 percent. I feel that\'s a rather
conservative number, but this is a number that\'s in the literature.

One of the things we must realize is that we\'re often using patients in
clinical trials, such as refractive surgery clinical trials, and these
patients have a history, and the history may often be contact lenses. So
we\'re entering patients in that are not \"pure normal\" patients, but
somebody that has a history of some kind of possible trauma to the
endothelium, and we can definitely say in the literature that there are
both transient problems with contact lens wear, but also chronic
problems in which we have pleomorphism and polymegethism shifts in the
tissue over time.

So these patients will often look like this, and I point these three
examples out because you\'ll notice that the cell densities are all
fairly high and all fairly much the same. Cell density is not going to
give you the full answer as to what that history of the patient was. We
have to look at the coefficient of variations, and we\'ll see that they
vary from 45 on up to 76. They can be quite high, and that\'s expressing
the fact that we have some large cells interdispersed among the smaller
cells.

The way we\'re going to analyze this tissue is by multiple methods out
there in the literature. The first one is a comparison method. Look at a
picture, look at a honey comb, and how many cells do we have? It just
tells you cell density.

The frame method is another method. Just cell density.

The next two methods, corner method and center method, are going to give
you actual cell area, and from that we can calculate coefficient of
variation and other values.

Let\'s take a moment to look at the frame method. The technique is, on
the screen or from a photograph, you put a box, and then you simply
count the cells within the box. The box is a small portion of a
millimeter. You adjust it up to a full millimeter, and that\'s going to
be the answer. So you just simply get cell density.

One of the really easy pitfalls in this is that in this example I\'ve
made a blue box, and the data over here is in blue, and a yellow box.
The blue box is twice the surface area of the yellow box, even though it
may not look it, and if you give somebody an opportunity and tell them
to put a box on a field, they\'re going to make a small box. What this
means is that if it\'s twice the surface area, if you counted 90 cells
within the blue box, you have to multiply it by 27 in order to get it up
to a full square millimeter. If you had the yellow box, you\'d count 45
‑‑ it was half the size ‑‑ and you\'d have to multiply it by 55. So
right off the bat, you have a two-fold error magnifier in your
calculations simply by the size of the box, and most people make small
boxes.

The other method is the center method. In this one, we put dots in the
center and calculate what the nearest neighbor is, and from this you
calculate a polygon, which is the cell, and so forth. Dr. Edelhauser
will discuss the patterns of this method in a few moments.

One of the things we must worry about is if you put the dot offcenter,
does it louse up the calculation? And with the Konan software, you have
a very nice opportunity of simply a dot and then asking for this
analysis. Come back, move another dot, ask for the analysis.

So I did this for 10 different cells, and you can see that the error is
fairly small. It\'s less than 1 percent.

I then dropped a cell. That is, took a dot away, and tried it with
various sizes of cells, and it didn\'t seem to matter. I even used a
hexagon pattern, which was a perfectly uniform pattern, and it looked
like each cell that you missed the dot on, you lost about a percent in
the accuracy of the answer.

Another question is how many cells do we need to count? This is the
classic one you see in the literature. If you count more cells, you get
a more accurate answer.

So I got a large field like this, divided it up into multiple boxes, and
then counted 10 cells, 20 cells, 30 cells, and so forth to create a
series of lines, as illustrated on this. So each one of these is an
effort of increasing the number of cells in the count.

You\'ll notice if you have a uniform, low coefficient of variation cell
pattern, you can get a fairly good answer right off the bat. It improves
when you get to about 50 and it\'s a slight improvement beyond that. So
you don\'t need to count an awful lot of cells.

Coefficient of variation? It\'s a little bit noisier. You certainly want
to be over 50 cells counted in order to get a reasonably uniform answer,
but there\'s always a spread in the answer.

This is more real life. This is a patient that may have had a contact
lens or some history of something or simply an older patient with a
higher coefficient of variation, 45. Do the same kind of analysis. Now
look at the spread. It\'s tremendous. If you counted 25 cells, you could
have anything from 2,000 to 3,200 for cell density. It gets better over
50 or 100 cells, but it never gets really tight.

Coefficient of variation is even worse. This is just summarizing. You
can look at this on your handout, but basically it says that if you have
a large coefficient of variation, you\'re going to get a larger spread
and you can\'t get away from that.

Also I want to mention some of things that are pitfalls in the analysis.
That is, when you ask the clinical site to count 100 cells, they may tap
100 cells on the cell pattern, as illustrated here on your right, but
the analysis using nearest neighbor ‑‑ for instance, if this was seven
dots and you asked for the calculation to be performed, you\'d only see
that you actually counted one cell, the one in the center. The others
were just nearest neighbor in the analysis.

So if you want somebody to count 100 cells, coming down we have to count
actually about 140 cells in the analysis. Now, that sounds like a small
point, but when you have a limited field to look at, you may not be able
to achieve that because there simply aren\'t enough cells on the field.

This shows data from a Medennium clinical trial. These are strictly the
control eyes, 123 good images plotted out after the counting, and we had
everything from 900 or so on up to 3,600.

You\'ll notice that if you had asked for 100 cells in the analysis,
we\'d have to have a field of about 2,400 cell density. Less than 2,400
cell density, there simply aren\'t the cells to look at in the specular
microscope field if using the Konan specular microscope.

Then every once in awhile we\'ll get poor images, which we are
unfortunately forced to used because maybe the control data wasn\'t
better than that, and you\'re really using very few cells in the
analysis.

Another issue is how uniform is the surface of the eye. This happens to
be my eye, and what I did was I looked at the central target, I looked
at a little bit further out ‑‑ 1 millimeter, 2 millimeters, and 4
millimeter zones ‑‑ and then I took pictures as I looked in various
spots on the field, as you can see here.

Then I asked the question, statistically, is this dot the same as this
dot and so forth? And it came out to no. So my surface, even though I
have no history of contact lenses and so forth, has a lot of
variability, and if you took answers from all over the place, you are
going to look like multiple patients. It\'s not going to look like one
patient.

Narrow the field down, still the same problem. Narrow it down, still the
same problem. Get down to about a millimeter out and it\'s certainly
better, but it\'s really good if you look at the dead center. If I
looked at that green target very carefully and took 10 pictures in a
row, they would really look like the exact same patient.

There is a little trick involved in this, and that is I happen to be an
emmetrope ‑‑ these are reading glasses ‑‑ so as I look off at the target
inside the machine, I see what you see on that screen, a red circle with
a green dot. If a person is a myope with 2 or 3 diopters off, he sees a
blur, and so asking him to cooperate to look at dead center becomes an
increasing challenge.

One more piece of data. What I did was I looked at the control data from
the Medennium group that I have and there\'s a single reading group,
which is me, but there are 58 subjects at seven clinical sites. So this
is real life. The patients had a real-life coefficient of variation, 36,
not the nice normal of 25 or so, and what we did was we had data
collected at baseline and three months, and I asked the question on that
patient is the baseline the same as the three-month data? And what it
showed me in a paired T-test was a .7, which is pretty good.

But there\'s a little more to the story. If I then looked at the data
and massaged it a little bit further and graphed out the percent
difference between these two time periods for each of the patients and
then made a cumulative graph on your Y axis, I can then ask if I have a
spread of 2.5 percent, how many patients are going to fall in that
group? And this said 50 percent. So you\'d have to have less than 2.5
percent difference between these two numbers to have 50 percent of your
patients in your group. If we wanted all of the patients, we\'d have to
go up to 9 percent to get 100 percent.

So it\'s really quite surprising, and there are references in the
literature that support these kinds of numbers. We\'re not looking at 1
or 2 percent spread in the data between these two time periods. In this
group, we were looking at 9 percent. So we\'d have to have a 10 percent
change in the event in order to be 100 percent sure that it was caused
by the event, rather than just the spread.

Some guidance for setting up clinical trials. You certainly want to have
careful control of the criteria of your study, which specular microscope
you\'re using, your experience, and the data capture. Who\'s doing the
capture and how often does he do it and how much experience? How many
sites are located? Each time you add a site, you\'re increasing the
variabilities.

So let\'s go right down to the final slide and what I would suggest.
First of all, I would suggest we all have the same microscope, and I
like the non-contact specular microscope simply because it means you\'re
asking for less skill from the technician.

I prefer one technician, I prefer to train that technician, and I\'d
like to check on the training of that technician to see if they really
are doing it frequently enough that they have kept their skills up. Most
of these people have lots of other things to do and they kind of get
soft on their skills.

I think a central reading center to limit some variability is also a
very good idea.

Thank you very much.

DR. WEISS: Thank you very much. You can take a seat when you\'re done,
Dr. McCarey, at the table.

DR. McCAREY: I\'m rebooting for the next one.

DR. WEISS: Oh, you\'re rebooting.

DR. EDELHAUSER: While Dr. McCarey\'s doing that, I\'m Dr. Henry
Edelhauser, and I\'m at Emory. My laboratory has been a reading center
for KeraVision and Staar, and I do a number of research contracts with
Alcon on intraocular irrigating solutions.

What I\'d like to summarize for everybody today is a very practical
summary now of what Bernie talked about and a little bit of the theory,
and Dr. Ramzy Azar was the one that helped out and was one of our major
reading center individuals, though he\'s presently in the Navy right now
down in Bethesda.

The purpose of what I\'d like to summarize today is using the robo
non-con specular microscope, which seems to be about the best specular
microscope to run a clinical trial, and particularly when you\'re
thinking about refractive surgery, because you\'re not applanating onto
the cornea. So we want to understand the variable issues that may be
found in specular microscopes. So our objectives in this 10-minute
presentation are to provide good examples in good and poor photography,
illustrate the variability, and illustrate the variability within a
single image that data has to be obtained from.

What is a good image? I think Dr. McCarey showed you. This is typical
panel that one would receive from the robo non-con. You notice on here
you can find distinct cells. You can identify at least 150 cells. The
cells can be grouped in a very uniform manner.

Then you may have to say, well, what may be good for clinical purposes
may not be good for research. For example, in many clinical times,
they\'ll only count 15, 20 cells, but for a research study, particularly
where you\'re quantitating endothelial cells over a long time, you want
to try and put a dot in every one of these corneal endothelial cells.

Things to consider that may affect the optical image. Dry eye, contact
lens use, wrong specular microscope settings ‑‑ you can go into the
manual mode with the non-contact ‑‑ and patients with keratoconus are
very difficult to get endothelial specularscopes.

Patient compliance. This is a real issue if the individuals can\'t see
that little green circulating dot and you have to work with the patient.
So training becomes very important.

Age of the patient, a little bit more difficult, and then training and
experienced photographer, and as I emphasize over and over again for
individuals and companies that are trying to under specular microscopy,
you have to train the individual out in the field.

Poor quality images are something that are an issue, and particularly
with preoperative because if your preoperative photos are poor quality,
this is going to carry through the whole study.

Here is an example where you have just a panel over here, and here\'s
another panel here. So really what was happening is that the patient was
moving his eye when this picture was captured.

Another type of poor quality image. Very difficult. Here you might be
able to obtain 30 to 40 cells in this particular panel. If this was a
preop, this patient is lost because there\'s identifiable cells that
could be measured.

Again, poor quality images where it\'s very, very difficult, and I can
tell you from being involved in a reading center and looking at over
10,000 of these with the laboratory, you get photos like this that are
preoperative and when you want this as a preoperative photo, how do you
start a baseline for this particular individual? This is where training
of the photographer or the individual running the specular microscope
out in the field is very important because that image will come up on
the screen, and if it\'s this one, they should sit the patient down
again and retake the photograph.

Conditions that potentially increase variability. Patients that have
Fuch\'s, polymegethism, pleomorphism, injury, and low cell density.
Particularly, there are some patients that do have a low cell density.

Here\'s an example of a patient that has guttata or Fuch\'s, and notice
you see these black spots here. Actually, these black spots are covered
by a very, very thin part of the corneal endothelial cell and the
refractive index is different here. Well, how do you analyze this
photograph? Well, you\'d have to group here or you\'d have to group
here.

So capturing the best image is very important. You have to make sure the
patient is comfortable. You have to instruct the patient to blink. You
have to instruct the patient not to move and to open his eyes wide. You
have to instruct the patient to focus on the green light, and as Dr.
McCarey said, it\'s difficult for somebody who has type of disease or is
extremely myopic because you can\'t see the green light as well as
somebody who\'s an emmetrope. You have to be patient. You have to work
with that patient and use of the manual setting to improve the quality
of the cornea is ‑‑ sometimes the corneas are thicker than the normal
setting, so you have go to the manual.

Things to consider when you analyze images. You have to locate the best
and most representative area, the number of cells, you have to look at
the quality of cells, and you have to use the area with the fewest
distortions, as I\'d shown in the very early aspect.

Here is an example of the best image. Well, the best image on this
specular here would have to be here, and this one you\'d have a very
hard time finding the best image. It may be somewhere along in this
area.

Dotting cells. You have to dot all the cells in the center and you have
to remain accurate and consistent throughout. We always recommend
dotting at least 150 cells if there are 150 or more than that on the
photograph because at least you\'ll get an analysis of 100 cells, 110
cells, and as Dr. McCarey showed you on the graph, the more cells you
can dot, the better the statistical analysis will be.

Where to group the analysis? Now, this is interesting. Well, if you
could dot every one of these, this would be the appropriate way to go,
but if you dot here, if you would look here, you\'d have a lot of big
cells up in this area and small cells here. So certainly, the diversity
in the cell count would be very large, and this is one of the
disadvantages of having specular microscopy done out in the field and
have the technician because the technician may just pick this area and
then that will be the preop, or they may pick this area, and then you
come back and your three-month data or six-month, they\'re going to
analyze up here in this area. So having a reading center or having one
person do all the analysis is very important.

What\'s wrong with this analysis? Well, here\'s an example of analysis
done in this area, just localized down in this area. Only 71 cells were
counted, but it still had an endothelial cell density of 2,639. So the
analysis really is not representative. It\'s introducing bias because
you\'re looking at a population of a lot of small cells here, you\'re
not likely to be able to repeat this analysis, and really we say that
you have not counted enough cells.

It is very important to group the analysis like this or as illustrated
here, and when you look at your grouping analysis, notice the box that
we\'ve drawn here. This is an improper grouping that you would see here
because you\'re doing this nearest neighbor analysis as the algorithm of
the specularscope and may only end up with 50 cells or something like
this, whereas if you group the whole group, you\'d end up at least
putting a dot in 150 cells. But see, technicians have to be trained if
they\'re going to do this, or your reading center.

Patients that have guttata. You may have some of these in a study group,
grouping here, here, here, or here.

DR. BULLIMORE: This is Mark Bullimore. Excuse me interrupting. You\'ve
talked about guttata twice and you seem to infer that you should count
around them when estimating cell density.

DR. EDELHAUSER: Right.

DR. BULLIMORE: So you don\'t include that area at all in your analysis,
even though there are no cells there.

DR. EDELHAUSER: Well, there\'s just usually one large cell that covers
that area, but we have found that in doing patients like that, if
they\'re part of the study group, the best analysis is to just use the
cells without including that guttae in there. The reason is is that if
you put that one large cell, you\'re multiplying this by such a large
factor that your cell number is extremely variable. See, you\'re wedded
to the algorithm of the specular microscope.

DR. BULLIMORE: Thank you.

DR. EDELHAUSER: And hopefully, in doing a study, you would not have many
of these patients in there, but I can tell you from the studies that we
have done with LASIK and things, you do find some patients that do have
guttata.

To analyze the cells, you need to be able to visualize the cells. You
have to identify a pattern. And would it be appropriate to take this
endothelial cell that has shown some damage?

Where the image is analyzed can create a great degree of variability, as
illustrated here. The old way which we used to do specular microscopy
with contact specular microscopy is take a wide field and then we\'d
have to trace the corneal endothelial cells, put a number in, and then
we would digitize each one of the corners. This is very accurate, but
again, notice the grouping of the cells.

Here are examples of variability. This is one specular image here. If
you analyze the endothelial cells in the lower portion, you\'d up with a
cell density of 2,976. If you analyze the endothelial cell density in
the upper portion, you\'d end up with a cell density of 2,873, a
difference of 103 cells and a 4 percent difference. So you can see the
variability that can occur and this can very easily occur if the
training of that individual is not appropriate.

Here are examples of variability within readers, and this occurred out
at our center when we were training the people out of our Vision
Correction Center to do this. Endothelial cell density 2,531 here and
2,358 here, a 7 percent difference just on the same pattern.

Here are examples of variability between readers, with having different
readers. So in this case, we had five different readers put dots in each
one of the cells, and you can see they varied from 2,531 up to 2,631. So
this is really a degree of variability. So training not only needs to
occur with the photographer, but also the person doing the analysis.

Just to show you this, the consequences of overcounting, if you skip two
cells, you have a significant difference. If you overcount three cells,
you have a significant difference. So this is where the training is
extremely important for the individuals.

Well, just to put this into a little perspective on this, and this is a
graph that we\'ve recently put together, the first study that was done
that we did back with Richard Yee, et al., this is what happens with
contact specular microscopy. Notice, from age groups from 10 up to 89.
Notice, this is the distribution of endothelial cells here.

Okay. We recently went back and did 125 patients through the various
decades with the non-contact robo, which is illustrated in the yellow
line, and notice that the lines overlap. Very early, we published a
paper in the AJO and I took the preoperative data from our LASIK
patients, which varied from 20 to 50, and notice those lines overlap.

There are two areas of outliers, and this was a mixed Asian group of
patients that we had in Emory when we looked at this, and notice the
Asian patients have a higher endothelial cell density, and a number of
years ago we had access to a Japanese population in Osaka when Dr.
Matsuda was with us, and in this population, notice that the Japanese
population in Osaka had many more endothelial cells than a Caucasian
American.

So this becomes a very interesting point of view when one wants to look
at endothelial cells in grouped patients if you\'re doing a study, say,
in the West Coast compared to, say, in the South or the Midwest.

Mike?

DR. GRIMMETT: Just a quick question. I hope you don\'t mind the
interruption.

DR. EDELHAUSER: No, not at all.

DR. GRIMMETT: The non-contact robo data, is that published somewhere? Is
that an abstract?

DR. EDELHAUSER: No, that\'s published, Mike. That\'s the original data
from Richard Yee\'s paper we published in Current Eye Research.

DR. GRIMMETT: In \'85.

DR. EDELHAUSER: In 1985, yes.

DR. GRIMMETT: Is there an updated one?

DR. EDELHAUSER: No, that\'s not published yet.

DR. GRIMMETT: Oh, I see.

DR. EDELHAUSER: It\'s in the process of being written up. We just
completed that within about two months ago.

DR. GRIMMETT: Thank you.

DR. EDELHAUSER: But I thought it was a very interesting comparison
because much of the data in the literature is from the contact scope,
and this is really the first longitudinal study with the non-contact.

Just to give you an example of the variability in the best of hands,
this was taken from our LASIK paper, where Ramzy Azar took all of the
photographs of the patients, and he then used his own eye throughout a
three-month time period where he took the pictures of his right eye and
his left eye. So this is 36 different photos, 18 of the OD and 18 of the
OS. His endothelial cell density is 2,545 and 2,600.

Notice the standard deviation, 45 cells. So the precision in the best of
hands with this, and this is from this AJO paper, is 1.7 percent and 1.5
percent. That\'s with one person looking and taking all the photos, and
I think this is very important.

A recent study that we\'ve done and reported at ARVO, which I think is
very important as we think about the endothelial cells, we measure
central endothelial cells, but peripheral endothelial cells are going to
become of interest, too, particularly when you think about phakic IOLs.

These are three graphs where lyserine red-stained human corneas,
something like 71 human corneas that we looked at. You can see the N
listed here. This line is the endothelial cell density in the center,
the paracenter, and the far periphery, about 4.5 millimeters from
center. You can see there is a progressive decrease of roughly a half a
percent per year all the way across the line, but still you do have a
higher cell density in the periphery that could aid in the sliding of
endothelial cells to the periphery.

So just to summarize this, then, what are the sources of variability?
It\'s difficult to return to the same location. When we were a reading
center for KeraVision, we did a reproducibility study with 10 patients
at three different sites where they took three consecutive readings, and
we ended up plus or minus 56 cells, very similar to what we measured in
the LASIK study. So you have an inherent error, just the
reproducibility, of 2 percent.

Poor image quality. We suggest trying to get at least 100 cells.

Training error. Training, and you have to have consistency. Reading
analysis. Training and consistency, and equipment calibration and
alignment is another very important issue that has to be.

So in summary, what the ideal situation might be is it could be a
company, it could be an independent reading center, it could be you need
your specular sites, and this data then should be sent to a reading
center. You should not have the sites do their own analysis. Then the
data in a mass fashion, which would be received to the reading center,
would be sent to the data processing center, and then for statistical
analysis then to the technology company, and obviously then on to the
FDA.

So I hope this little bit of a summary was important and I was able to
show you some of the variability of the technique. It\'s a good
measurement, it\'s a hard measurement to get, and what is very important
is that you do certainly want to see what the state of the corneal
endothelium is.

Thank you for your attention.

DR. WEISS: I\'d like to thank you both for excellent presentations.
Perhaps you could come up to the table and the panel could start their
questions.

I would just like to ask you a couple of elementary ones. What would you
suggest as the minimal time of follow-up in order to detect endothelial
cell loss after phakic IOL implantation? So what\'s the shortest study?

DR. EDELHAUSER: Well, I think certainly a three-month time period,
that\'s a reasonable approach to take it. I mean, are you trying to say
how soon after ‑‑

DR. WEISS: Two years, three years, five years? What would your wish list
be?

DR. McCAREY: If the literature is any indicator, I would imagine that
the most active changes are going to occur probably within the first six
months, and then afterwards you\'re probably going to level out into
some kind of a steady effect. So the initial trauma of the procedure,
let\'s say the first six months you need the data. Afterwards, you might
need data every six months for maybe two years, and then hopefully
you\'re going to see some kind of a level line that you\'re dealing
with. If you don\'t, you\'re just going to have to go further.

DR. WEISS: So just to clarify if I understand you correctly, you would
say two and a half years from implantation?

DR. McCAREY: Certainly two years.

DR. WEISS: Two years from implantation as a minimal, unless there is
anything else that you can tell.

DR. McCAREY: Correct.

DR. WEISS: If a patient is a contact lens wearer before, that\'s an
evolution of what is occurring with the endothelium as well. Before they
have their phakic IOL, how long should they be out of contact lenses so
you get a stable specular microscopy before they can be entered into a
study?

DR. McCAREY: Yes. That\'s almost a presentation on its own as to how the
patient is able to return from this polymegethism state from contact
lens wear. It looks like it\'s very, very, very slow, if at all, there
is a correction from that polymegethism change. So it means that you
could look at a patient one, two, three years, five years out of having
not wearing their contact lenses and they would still have the effect of
wearing the contact lenses.

The next part of the issue is does this mean that the eye is a little
susceptible to further trauma? And the literature would indicate that
these eyes are more susceptible to trauma. They respond more negatively
to trauma than a person who had a normal CV and no contact lens history.

DR. WEISS: So should that be an exclusion criteria then?

DR. EDELHAUSER: No, I wouldn\'t think so. It shouldn\'t be an exclusion
criteria if somebody has polymegethism.

DR. WEISS: No, I mean contact lens wear, because it sounds like it\'s
such a confounding variable that you ‑‑

DR. EDELHAUSER: It is, but I think there is variability within the
degree of polymegethism because if you\'re thinking of phakic IOLs and
everything, basically all these people have worn contact lenses.

DR. McCAREY: I agree with Dr. Edelhauser. That\'s the problem. You\'re
going to lose an awful lot of your patients.

The second part of the story about polymegethism is it\'s a stress from
oxygen. If you are an old-fashioned PMMA lens wearer, you have the most
stress. If you have the more modern, let\'s say the silicone materials
or a high-water content hydrogel, you\'ll probably have less stress. So
it\'s a sliding scale as to how much stress they have had from their
contact lenses.

I think what I want to point out is that the endothelial cell density is
not alone an indicator as to the history of that patient. You\'d also
want to know what\'s going on with their CV, the spread in the cell
sizes, and I think good data collection is probably more important a
statement than eliminating these patients.

DR. WEISS: If I had to put you on a spot and ask you to give a bare
minimum ‑‑ not the range, but the bare minimum ‑‑ you think that someone
would have to be out of contact lenses, would you be able to give me a
number?

DR. McCAREY: It would just be a wild number and I would certainly ‑‑

DR. WEISS: A wild number might still be helpful.

DR. McCAREY: Certainly six months, but I don\'t really know for sure.

DR. WEISS: Okay. Six months.

Would Asian corneas then have to be grouped differently because they\'re
starting out with more endothelial cells?

DR. EDELHAUSER: I would think that would be a subset that should be
analyzed separately. From past experience with that, all Asians that
we\'ve looked at have a very higher cell density, and it depends upon
where the study is going to be conducted, but I wouldn\'t use an
exclusion. I\'d just use it as an added subset.

DR. WEISS: A subset. Thank you very much.

DR. McCAREY: Could I add one more thing on this?

DR. WEISS: Yes.

DR. McCAREY: I think that the contralateral eye is a goldmine, that a
lot of these issues that you\'re referring to can be lessened as far as
you\'re concerned if you know the history of the contralateral eye.
Follow both eyes and make the data relevant within the patient
themselves, rather than some kind of a standard regression line from a
group. I think will solve a lot of problems.

DR. WEISS: So in this case, you would suggest, at least from the
endothelial cell portion, that it would be very helpful only to do
unilateral phakic IOL surgery.

DR. McCAREY: Yes. Unfortunately, that\'s what I would state.

DR. WEISS: Thank you.

We\'re going to go around. Dr. McCarley, then Dr. Burns, then Dr.
Bullimore, Dr. Matoba, Dr. Grimmett, and then we\'ll go on down the
line.

MR. McCARLEY: This is Rick McCarley. I knew if I waited around long
enough, I\'d get a degree, too. So thank you.

(Laughter.)

MR. McCARLEY: It\'s just Rick.

DR. WEISS: I think I\'m going to start with first names and go back to
the first names.

(Laughter.)

MR. McCARLEY: There you go. Thank you.

You\'ll see my eyebrows going up several times today because obviously
I\'m involved in a clinical study on phakic intraocular lenses in the
U.S. that\'s been going for about five years now, and in fact 15 years
in Europe. So I have a lot of ‑‑ I\'ll call it practical experience, and
boy, I wish I knew then what I know now. We do have a lot of data and I
wanted to share some of this because it applies to all of us. These
discussions have happened in the ANSI standards, so I\'m pretty well up
to date on what has happened in the industry and what data we\'ve
collected.

But a couple of the comments, one is the patients not only wear
contacts. Most of these patients that we\'ve seen have polymegethism,
but many of them, we\'re talking about -15 to -20.

DR. WEISS: Actually, I\'m going to interrupt you for a moment. Because
of the time constraints, what I\'d like to do is use the benefits of our
experts\' expertise, and I would prefer the comments get directed to the
comment portion.

MR. McCARLEY: That\'s okay.

DR. WEISS: And if you have any questions to direct to Dr. McCarey or Dr.
Edelhauser, use this time for that.

MR. McCARLEY: Okay. Then I will ask the question directly. Have you ever
studied a population of high myopes individually and compared that to
the normal population?

DR. EDELHAUSER: No, we haven\'t. The only high myopes that we\'ve really
looked at were part of our study that we published on LASIK, where had
100 consecutive patients that we looked at and there were only, I think,
eight to 10 at the most that were high myopes.

MR. McCARLEY: I see. And when you\'re analyzing the endothelial cell
data over a large population, the comment about the subgroup of Asian
eyes, are we looking at percent changes, so it really doesn\'t matter
what their beginning or ending is? So looking at a subgroup really
doesn\'t matter. If they start off with more, we\'d expect them to end
up with more.

DR. EDELHAUSER: I think that\'s how the study design is set up and how
the statistical analysis is done.

MR. McCARLEY: Right.

DR. EDELHAUSER: I mean, as an independent reading center, we want to be
masked in that. So the criteria would be in the early study design and
how you\'re going to do that.

MR. McCARLEY: Thank you.

DR. WEISS: Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Yes, I have maybe three related questions. The first
one is both of you alluded to cell density not being uniform over the
surface of the eye. Would you think it would be worth some sort of a
dynamic sampling strategy to try to isolate the maximum cell loss or is
that relatively reliable in the center? I\'d just appreciate your
thoughts on that.

DR. McCAREY: I think you\'d be opening up a can of worms if you
approached it that way. I think you\'re probably best trying to get
central readings, and with instruments like the Konan, hopefully the
patient can cooperate and look at the target and you\'re getting the
same field.

On my own eye, I could take 10 pictures, and every one of us having
slightly different patterns and you can see an odd cell here and there,
and within the 10 pictures, I could see the same little couple of cells.
I can come back two or three months later and do that again and once
again see those same little odd cells.

So I think that the key here is training and cooperation from the
patient and the central cells, and that gets rid of some other cans of
worms.

DR. BANDEEN-ROCHE: Thank you.

DR. EDELHAUSER: Let me just add one other thing. I think in order to get
a representative, it is recommended, and we certainly have recommended
this, that if you\'re going to take specular photographs, at least try
and get three photographs, and then at least have the reading center or
whoever is doing the analysis try and then analyze the best one of this,
or in the early training of your individual, if you have them take
three, and then take the average to see where they are. So again, it
comes back to teaching the photographer to get a representative photo.

DR. BANDEEN-ROCHE: Thank you.

The second question goes to variability over repeated readings, say,
over a three-month time period, and you alluded to in the best case
percentage variability of 1.7 and 1.5 percent. I\'m curious. How much of
that is variability in the reader versus natural variability in cell
density over three months? And when you refer to those rates being the
best, I tend to say, well, suppose somebody just counted more cells?
Couldn\'t it get better? If you could respond to that.

DR. EDELHAUSER: In this particular case, I say it was the best because
we had one person taking the pictures of his eye and counting as many
cells as possible to come up to do this, and I think that what you\'re
dealing with in this particular case is the variability of the machine
and the algorithm. Because don\'t forget, in this particular case,
you\'re, say, dotting 150 cells. At best, 160 maybe is all you can put
on there. Then you push the button and the algorithm pops up here, and
what you\'re dealing with is that\'s what you\'re left with, the
analysis of those particular cells that you\'re dealing with.

DR. McCAREY: I kind of take a little bit different approach to that. I
think the math is the math. It\'s not changing. The computer\'s not
changing. The machine is hopefully focusing the same and keeping the
same magnification. So your variation isn\'t in the equipment. It\'s in
either where the picture was taken ‑‑ well, that\'s probably the heart
of it, where the picture was taken, because there is a variation across
the surface.

Now, you mentioned the best answer and the worst. I showed you 9 percent
of a spread in order to get all the patients in the group. That\'s with
seven clinical sites, 58 patients, and no expectation that I was going
to do that analysis. That\'s the hardcore reality.

Whenever you look at a paper that comes from a given site ‑‑ whoever it
may be, our lab or Bill Bourne\'s or someone else\'s ‑‑ they are doing
the entire study themselves. They are giving you their best shot. They
know they\'re going to do the study, and it always comes out cleaner
that way. So my 9 percent is probably reality and the equipment probably
is as good as 1 percent.

DR. BANDEEN-ROCHE: Thank you, and a very brief final question that goes
to guttata. So the point of not counting that, I take it that induced
guttata is not a primary problem in phakic IOLs?

DR. EDELHAUSER: Provided it doesn\'t cover the whole surface of the
corneal endothelium. I mean, we\'ve all seen patients that have guttata
that go from limbus to limbus, and then occasionally you\'ll have a
person who will sit down and you\'ll get one guttae in the area. I mean,
you still can use that photograph. So I think there are various degrees.

DR. WEISS: Thank you.

Dr. Burns, did you have some questions?

DR. BURNS: Yes, two. Steve Burns. Two simple questions.

First, is it true that if you take, say, three sets of images that the
one with the highest count is best? I thought I heard you say that, but
I might have misinterpreted it.

DR. EDELHAUSER: No, I think you the best image that I was implying is
the one where you have a good distribution of cells over the whole
screen that you can see, and not one where a patient may have moved
their eye a little bit and you only get a strip of the endothelial
cells. So the best image that I would suggest would be one that has as
many cells uniform across the full screen.

DR. BURNS: So given that you\'ve got three good images, do you just
average them? Do you recommend averaging those counts for that data
point?

DR. EDELHAUSER: Yes, yes.

DR. BURNS: The second question is when you were talking about how long
you\'d follow up, was that sort of in laboratory-type data or were you
taking into account the realities of variance from a trial? So the two
and a half years you were suggesting, do you think you\'d have to
lengthen that given the variability you get from a multisite study?

DR. EDELHAUSER: You might. The best illustration I\'d give you is our
LASIK data, and we looked at this very carefully for 100 patients and we
followed them up to three years. Of the 100 patients, we able to get 63
of them back ‑‑ again, this is all volunteer at this particular stage ‑‑
and we really found no change over a three-year time frame. But I think
with something that has the potential where endothelial cell populations
may be decreasing, going out to two or three years might be important.

DR. WEISS: Dr. Bullimore?

DR. BULLIMORE: Mark Bullimore. I\'d like to thank both of you for
coming. It\'s a fabulous presentation and it\'s very encouraging for
those of us who do clinical research in general to see the level of
rigor with the reading center. I mean, that was very refreshing.

We took some data on the Konan probably under the worst-case scenario,
and our precision was probably closer to 10 percent than 2 percent, but
we weren\'t counting the number of cells and we weren\'t doing all the
other sophisticated things that you gentlemen do.

I have hopefully a couple of quick questions. First of all, when you
talk about coefficient of variation that\'s what other people, or maybe
yourselves, would also refer to as polymegethism? Are those two terms
equivalent or interchangeable?

The other thing is, and this is a particular concern given the fact that
many of the patients having phakic IOLs will be long-term contact lens
wearer, you inferred or implied that if you take a patient out of
contact lenses, there would ultimately be a very slow or potentially no
long-term recovery from that insult. Did I hear you correct?

DR. McCAREY: That\'s strictly from the literature. It\'s not from my own
laboratory experience, but Brian Holden has done lots of work in this
area, and it repeatedly shows up that that\'s true.

DR. BULLIMORE: So taking that to the next step, were we at some future
date to be looking at these data, you would not worry about that contact
lens or prior contact lens wear as a confounding factor in any changes
in endothelial count that occurred after the patient had a surgery?

DR. McCAREY: There is literature out there that tells you that large
polymegethism values often lead to a patient being more susceptible to
the trauma of a given surgery as compared to patients with a lower
coefficient of variation. So they do have the potential to be more
susceptible to damage.

DR. BULLIMORE: I see, but that\'s a short-term effect of the surgery,
rather than their sort of five-year history, say.

DR. McCAREY: I don\'t really know if it would mean that the five- and
10-year periods would still be at a higher rate of loss or not. I don\'t
know.

DR. BULLIMORE: Did you want to go ahead?

DR. EDELHAUSER: There may actually be a benefit of removing the contact
lens because I say from our experience, in our three-year data from the
LASIK patients, we actually did see an improvement in the coefficient of
variation, and all these patients were contact lens wearers.

DR. BULLIMORE: And a final question. There has been a great deal of
emphasis on your slides and in other materials I\'ve looked at on the
topic on endothelial cell density. Do you think that should be the
primary outcome measure or should we be looking at coefficient of
variation as the primary outcome measure in a long-term study or would
you consider both to have equal weight?

DR. EDELHAUSER: I think cell density would be the number one aspect of
it. The difficulty with the coefficient of variation that we have if you
use the robo, to some extent that data is a little soft, and the reason
I say that is soft is because you\'re using the center dot method. If
you were tracing cells and using the corner method, that data is much
stronger.

One of the things that I have found over the years of using the robo, if
you have a patient or a subject that has a high coefficient of variation
‑‑ say, .6, or like many of the diabetic patients ‑‑ it shows up, but
the difference between .27 and .35 is not really a significant change.

DR. BULLIMORE: So without wanting to put words in your mouth, the
precision of the coefficient of variation method is not particularly ‑‑
let me rephrase that. The precision of the coefficient of variation
measure is not particularly impressive.

DR. McCAREY: Well, the coefficient of variation, I passed the slide very
quickly, but the calculation is that you\'re dividing the mean cell area
into the standard deviation or the spread in that mean cell area. So I
feel that it is a piece of informative information, but you do get a lot
of noise, though, in it from the fact that there is a spread in the
data. I\'d personally like to see that information carried forth in the
study.

DR. BULLIMORE: I lied, Madam Chairman. I do have another question.

I\'m very familiar with a paper by Scott McCray on long-term PMMA
contact lens wear, where he looked at a cohort of patients who\'d worn
PMMA lenses for 20 years and reported their outcomes, and one of the
things I found compelling about the paper is actually, and it\'s not
emphasized in the paper, but the cell density in the contact lens
wearers centrally was actually higher than the controls.

Okay? The take-home message was that there was this subset of patients
who fell below a given value of cell density. I think it was nine out of
the 81 contact lens wearers compared to two of the controls, which was
statistically significant.

So in his analysis, and using that as, if you like, an analogy to what
we\'re doing here with phakic IOLs, would it not be more appropriate,
rather than emphasizing the mean endothelial cell density, to look at
sort of, for want of a better phrase, incident cases of significant or
substantial reductions in cell density? Have you explored that parameter
yourselves or is it in the literature?

DR. EDELHAUSER: It\'s not in the literature, but in the database that
KeraVision submitted to the FDA, I know it\'s there because they went
back and looked very significantly at patients who may have lost greater
than 10 percent of their cells, and they were reported.

The other interesting thing in that paper you\'re referring to by Dr.
McCray, of that subset of patients, there were a group of contact lens
wearers who actually lost cells.

DR. BULLIMORE: Yes. That was my point, and it was nine out of the 81
were way below what you might consider the normal range, but when you
actually averaged the cell density ‑‑

DR. EDELHAUSER: It was lost.

DR. BULLIMORE: It was lost. So I think we should maybe keep that in
mind.

DR. McCAREY: When you get polymegethism, you actually appear to be
getting smaller cells, not just losing cells and big ones reappear. That
would be a misconception. There\'s actually an appearance of what appear
to be smaller cells. Recently, and I unfortunately don\'t know the
author, there was a description of how this occurs.

DR. BULLIMORE: That was Michael Delaty, probably.

DR. McCAREY: I don\'t remember, but he has certainly has a lot of
articles.

You can actually see a triangular-like pattern occurring and that
triangle shows a smaller top to the aqueous, what looks like a smaller
cell. The volume of the cell may be the same. So there is a shift in the
dimensions of cells, rather than a loss of cells.

DR. BULLIMORE: Sort of from a cylindrical profile to a trapezial.

DR. McCAREY: Right, and so it appears that they could have a very high
cell density when that\'s really true if you counted the whole number of
cells across the surface.

DR. BULLIMORE: Thank you both again. This has been very, very helpful.

DR. WEISS: Thank you.

Dr. Matoba, did you have questions?

And I will again reiterate, because we\'re already going to be off time
and running over. So if the members of the panel could make their
questions short and sweet and directed to the issue at hand, I\'d
appreciate it.

DR. MATOBA: Do you want us to identify ourselves?

DR. WEISS: Yes. I mean, we can identify ourselves for the first time
around, and then I think the transcriptionist won\'t have a problem.

DR. MATOBA: Okay. Alice Matoba. My question is your presentation
indicated that there are significant differences between races in terms
of endothelial cell density, and I wonder if you have any sense whether
there can also be differences between races in terms of the minimum
endothelial cell count you would need before one starts to develop
clinical edema?

DR. EDELHAUSER: I don\'t think that\'s in the literature at all. I mean,
just as a little bit of a sidelight, if you go back and looked at the
original radial keratotomy, it was done by Sado, and the reason he was
somewhat successful I think is that the population of individuals he did
the study on had more endothelial cells. So no, we don\'t know the
minimum, and the best data would probably come from Japan, Dr.
Matsuda\'s laboratory.

DR. WEISS: Dr. Grimmett?

DR. GRIMMETT: Dr. Grimmett. My question was asked by Dr. Bandeen-Roche
and answered, so I\'ll pass at this time.

DR. WEISS: I\'m just going to ask you a quick follow-up question, then.
I understand that you would want CV as part of specular microscopic
studies. Is there a number that you would assign beyond which this is of
concern? I\'m being a very concrete person.

DR. EDELHAUSER: Are you talking about an upper level?

DR. WEISS: Upper level, yes.

DR. EDELHAUSER: Well, the thing that you see in your upper levels are
CVs up around, say, 45 and above. You know, that\'s a very high number.

DR. WEISS: That\'s of concern.

DR. EDELHAUSER: Yes.

DR. WEISS: Thank you.

Dr. Bradley?

DR. BRADLEY: Dr. Bradley. A couple of statistical questions, really. You
seem to be suggesting you should be avoiding contact lens wearers in the
sense that I got the impression you were treating that as perhaps a
confounding source of an independent variability, but if the contact
lens wear interacts with the effects of phakic IOLs, are you then more
susceptible to this? And these are the sorts of patients that might be
getting phakic IOLs. Surely, they shouldn\'t be excluded, but should
they be specifically included in such a study? Could you comment on
that?

DR. McCAREY: I agree completely with what you\'ve said. I just want to
make sure that you\'re aware of which patients has had a contact lens
history.

DR. BRADLEY: Second question. Again, I think statistically you did quite
a thorough job of demonstrating different sources of variance, and I
lost track a little bit of the individual sources of the variance, but
it seemed you put that all together in a graph and you suggested that in
order to detect a change in cell density in an individual eye, it would
have to change by 9 percent.

DR. McCAREY: With that set of data that I presented to you, yes.

DR. BRADLEY: So the question, and I wondered if you knew the answer, is
what would be the sample size required to detect a clinically
significant change in the sample of eyes that might be used, for
example, in the study of phakic IOLs?

DR. McCAREY: I\'d have to go back to the computer. I don\'t know the
answer. It\'s a statistical question that I didn\'t ask.

DR. GRIMMETT: Michael Grimmett. I\'ll present that during my talk.

DR. WEISS: Dr. Huang?

DR. HUANG: Andrew Huang. My question is that so far we have emphasized
the physical characteristics of the endothelium, but we all know corneal
thickness is a function of the corneal endothelial functions. Do the
speakers have any thought about what\'s the value of corneal thickness
in terms of evaluating the cornea\'s general health?

DR. McCAREY: Well, as part of an answer, and I\'m sure Dr. Edelhauser
can expand on this, but you can get endothelial cell counts down below
1,000 to 900 and 500 and still have normal corneal endothelial
thickness.

DR. HUANG: Exactly, yes.

DR. McCAREY: So it seems to be not as sensitive an indicator as to what
trauma may have happened to that tissue.

DR. HUANG: But by the same token, the flipside of the coin is that if
you have a decrease of cell density from your graph, from the aging
population, from 3,000 or 4,000 at birth to 2,000, but the patient did
not really have any functional visual disturbance, is that a bad thing
to have a decrease in those endothelial cells or is that a good thing to
have a healthy corneal thickness?

DR. EDELHAUSER: Well, I think there\'s a limit obviously. I mean, a
corneal endothelial cell population between, say, 1,000 and 2,000 will
survive very nicely, because we see this in many cases with patients
with guttata and we see it with postkeratoplasty with patients and it\'s
fine.

I think that obviously when you set up a study that you want to do this
where there\'s a potential loss of endothelial cells or you want to see
it, you don\'t want to start out with patients that have 1,400 cells,
for example. So you\'d really want to have ‑‑ a \"normal\" endothelial
cell population with some polymegethism would be fine, up around 2,500
cells per se.

DR. HUANG: But by the same token, you may now have started with the
patient in, say, the Asian population with an endothelial cell count of
2,500, but with a corneal thickness of thicker than 600 microns.

DR. EDELHAUSER: Occasionally, yes, you do see. Some people do have
thicker corneas.

DR. HUANG: But that itself may be indicative of the corneal endothelium
is compromising.

DR. EDELHAUSER: I understand. Sure. That\'s true, very much so.

DR. HUANG: Yes. Seeing the cell number does not necessarily mean the
cell is alive.

DR. EDELHAUSER: Right, but I think you bring up, if corneal thickness is
going to be an issue, again, that\'s another training point, and, one,
the corneal thickness measurements off of some of the specular
microscopes are not that accurate compared to ultrasound.

DR. WEISS: Dr. Mathers?

DR. MATHERS: Presumably, you would recommend that we do not include
patients with Fuch\'s dystrophy and significant guttata because that
would confound this measurement considerably, correct?

DR. EDELHAUSER: Yes.

DR. MATHERS: But you see an occasional guttata, maybe one or something
like this, in a fairly large percentage of the population. Could you
hazard a guess as to how many in single field could be there and you
would qualify them to be excluded?

DR. McCAREY: Well, as a reader of the images, it isn\'t so much if
they\'re present. It\'s can I get a large enough area remaining that\'s
contiguous for counting of the cells. So I do not count around the
cells, and I don\'t want to count a narrow sheet between guttata because
that will louse up the algorithm.

DR. MATHERS: But to do this study, you want to have as clean a group as
possible. So presumably, we wouldn\'t want to have patients where we\'re
fighting the guttata.

DR. McCAREY: Yes. This is probably one of the reasons I like to see more
than one picture taken because if there is a random guttata, I try to
select the picture with the least problem.

DR. MATHERS: So you\'re not going to ‑‑

DR. McCAREY: Rather than averaging the three. That\'s not so important
to me because I think that when you consider the surface area, it\'s
.003 percent of the surface for one picture. What\'s one more picture
out of the whole surface? Very little.

DR. MATHERS: Yes, right.

DR. McCAREY: But you want to get a good picture, and if it means getting
a good contiguous field of cells, then that\'s what a good picture is.

DR. MATHERS: All right.

DR. WEISS: I get the impression that Dr. Mathers is trying to quantify
it because we\'re doing a guidance document.

DR. MATHERS: Yes, right, because if you take enough pictures, you\'re
going to get a spot where you can count 150 cells and in a single field
you might still have 15 guttata. We may not want to include this in a
study where we\'re looking at this because those guttata are going to
indicate a confounding population. We need some kind of measure as to
say this person has too many guttata to include in a study like this.

DR. EDELHAUSER: In a preops study, yes. I mean, I think that this could
be an exclusion criteria.

DR. MATHERS: Right.

DR. EDELHAUSER: And that would be put in there. You know, obviously,
there are patients that have few guttata, but there are a lot of
patients that have a lot of guttata and they should be excluded.

DR. MATHERS: Okay. We\'ll call it a lot.

And presumably, when you suggested a two-year follow-up, you\'re
speaking of an insult and then a process of evaluating the endothelium
after that time, but if you have an ongoing insult, ongoing
inflammation, presumably then would you modify your two-year
recommendation if you\'re going to assess that?

DR. EDELHAUSER: Indeed, I would. You know, if you\'re going to follow
these patients, three years certainly would be reasonable to follow
these patients out.

DR. McCAREY: Are you implying a chronic inflammation?

DR. MATHERS: Chronic inflammation.

DR. McCAREY: If it was a chronic inflammation, wouldn\'t you expect a
chronic loss?

DR. MATHERS: Correct.

DR. McCAREY: So you would expect to see eventually a linear line
occurring, and that\'s when I\'m telling you that you\'ve followed them
long enough. You don\'t have to follow them infinitum. You need to know
what\'s going on at a steady state.

DR. MATHERS: Right, but that would presumably be longer than an initial
insult period study. So you were asked to give an estimate and when you
said two years, certainly that would be longer if you have a chronic
process. Can you give a time?

DR. McCAREY: I still kind of flip the response back to you by saying
that I\'m looking for a linear response.

DR. MATHERS: Yes.

DR. McCAREY: And if it\'s still not linear at the end of two years, I
have to keep going. I have to go for a longer follow-up time.

DR. MATHERS: Right, but we need ‑‑

DR. McCAREY: And I would not know how long it would be.

DR. MATHERS: You don\'t know.

DR. McCAREY: Yes.

DR. MATHERS: Okay. Fine.

DR. EDELHAUSER: I think, Dr. Mathers, the longest study that we\'ve
followed through are the LASIK patients, and that\'s been three years
out.

DR. MATHERS: Right.

DR. EDELHAUSER: So I haven\'t really participated and I think with the
KeraVision, their three-year data is just now coming in and being
analyzed.

DR. WEISS: Dr. Owsley?

DR. OWSLEY: Cynthia Owsley. Dr. McCarey, you mentioned that when people
stop wearing their contact lenses, the cell density counts, if we look
at the literature, suggest that it\'s pretty stable or there\'s not this
miraculous going back to the norm, whatever that is. From the pragmatics
of doing a clinical study on patients, most of whom will be contact lens
wearers and who have very severe myopia, do you feel it\'s too
burdensome on patients to have them be without the contacts for six
months and is that maybe a little inflated? I mean, I know they can do
the spectacles, but being a myope myself, I know that a lot of contact
lens wearers, they like to wear their contacts and not the spectacles.
Just in terms of patient enrollment issues.

DR. McCAREY: I have a great answer for that. I\'m a Ph.D. I don\'t have
to worry about the clinical part. I really don\'t know how to answer you
because ‑‑

(Laughter.)

DR. OWSLEY: That\'s a good answer.

DR. WEISS: Dr. Swanson, did you have any questions?

DR. SWANSON: No questions at this time.

DR. WEISS: Great.

I want to thank you both very much. Those were excellent presentations
and extremely helpful to us, and I thank you for your good humor with
putting up with our questions as well.

So you can move back from the table if you would like, and we next have
Dr. Liliana Werner from the Storm Eye Institute, who will be speaking to
us on lens opacity.

Donna, do you have something to say first?

MS. LOCHNER: I\'d just like to introduce Dr. Werner a little more
formally. She is an assistant professor of ophthalmology at the Storm
Eye Institute at the Medical University of South Carolina in Charleston.
She is the senior scientist of the Center for Research on Ocular
Therapeutics and Biodevices.

She received her doctor of medicine from the faculty of medicine of the
Federal University of Minas Gerais in Brazil in 1989, her residency in
ophthalmology at the Felicio Rocho Hospital in Brazil, and two
postresidency programs at the University of Paris and the Hotel-Dieu
Hospital in Paris. In 1999, she received a Ph.D. from the University of
Paris and began her work at the Storm Eye Institute.

She is editor, together with David J. Apple, of the summer 2001 issue of
the International Ophthalmology Clinics and is currently serving as a
scientific referee for many ophthalmology journals. She was recently
selected to joint the International Intraocular Implant Club and
starting in September of 2002, she will be the director of research of
the new David J. Apple Laboratories for Ophthalmic Devices Research at
the John Moran Eye Center at the University of Utah in Salt Lake City.

Thank you.

DR. WERNER: Good morning. I would like first of all to thank the FDA
members for the opportunity to be here and participate in this meeting,
and I will be discussing the issue of cataract formation after
implantation of phakic posterior chamber intraocular lenses. This
presentation is based on a review of the literature, but also on some
studies we performed in our center and, as mentioned, soon we\'ll be
moving back to Salt Lake City, where the center was in fact founded in
the \'80s by Dr. Apple and Dr. Olson.

So in fact what we did is an update of the report we prepared for the
ANSI meeting in Newport Beach last year, and I would like to start with
a brief overview of the cell types involved in the problem of
crystalline lens and capsular bag opacification.

So if you look at this picture, we can in fact divide the crystalline
lens epithelium into two different biological zones, and in this zone we
have the A-cells, and these cells are attached to the inner surface of
the anterior capsule, and when the cells are disturbed, they have the
tendency to remain in place and undergo a process of fibrous metaplasia.
These cells are in continuity with the cells in the equatorial region,
or the E-cells, and these cells, on the contrary, when they are
disturbed, they have the tendency to migrate and proliferate, forming
bloated cells.

So both cell types are involved in the different forms of capsular bag
opacification. For example, anterior capsular opacification after
implantation of different intraocular lenses. Also, different forms of
secondary anterior to capsular cataracts. Also, interlenticular
opacification between piggyback lenses, and finally posterior capsular
opacification after implantation of different intraocular lenses.

So here, for example, you have the A-cells being the most important cell
type involved in the process of anterior capsular opacification after
implantation of different intraocular lenses for cataract surgery, and
you can see here a beautiful example of the anterior capsule being
opacified only where it\'s in contact with the IOL material.

So here you have another example, and this is a case of capsule
contraction syndrome, and because you have asymmetric fibrotic formation
and asymmetric contraction, the lens is also decentered.

Whenever you prepare those specimens for histopathological evaluation,
that\'s what you\'re going to find at the level of the capsule axis
edge. So there are always these fibrocellular tissue attached to the
inner surface of the anterior capsule, and this in fact corresponds to
the opacification in this border.

And of course, the A-cells are also the cell type most involved in the
anterior capsular cataract associated with phakic IOL implantation, and
here I have a bilateral case provided by Dr. Koch. So we have here the
opacity in the right eye and in the left eye. I\'ll be talking a lot
today about the ICL because the available literature is related to the
ICL and also these are the specimens we have available to us in our
center.

So what happens in this case is that the surgeon has to explant the lens
and then he is going to perform the cataract procedure. So we are
recommending them to save for us the capsule excess fragment so we can
perform histopathological analysis of this anterior capsule fragment,
and in fact it\'s been very interesting to notice that there are many
similarities between anterior capsule specimens obtained in different
situations.

So for example, here you have the capsule excess edge of a case of
anterior capsular opacification after implantation of a silicone lens,
here you have the specimen, the capsule excess specimen obtained during
the surgery of an anterior subcapsular cataract secondary to uveitis,
and finally here is the specimen we received in our center. It\'s the
capsule excess obtained during the cataract procedure for a case of
anterior subcapsular cataract after phakic IOL implantation. So in fact,
if you see these three examples, you will always find this fibrocellular
tissue attached to the inner surface of the anterior capsule,
corresponding to the opacification.

Finally, the E-cells are the most important cells involved in the
process of posterior capsule opacification and mostly in the pearl form
of posterior capsule opacification. Both cells, and mostly the E-cells,
are involved in the process of interlenticular opacification between
piggyback lenses, and when you analyze such specimens in histopathology,
you are going to find residual corneal material and pearls very
similarly to what is observed with posterior capsular opacification.

I\'d like now just to summarize the evolution of the designs of the
phakic posterior chamber lenses.

So, as you know, these lenses were introduced by Fyodorov in the \'80s
and the first designs were pupil-fixated lenses. So this lens, for
example, was supposed to stay in the sulcus, but the optic component
would protrude through the anterior chamber through the pupil.

The second generation was represented by the Chiron Adatomed silicone
lens, and in fact this lens was withdrawn from the market because of
cataract formation. This was really a very thick lens.

Finally, the third and current generation is represented by the Staar
ICL manufactured from the collagen material. This is a much thinner
lens, and in fact there are different models of this design and each
model has different vaulting characteristics.

The third generation is also represented by the Medennium phakic
refractive lens, or PRL, manufactured from silicone, and this is also a
very thin lens, and you have here the myopic model and the hyperopic
model.

So let\'s talk about some relevant aspects of fixation and sizing. We
had the opportunity to analyze some Chiron Adatomed silicone lenses
which were explanted because of the problem of cataract formation. Then,
after analysis of the lenses, we reimplanted the lenses in eyes of
different sizes, and in fact we could observe from the posterior view or
a side view that the lens was really too big and too thick. The lens was
really sitting on the zonulas. We could not fixate the lens in the
sulcus, and because it was very thick, it was in large contact with the
posterior surface of the iris and anterior surface of the crystalline
lens.

With respect to the ICL, consecutive V models of this design had
different vaulting characteristics, and this was done in order to reduce
the possibility of cataractogenesis. Apparently, the sizing is important
for this design. So a lens that\'s too large will be followed by
excessive vaulting, but a lens that\'s too small for the eye will be
unstable and eventually become decentered.

Dr. Ferdinand Trinidad from Brazil very nicely summarized different
situations with incorrect sizing of the ICL. So for example, if you have
a lens that\'s oversized, the vaulting will be excessive and there will
be a large area of contact between the lens and the posterior surface of
the iris.

Here, for example, there is a central vault, but a large mid-peripheral
contact, and you have a pool of aqueous humor that\'s stagnated between
the lens and the crystalline lens, and eventually, as we\'re going to
discuss further, there is the possibility of some metabolic
disturbances.

Finally, if the lens is clearly undersized, the lens will be unstable
and there will be a large area of contact between the lens and the
anterior surface of the crystalline lens.

So the sizing issue is eventually a very important issue for phakic IOL
implantation in general, and in general surgeons are using the
measurement of the white to white to finally choose the size of the lens
that\'s going to be implanted in the eye of the patient.

For example, for the ICL, if you review the literature, surgeons would
measure the white to white and then add 0.5 millimeters for a myopic eye
or they subtract 0.5 millimeters for a hyperopic eye, but this
measurement can be so inaccurate, and sometimes we receive some cadaver
eyes in our lab and we don\'t even know exactly where to measure.

This is a very recently published paper by this group. They analyzed 43
eyes of 24 patients. They patients were aged at around 34 years and they
were highly myopic or hyperopic. They performed measurements of the
white to white with surgical calipers, and they tried to look for a
correlation between the white to white and the sulcus diameter measured
with composites of UBM photographs.

They concluded that the traditional estimation of the sulcus size
through the limbal measurement is inadequate. So the limbus size alone
would not be able to predict the sulcus size.

We are also trying to do different studies using cadaver eyes regarding
the sizing. For example, we are actually working on this protocol where
we get different cadaver eyes, we measure the anterior/posterior length,
then we mark the 12 o\'clock position, and we localize the horizontal
meridian and the vertical meridian. Also, we perform measurements using
a plastic sizer of the anterior chamber diameter, and after that we try
to fixate the eye with special techniques which allow us to keep the
geometry of the whole anterior segment. Then we select the meridian to
be studied with the form sections, and then we directly measure the
angle to angle and the sulcus to sulcus with surgical calipers.

So in fact, we have some eyes where we studied the vertical meridian and
other eyes where we studied the horizontal meridian, and this is
preliminary data and the study is not finished, but it\'s already very
interesting to notice that, for example, here, for the same measurement
of the white to white, which here is 11, we obtained real measurements
of the sulcus to sulcus which went from 11 to almost 13. So then if you
would choose an 11.5 ICL to implant in these eyes, what would happen
with the eyes between 12 and 13?

So I would like to mention the new technology that\'s being developed
that will help in the issue of the sizing, and I mention this device
because this is the device we are having the opportunity to work with
right now.

So we are working this protocol where again we use cadaver eyes and we
measure the anterior/posterior length, then we mark the 12 o\'clock
position, measure the white to white, and with this prototype of
ultrasound we are performing of the anterior chamber diameter and then
the sulcus-to-sulcus diameter. Then we prepare the eye with these
special techniques for fixation. We perform the sections in the region
we choose, and finally we perform the direct measurements of angle to
angle and sulcus to sulcus.

This is also preliminary data, but so far we analyzed nine phakic
cadaver eyes, and if you compare the angle-to-angle measure by calipers
and ultrasound, the results are very similar and this is valid also for
the sulcus to sulcus, and this is also valid for pseudophakic cadaver
eyes we analyzed. So far, we analyzed only six.

When you look at the pictures you obtain with the ultrasound, in fact
they apparently reflect very nicely the morphology we obtain after the
fixation of the specimen, which allows us to perform the measurement
which appeared to be very accurate. So here you have an example of a
phakic cadaver eye, and here the same analysis is performed in the
pseudophakic cadaver eye.

Of course, this technology is going to be extremely important in the
follow-up of patients implanted with different phakic IOLs. It will be
important for the measurement of the distance between the edge of the
lens and the mid-periphery of the cornea. For example, in the phakic
anterior chamber intraocular lenses, and also extremely important to the
measurements of the posterior surface of the lens and the anterior
surface of the crystalline lens in phakic posterior chamber IOLs.

So let us review briefly the surgical implantation. We have to remind
you there are lots of opportunities for the surgeon to create the
cataract observed in the postoperative period.

So the first thing the surgeon has to do is in fact to perform these YAG
laser iridotomies. In general, they use two superior iridotomies placed
90 degrees apart, and this is performed one or two weeks before surgery.
There are some studies indicating that these have eventually a
cataractogenic effect also and that they contribute to pigment
deposition which we always observe on the surface of these lenses. Also,
in an alternative way, the surgeon can perform one single surgical
iridectomy.

After that, the surgeon has to perform the incision. These are foldable
lenses, the incision is very small, and it can be used to correct
preexisting astigmatism. The surgeon has to inject viscoelastics, which
is extremely important in the protection of intraocular tissues and also
to allow the lens to unfold in very controlled manner.

Both lens types can be inserted with forceps and also injected within
the anterior chamber, and then finally the haptics will be placed behind
the iris with spatulas or hooks, and this is a very important step
because no pressure should be placed on the crystalline lens at that
time. Then the pupil is constricted with miotic agents, the viscoelastic
is removed, and the wound is closed.

So of course, the crystalline lens should ideally not be touched at all
during the whole surgery, but as you can see, there are many
opportunities to have accidental contact with the anterior capsule of
the crystalline lens not only during the placement of the haptics behind
the iris, but also injection of viscoelastic behind the iris, et cetera.
So anterior capsule trauma, as we review the literature, you will notice
that this may lead to crystalline lens opacities months later after the
procedure.

There are some studies indicating that in many ways high myopic patients
are going to have cataract and with earlier onset. For example, I can
cite this study indicating that moderate to high myopic patients had an
association with age-related cataract. For lower levels of myopia, this
relationship has been disputed. They also indicated that early onset of
myopia is a strong independent risk factor for cataract.

But we can not forget that they are talking here about age-related
cataract. They are talking about mostly nuclear cataract, and when you
review the different forms of cataract according to the age they appear,
you\'re going to notice that anterior subcapsular cataracts are very
rare forms of age-related cataract unless they are caused by
inflammation or injury.

So I\'d like to summarize some of the specimens we are receiving in our
center. We had the opportunity, as I mentioned, to analyze some silicone
Chiron Adatomed lenses and we have recently received eight ICLs, all
explanted because of cataract formation. There are some bilateral cases
and the lenses were explanted between one year and four years after
implantation.

Here you have some examples. This is one of the eyes of the patient, and
here the corresponding ICL explanted from this eye, and this is the
contralateral eye and the corresponding ICL explanted from the eye. So
this surgeon not only submitted the ICL he explanted, but also he
submitted the fragment of capsular excess while he performed the
cataract surgery.

So in general, when you analyze the surfaces of these ICLs, you always
find some pigment deposition, as you can observe here, and in these
specimens, stained with different techniques, you always can observe the
fibrocellular tissue attached to the inner surface of the anterior
capsule which is corresponding to the opacity.

This pigment deposition can be very discrete, as in the previous case,
but it can also be very important, as you can see here in this bilateral
case. These lenses were also explanted because of cataract.

What about the mechanisms of this cataract formation? This study is very
interesting because it summarized many of the factors that are
eventually important. So these patients were implanted with the ICL and
they observed an anterior chamber reduction in 9 to 12 percent of the
cases. Central endothelial cell density decrease, not progressive, but
very interesting, they report an increase of the aqueous flare in 50
percent of the cases with stabilization, but always above preoperative
values. They reported progressive decrease of crystalline lens
transmittance with time, contact ICL iris in all eyes, peripheral
contact ICL and crystalline lens in 60 percent of the cases, central
contact of the ICL and crystalline lens in 15 percent of the cases, and
changes in ICL axis in 10 percent of the cases with rotation of the lens
in the postoperative period. But they didn\'t observe any cataract
formation after the follow-up.

So of course, we mentioned already surgical trauma can cause these
cataracts were are observing after implantation of phakic lenses. We
cannot forget the possible effect of the YAG laser for the iridotomy. We
cannot forget the accidental contact of the anterior capsule is possible
during different surgical steps. Intermittent microtraumas can also
cause these cataracts. There is an increased crystalline lens curvature
during efforts for accommodation. It was demonstrated that the lens can
rotate inside the eye in the postoperative period, and of course, there
is always an increase in the overall lens size throughout life, so the
distance between the phakic lens and the crystalline lens is not always
going to be the same.

So what about constant trauma? This apparently is extremely important.
So here in cases of clearly undersized lenses, there would be a large
area of contact between the lens and the anterior surface of the
crystalline lens.

Also, there is the possibility of a continuous disruption of the
blood/aqueous barrier with subclinical inflammation, and this is caused
by friction between the iris and the phakic lens, and eventually by the
ciliary sulcus fixation also. These have effects not only on the
crystalline lens transmittance, but eventually on the corneal
endothelium.

What about crystalline lens metabolic and nutritional disturbances? We
already commented on this situation, for example. There is a pool of
aqueous humor stagnated between the lens and the anterior surface of the
natural crystalline lens. So this could be caused by the previously
mentioned subclinical inflammation, but by any cause of blockage of
normal circulation of the aqueous humor.

When we reviewed the literature, in fact we performed a review from \'96
to 2002, and we could only find studies regarding the early Fyodorov
lenses, the Chiron Adatomed silicone lenses, and the ICLs. We could not
find any studies regarding the PRL. I\'d like to comment on some of
these studies because they have very interesting points which are
eventually very important.

So for example, in this study of patients implanted with the Chiron
Adatomed silicone lens, there was no space between the phakic lens and
the natural crystalline lens in all cataract cases, which places
eventually this factor as one of the most important factors.

In this study by Zaldivar and coworkers and studying patients implanted
in the ICL, he reported one eye with a peripheral anterior subcapsular
opacity which developed in the region of the peripheral laser iridotomy,
showing again that these iridotomies eventually have a cataractogenic
effect.

So this group in Brazil studying patients implanted with the Staar ICL
reported an anterior subcapsular opacity in the central non-contact
area. So the contact eventually is very important, but maybe there are
other factors or maybe the follow-up was just not enough.

This group, also studying patients implanted with the ICL, reported
anterior subcapsular opacity which developed 24 hours after surgery. So
we may think that this was really caused during the surgery and not by
the lens itself.

So this group reported one case of nuclear cataract in a 53-year-old
male. He had already some degree of nuclear sclerosis, so of course,
this is not the kind of cataract we are talking about here. This is
maybe just age-related cataract and is not related to the procedure and
not to the lens also.

This is one of the very few studies which really describes the evolution
of the opacities. So they describe opacities which appeared superiorly
and then progressed involving the optical zone, and in all cases there
was in fact a satisfactory central ICL vaulting in the cases of
cataract, indicating that in these particular cataract cases, the
contact was not the most important factor. I like to cite this study
because in general there are many surgeons that would say that some
peripheral opacities would never progress.

Finally, this is maybe the only study which compares patients implanted
with an ICL in one eye and the Chiron Adatomed silicone in the other
eye, and they demonstrated that the silicone lens was associated with
more cataracts and the cataracts appeared earlier in the postoperative
period. In all cases, no space was observed between phakic lens and
natural lens, so again, here we believe that the contact is the most
important factor.

So when you group all these papers together, it\'s a big problem to
really understand what is the real incidence of cataract. With regards
to the silicone lens, the rates vary from 0 to 52.9 percent and
regarding the ICL, they go from 0 to 25 percent.

So why is that? First of all, because the definition of cataract and
opacity is really not the same, some surgeons will report just the
cataracts that are creating visual problems for the patient, and some
opacities that are not decreasing the visual acuity would not be
reported.

Also, there is such a variation in the age of the patients included, and
also such a variation in the follow-up considered, and in some studies
they would say that the follow-up is from three months to two years, but
in fact maybe just two patients had the follow-up of two years and the
great majority were followed up for six months only. And in some studies
‑‑ for example, for the ICL ‑‑ during the same study different models of
the same design were implanted, and you know with different vaulting
characteristics, so the effect for cataract formation would not be the
same.

So there is a great need of standardization of these studies evaluating
cataract formation. First of all, the parameters used for the YAG
iridotomies should be described, because eventually this is
cataractogenic. All trauma to the anterior capsule during this surgery
should be noted for future reference. A follow-up period should be at
least two years because in fact, according to the literature, the
majority of cataracts appear between one and two years after the
procedure. And of course, we have to evaluate very nicely the
relationship of the phakic lens with anatomic structures because the
contact is one of the most important factors.

Also, of course, we need a very accurate method to choose the IOL size.
To use just the white to white to choose the overall size of the lens
that\'s going to be implanted is not accurate at all, and that\'s why
we\'re having so many complications, and this could really be avoided.

There is a need of evaluation of subclinical inflammation with laser
flare meters because in some cases, there was a very good vaulting lens
and a cataract appeared anyway.

There is a need of evaluation of explanted phakic lenses with
histopathological analysis of adjacent tissues, but if you ask me right
now if just with histopathologic studies alone we will be able to
differentiate cataracts caused by the surgeon and cataracts caused by
the lenses, the answer is that we don\'t know yet. We have just one
specimen and we would like to look for more specimens to have an
impression about that.

And of course, we need to describe the evolution of the anterior
subcapsular opacity.

So let\'s talk about the possibility of a classification for cataract
formation after phakic IOL implantation. So as I mentioned, some
surgeons would say that all the opacities they saw are peripheral and
they are non-progressive, but we have this paper indicating that the
peripheral superior opacity progressed, involving the optical zone. So
if you have a classification, we should maybe classify the opacity in
each visit to have an impression about the progression of the problem.

So as you know, there are systems for the classification of cataracts
and they are all based on standard retroillumination photographs and the
total area of the opacity. These are three well-known systems, the LOCS
system, Wilmer system, and Oxford system.

Here, we have some pictures showing how to classify nuclear, cortical,
and posterior subcapsular cataracts with the LOCS system, all based on
these standard photographs. This could eventually be applied to cataract
formation after phakic IOL implantation. This is how we grade the
cortical opacities according to the Wilmer system and this is the way we
score anterior subcapsular and posterior subcapsular opacities according
to the Oxford system.

Also, there are very sophisticated systems combining high-resolution
digital retroillumination imaging with image analysis systems, allowing
objective and quantitative measurement, for example, of posterior
capsular opacification, which eventually would be very useful in this
clinical situation.

So in a way, if there is a way to do a classification, this
classification should indicate the location of the opacity. For example,
peripheral or paracentral or central opacity. Also, maybe there is a
possibility to have an index for the intensity of the opacity, and of
course, we would have to score the area of the opacity, and by doing
that in each visit, we will have an impression about the evolution and
the progression of the opacity and we would really understand better the
phenomenon.

Thank you very much for your attention. Thank you very much again for
the opportunity.

DR. WEISS: Thank you very much for an excellent presentation. Would you
be able to take a seat at the table, and we\'ll open up to the panel for
some directed questions.

Dr. Bandeen-Roche, then Dr. Matoba, and then we\'ll continue around. Dr.
Bandeen-Roche?

DR. BANDEEN-ROCHE: Yes, I want to thank you for your presentation ‑‑
very clear ‑‑ and your careful recommendations about the data to collect
involving the surgery I think was great.

Just one brief question. You talked about the importance of tracking the
evolution of the cataract and discussed grading. What implications do
you think there are for the frequency of evaluation and do you think
that that should be by passive surveillance or by active surveillance?
Just elaborate a little bit more on how to track the evolution of
cataract.

DR. WERNER: I don\'t have a precise idea about when all these gradings
should be done. Of course, immediately after the postoperative period,
within one month to anything that\'s very fast developed, and maybe six
months, one year, two years, because this is what we see in the
literature.

But this is not only to just have the score. It\'s also for us to
understand the phenomenon because still there are many surgeons who
believe that the cataract is really not a problem because they have just
opacities in the periphery that never progress, and we need to
understand if they are not really progressing or he is just not
observing.

DR. BANDEEN-ROCHE: Thank you.

DR. WEISS: Dr. Matoba?

DR. MATOBA: In regard to the development of cataracts in areas of
contact between the IOL and the crystalline lens, how much do you think
the lens material or the nature of the lens material contributes or is
it mostly, you think, a mechanical effect?

DR. WERNER: Well, I don\'t know if I can answer this question because we
only have results about the ICL, which we know the material. There is
another lens made of silicone and I\'m not aware of their results, so we
cannot really compare if there is a material effect.

Also, as I mentioned, there are papers showing that cataract is formed
only in the area of contact. Other papers would say that it was formed
in a different area, but maybe the follow-up was not enough. So there
are still many questions about that.

DR. WEISS: Dr. Bradley, Dr. Huang, and then Dr. Mathers.

DR. BRADLEY: Just a clarification on the peripheral cataracts you
described. How peripheral are they and, for example, would they become
visually significant under nighttime viewing conditions where the pupil
would dilate?

DR. WERNER: Well, when you look at the literature, it is really not
described, and sometimes, in very early papers, they would describe some
peripheral opacities that would cause some glare in light conditions of
evening or something like that. But talking to surgeons, they would say
that the peripheral opacities which are barely visible in the pupil
dilation, they would not cause any problem.

DR. WEISS: Dr. Huang?

DR. HUANG: Two questions. The first question was regarding your earlier
presentation, you seem to have implied there were two types of cells
that were induced in the two different locations of the cataract. One is
A-cells induced in the anterior capsule, and then E-cells induced in the
posterior capsule. Is there any vital stain that can help you to
distinguish what type of cells are responsible for the evolution of this
cataract?

DR. WERNER: When you perform histopathological studies, in fact what you
see is that both cells are always involved in everything, but there is
always a predominate type. For example, even for PESU, you have a
fibrotic form of PESU and you have a firm form of PESU, and when you
perform normal stains, you can see even morphologically they are very
different because E-cells always have the tendency to be bloated, and
the other are elongated fibrotic cells, fibrotic-like cells.

DR. HUANG: In the LOCS III grading system, it\'s really a numerical
system and there is a highly individual variation. Do you have any
suggestion how to standardize if that system were to be chosen for the
cataract characterization? And also, I believe the LOCS III does not
have any geographical information about a cataract, and so do you have
any suggestion how to modify the system?

DR. WERNER: I believe there should be a geographic thing because it\'s
very important for the areas of contact who are outside the contact of
the lens. So in this case, it\'s very important.

But with regards to your first question, I think we should start by
collecting many pictures from surgeons to create standard pictures, as
they have in the LOCS system, and we have some, but we need more
pictures to have really different grading if we use such a system based
on standard photographs.

DR. WEISS: Dr. Mathers?

DR. MATHERS: Do you think that the photographs, the retroillumination of
the opacification, can the photographs detect smaller anterior
subcapsular cataract formation than the slit lamp can detect it? What do
you think is actually the finest, highest resolving method?

DR. WERNER: We have experience with these systems based on
retroillumination photographs for posterior capsular opacification, and
this is the best we can have for that.

DR. MATHERS: Do you think that\'s higher resolution than the human eye
achieves with the slit lamp?

DR. WERNER: Eventually, yes.

DR. MATHERS: Yes. And have you any experience using confocal microscopy,
which could actually focus onto the anterior capsule and have even
higher resolution? Do you think that that\'s possible?

DR. WERNER: Well, my own experience with confocal microscopy regards the
cornea, and I know that there are some objectives which you could switch
in some devices and have an imaging of the anterior surface of the
crystalline lens. I have no experience with that and I don\'t know if
there is any data available published about that.

DR. MATHERS: Sizing is clearly an important process here. Do you think
that the high-resolution ultrasound will give the best sizing data and
can that be used clinically to determine which size to put in?

DR. WERNER: We are evaluating this right now with these cadaver eyes.
The results have been very interesting. So I don\'t know exactly the
status of development of the technique, when it\'s going to be available
‑‑ maybe this year ‑‑ but apparently it\'s the best we can get for the
moment.

DR. MATHERS: Do you think that the issue of visual significance could be
assessed best with glare testing or what would you suggest as the most
significant, highest-resolving method to test the small amounts of
visual impairment you might get from an early cataract?

DR. WERNER: Yes, it is a very good question, because in some cases
discussed with the surgeon, the lenses were explanted because of glare,
and not really decreasing visual acuity. So glare is very important.

DR. MATHERS: You think it\'s better than contrast sensitivity testing as
it\'s normally performed?

DR. WERNER: Maybe both.

DR. MATHERS: Just your opinion.

DR. WERNER: Maybe both should be associated in this case, yes.

DR. WEISS: Mr. McCarley, did you have a question as well?

MR. McCARLEY: One question just quickly. In your experience, and maybe
one of the clinical ophthalmologists can answer this maybe even better,
a cell flare meter is used to determine subclinical inflammation. Is
that different in a posterior chamber lens than it would be, for
instance, in an anterior chamber lens?

DR. WERNER: Well, what we saw in the literature is that there are also
increased values of flare cell meter with anterior chamber lenses, and
apparently the values are even higher and they also stabilize above the
preoperative values, contrary to cataract surgery, where you have higher
values, but these have a tendency to come back to preoperative values
after one year or so.

DR. WEISS: If there are no other questions, I want to thank you, Dr.
Werner, for your excellent presentation.

We can move on to the open public hearing session. Is there anyone who
wanted to make any statements?

(No response.)

DR. WEISS: If not, I\'m going to put a question to the panel. If we have
perhaps a 15-minute coffee break and skip lunch, we might be able to
catch earlier flights, as I know is in the interest of some. Are any of
you interested in doing that, taking a 15-minute break, rather than ‑‑
so we have two hands up for Dr. Bullimore and Dr. Matoba, and Dr.
Mathers for sure. I would say that passes without a formal vote.

So we\'ll take a 15-minute coffee break and we\'ll see you back here in
15 minutes.

(Recess.)

DR. WEISS: We will now start the FDA presentation and Donna Lochner will
introduce the questions for panel discussion.

MS. LOCHNER: Yes. I\'m just going to go through the questions and give a
little bit of background to where we were coming from with each
question.

We\'re going to begin today with the endothelial cell density study.
After I\'ve stepped through this question, I\'ll turn the floor over to
Dr. Grimmett, and then the panel will discuss the endothelial cell issue
before going on to the next questions.

First, \"Please comment upon the inclusion criteria recommendations
found in Table 1.\" This topic is still being actively discussed, and
particularly with the ANSI Standards Committee, and so we believe any
comments will be very timely.

Table 1, which is just shown right here, provides the recommended
minimum endothelial cell densities, and these values for minimum
endothelial cell density are generally being used in current U.S. phakic
IOL studies. These values were determined over the course of several
meetings over the years with input from FDA, industry, and
ophthalmologists that attend these standards meetings. Allow me to
hopefully clarify how the minimum densities per age category were
determined.

This slide is included as Attachment B in the handout. First, the
approximate initial cell density for a 21-year-old, as shown in the
second column in this table, was taken from the 1997 Moller-Pedersen
article and the citation for this article is provided in the handout,
but not on this slide.

For the 35- and 46-age categories, the cell density at time of implant
was approximated by assuming .6 percent yearly cell loss due to normal
aging, with the .6 percent figure taken from the 1997 Bourne article, as
referenced earlier by Drs. Edelhauser and McCarey. This was done to
provide a check of whether the minimum inclusion criteria per age group
were reasonable.

The third column, the estimated rate of cell loss per year, represents
potential rates of loss due to the phakic IOL. In other words, 1.5 and 2
percent assumed loss from the phakic IOLs were used as examples to then
calculate the age when the cell density would be less than 1,200 cells
per millimeter squared and less than 1,000. These ages, shown in the
fourth and fifth columns, assume a surgical loss of 10 percent and
compound the 1.5 and 2 percent loss annually.

Finally, in order to determine the minimum cell density inclusion
criteria, we looked at the starting densities that would ensure greater
than 1,000 cells at age 70 for the 21- to 25-age range, and at 75 for 26
and older.

So this table verifies that the minimum inclusion criteria, as shown on
Table 1, would be sufficient in a worst case situation to allow for
adequate cell density for the health of the cornea for roughly the life
of the patient, assuming a 2 percent annual loss from the phakic IOL and
that patients would have at least 1,000 per millimeter squared at ages
70 to 75.

As you can see, there are various assumptions inherent in the inclusion
criteria and because of the iterations this has undergone because of the
committee process, we are very much interested today in the panel\'s
comments on this inclusion criteria.

Our statistical calculations suggest that 200 subjects should be
sufficient to detect a 2 percent loss using measurements at multiple
visits in order to establish linearity of the loss. The measurements, as
currently proposed, would taken at the three- or six-month visit, the
12-, 24, and 36-month visits.

Further, although the statistics suggest that 200 subjects would be
sufficient, we recommend that specular microscopy be performed on all
subjects enrolled in the study to ensure that 200 analyzable photographs
are obtained.

Last, we recommend that multiple images be captured at each visit and
the mean endothelial density from those multiple images be used in the
analysis.

We are asking for panel comments on these criteria as well.

Now, I\'d like to turn the floor over to Dr. Grimmett for his review.

DR. GRIMMETT: Thank you, Donna.

This is Michael Grimmett. I\'ve prepared some comments in outline form
which at least the panel members should have on their table. It\'s a
10-page outline, and I promise to go very quickly through it. There are
four tables as well.

Regarding the questions, I think I\'ll go through my outline first. I
was doing the bulk of this thought process and review prior to having
the questions. I was doing the work, I\'d gone on vacation out in Santa
Fe, and I\'m relieved and grateful that in the open public hearing
session, my wife did not comment on the timing of that review.

(Laughter.)

DR. GRIMMETT: Notwithstanding that, I think I\'ll do this review first,
and then we\'ll come back to the questions if some of the issues are not
resolved.

Just in general, and some of this has been alluded to by the previous
speakers, the peer-reviewed literature on phakic IOLs has numerous
limitations, and it\'s important to recognize that when reviewing any
data that\'s reported in the literature. Mostly, the data are
retrospective in design, they\'re non-randomized case series, they have
extremely low numbers of eyes reported, there is poor accountability for
the longer follow-up intervals, and in general morphometric endothelial
analyses are not generally reported. So coefficient of variation and
percent hexagonality are not there.

Additionally, my review is not exhaustive or comprehensive.

I think it\'s instructive to look at phakic IOL types because we can
separate them into three different animals that have different
implications for the corneal endothelium. I\'ve separated them into
anterior chamber type and posterior chamber type. Of the anterior
chamber type, there are two, angle-supported and iris-fixated.

Looking at the literature on the angle-supported lens, I\'ll just give
you a smattering of some articles to go over what are reported
endothelial cell losses and what\'s known about design parameters that
would impact our recommendations regarding future phakic IOL studies.

To start with, angle-supported lenses, a first-generation lens, the
Baikoff ZB lens, had a distance between the IOL edge and the endothelium
of only 1.16 millimeters, and that was the key factor. It was determined
that there was a high endothelial cell loss secondary to excessive
contact between the IOL optic edge and the endothelium. One report by
Jimenez-Alfaro reported a 16 to 18.8 percent loss at one year and a 20
to 28 percent loss at two years. Another report reported up to 56
percent loss with a shorter follow-up. Of the second report, 37.5
percent had morphologic or cell density changes.

Quotes in these articles include \"We have stopped doing this surgical
procedure\" and \"Further implantation of this IOL is unacceptable.\"

The second-generation lens, the Baikoff ZB5M lens, was manufactured
until 1997. The major difference here is that they increased the
distance between the IOL edge and the endothelium, increasing that to
1.56 millimeters. Endothelial cell loss in one study was reported at 4.5
to 5 percent cell loss at one year, 5.6 to 6.8 at two years, and 5.5 to
7.5 loss at three years.

A separate study by Perez ‑‑ forgive me for my pronunciation ‑‑
Perez-Santonja found an endothelial cell loss of 12.33 percent at one
year and remaining relatively stable at two years.

Then the larger study was recently reported in Ophthalmology found that
at one year there was a 5.53 percent loss, and interestingly, after year
2, while the numbers fell down significantly in terms of total eyes
examined, the overall loss approximated normal aging losses. That is,
preop to year one was at 5.5 percent loss; year 1 to year 2, 1.37
percent loss; year 2 to 3, .72 percent loss; year 3 to 4, there was a
.28 percent loss; year 4 to 5, there was a .55 percent loss; year 5 to
6, .37 percent; and year 6 to 7, .56 percent.

So based on this study, and the reason I find this instructive, is that
they give us some information regarding what is a reasonable duration to
follow these particular lenses before they come to the panel. If we take
this data, which is one of the largest subsets that I could find in the
published literature, in year 3 they still had 157 eyes, albeit they\'re
mixing lens times. They\'re either started or stabilized, and they found
stabilization from the two- to three-year period, and you can tell three
years is the appropriate duration of a study.

A fourth-generation lens, ZSAL-4 by Morcher, had a distance from the IOL
edge to the peripheral cornea of 1.65 millimeters and they reported an
endothelial cell loss of 3.5 percent at one year and 4.2 percent at two
years, albeit the numbers are low. There are only 18 eyes. They
commented that there is a fifth-generation lens, but I could not locate
it in the published data regarding this product.

Another anterior chamber angle-supported lens in the literature is the
Nuvita lens by Bausch & Lomb, and it\'s a single-piece PMMA IOL. In one
study of 21 eyes by Allemann in Ophthalmology, they reported a 10
percent cell loss in the first year, another 4.3 percent in the second
year, and, given these large numbers, certainly if that were to come to
the panel, I would want to see more data.

The next category of anterior chamber lenses are iris-fixation lenses. A
Worst-Fechner lens developed in the late \'80s, one particular study
just reported two eyes of greater than 50 percent cell loss, but they
didn\'t provide any mean cell density analyses or morphometric analyses.
A separate study in 1996 by Perez-Santonja reported a 13 percent loss at
one year, another 4.6 percent at two years, indicating to me that the
central endothelial cell loss did not stabilize over a two-year period.
The N was only 30 in this particular study.

The Artisan or Iris-Claw lens, the prior nomenclature which is
unfortunately called the Worst Iris-Claw lens ‑‑

(Laughter.)

DR. GRIMMETT: Those are synonymous as far as I understand. There may be
some design changes I\'m not aware of, but I believe they\'re in the
same family.

It had reported some distances from the corneal endothelium in various
publications. For example, a -15 diopter lens with a 3.2 millimeter
anterior chamber leaves 1.97 millimeters from the corneal endothelium.
Because these lens are fixated at the iris itself and not vaulted above
the iris, certainly you would expect more distance, and this is what
we\'re seeing. There\'s more distance from the endothelium. So the
angle-supported lenses, in my view, given their proximity to the cornea,
have a higher risk to the corneal endothelium than, let\'s say, an
Iris-Claw lens, assuming that the anterior chamber (inaudible) is
constant, whatever it happens to be.

Looking at some data regarding endothelial cell loss on the Artisan
lens, a study by Menezo showed a 6.6 percent loss at 12 months for 109
eyes and 9.22 percent at two years, but I think it\'s instructive just
to look at the differences. It\'s 6.6 percent preop to year 1; 2.63 year
1 to 2; 2.5 percent year 2 to 3; 1.74 year 3 to 4.

They found that the cell loss correlated to increased power of the lens,
the thicker lens ‑‑ that is, perhaps closer to the endothelium ‑‑ and
shallower anterior chamber depth, which would also tend to bring the
lens closer to the corneal endothelium.

This particular study reported morphometric measurements regarding
percent hexagonality and coefficient of variation.

They also find some changes that I found instructive. They found that
there were statistically significant decreases or changes at six months
and then return at approximately two years with gradual resolution back
to near preop factors in their four-year study.

Then the final category of lenses would be posterior chamber lenses,
which we\'ve heard a great deal about already here today by the
speakers. Dr. Werner\'s excellent presentation showed us pictures of the
Fyodorov posterior chamber lens, which is not in general clinical use,
with cell losses of 10 percent at 12 months.

Interestingly, the Chiron Adatomed lens that Dr. Werner indicated was
pulled because of cataract formation, at least the two studies I pulled,
did not report any endothelial cell data whatsoever, reports by Fechner
and Marinho. I didn\'t locate any other studies on those lenses.

The Staar Surgical ICL that we heard about today already, one study by
Zaldivar of 124 eyes didn\'t report endothelial cell counts, and in
another study by Arne, cell loss was actually remarkably low, 2 percent
at 12 months and 2 percent at 24 months, and no eye had an endothelial
cell loss greater than 3.8 percent at one year in 58 eyes. Since these
lenses are in Phase III trials, I\'m certain there\'s some data targeted
and reviewed by the FDA in a confidential fashion regarding larger
sample sizes.

Knowing what the literature has to say about endothelial cell loss and
the differences between these three types of lenses would help us give
guidance regarding future manufacturers\' studies. It\'s important, as
Dr. Edelhauser alluded to, to look at normative data, so that we know
what the natural rate of loss is for corneal endothelium in order to
gauge our comments.

Rates of normal endothelial cell loss range between .3 and 1 percent per
year, depending on where you look. I\'ve quoted the various studies. The
Bourne article in 1997 with the .6 percent rate is frequently quoted,
but there are slight differences in the literature in that regard. It\'s
in somewhere in that range.

As far as surgical procedures, we all know that operative procedures can
create both a direct surgical instantaneous hit to the endothelium as
well as possibly change the annualized cell loss rate. Cataract surgery
as far as Bourne\'s article in 1994 reported a mean 2.5 percent cell
loss per year over a 10-year period. It\'s important to realize that
these were intracapsular and extracapsular surgeries with iris-sutured
lenses, transiridectomy clip lenses, and a few posterior chamber lenses.
There are some other articles that indicate that cataract surgery causes
a 1.1 percent cell loss rate per year, and a Werblin article in \'93
said that one year is an 8.8 percent loss, and you\'ll note that in the
FDA table previously shown by Ms. Lochner and in some of the assumptions
I\'ll later make, we just round that figure to a 10 percent surgical
loss at the time of the procedure, which obviously is different from the
future cell loss rate that may be increased over normal.

As a point of interest, penetrating keratoplasty has a 7.8 cell loss per
year.

I went ahead and quoted the age-stratified normal endothelial cell
density values, both from the Yee article in 1985 as well as a
pathologic analysis. The difference between the studies, one is specular
microscopy, the other is pathologic. I found they were similar in terms
of mean values. The lower age bracket, age 20 to 29, they start at 2,900
cells and by the time you get up to age 80-89, there are 2,300 mean
cells. The main difference is in the standard deviations.

Dr. Edelhauser earlier indicated that the non-contact robo data agrees
with the Yee data, and I quite frankly find the standard deviation
values in the path study to be huge, plus or minus 500, plus or minus
690. In talking with Dr. Edelhauser on the break, he\'s going to look
further into the Moller-Pedersen article regarding the standard
deviations, but I tend to gravitate toward the Yee article with the
standard deviations.

The peripheral cornea, if measured, is known to have increased cell
density. Per some data that Dr. Edelhauser provided, there\'s a 5.8
percent increase in cell density in the paracentral region and a 9.8
percent increase in the peripheral cornea.

The next category that I did, knowing the peer-reviewed literature and
now knowing normative data, is I tried to determine what would be some
thresholds for unacceptable rates of endothelial cell loss. There are
two different questions, I believe.

One, as a panel member, when an application comes to panel, we all be
concerned about what is an acceptable cell rate when we get that
application with a particular observed cell loss rate. The reason it\'s
important to get some judgement about acceptable cell loss rates now is
it will help us give guidance regarding what or how low should
thresholds be that we\'re actually trying to screen for to make the
determination how big the sample sizes must be. So we have to have a
sense for what are the maximum and minimum ranges for thresholds that
we\'re even looking at, so we can give some type of guidance regarding
sample sizes.

I certainly don\'t expect anyone right now to define an acceptable cell
loss rate. That will certainly be a hotly debated topic once an
application\'s received, but I think it\'s instructive that we go
through the exercise to see what our limits are, maximum and minimum
unacceptable rates of cell loss.

I\'ve approached this argument by first looking at life expectancy data.
The RP-2000 mortality table is based on a study of the mortality
experience of pension plans conducted by the Society of Actuaries and
was in response to pension legislation that directed the Secretary of
Treasury to promulgate the use of updated mortality tables for various
pension calculation purposes.

According to that table, the life expectancy for a 21-year-old male is
58 future years or an age of death of 79. The life expectancy for a
21-year-old female is 62 future years, so an age of death of 83. Those
are United States data.

Realize that depending on your entry date, you\'ll have change,
obviously, to your age of death. If you enter at age of 80, you don\'t
have an age of death of 79.

(Laughter.)

DR. GRIMMETT: But I used it as a fixed value for this particular
analysis, so as to not get confused with multiple iterations of the
tables. Suffice it to say that when you enter at 20, 30, or 40, it may
only differ by a few years in terms of your age of death.

The minimal acceptable corneal endothelial cell density value is
critical, and Ms. Lochner presented a table regarding a 1,200 threshold
and a 1,000 threshold near death. I picked values on either side of the
range to show the range of acceptable cell loss for sake of argument.

In one of Dr. McCarey\'s earlier versions of a slide, he quoted a
minimal acceptable rate of 1,500 cells. Whether we call that number
1,500 or 1,400 or 1,300 or whatever it\'s picked as is not really the
crucial value, but I think a larger number has the argument that if
these patients get into any kind of trouble with their phakic IOL,
number one, it allows you to do a surgical procedure to possibly correct
that, whether it be explantation of the IOL or manipulation of the IOL.

Secondarily, we all know as clinicians that as patients enter their
early 70s, they have a much higher likelihood of having us see them with
cataracts just from age-related phenomena. Whether or not it\'s
increased with phakic IOLs remains to be determined, but this larger
target value near or at the age of death will certainly allow a future
intraocular surgical procedure, such as cataract surgery. If we run all
of our calculations and run them right down to the wire and leave them
the bare minimum and leave half of the years to the time of death, you
are not giving that patient the opportunity to have any intraocular
intervention of any kind. So that\'s why I picked the number of 1,500,
and Dr. McCarey in an earlier version happened to put that number there,
so I went with it.

The next number I used is a potential corneal edema of 800 cells per
square millimeter. Acceptance of this particular target will not allow a
future intraocular procedure, in my opinion, and certainly if I had a
patient of advanced age with immense nuclear sclerotic cataract
requiring higher phaco times, I would not be comfortable performing
phacoemulsification with entry cell count of 800. I would certainly
advise the patient clinically that they would have a higher chance of
having postoperative corneal edema.

In the literature, there\'s been a quote of 500 cells for imminent
corneal decompensation, but I think it depends on the actual function of
the remaining cells. So the exact, precise figure is not locked down,
but in my opinion, clinically it\'s somewhere in the area of 800.

The assumptions I made for my threshold analysis is that the endothelial
cell loss, as calculated, was an instantaneous, exponential endothelial
cell loss rate, that they lose 10 percent at the time of the surgical
procedure, and then they have a continuous stable annualized exponential
cell lose rate after that time. I used a round down analysis of any
remaining fraction. I used .99 rounded down because partial cells do not
survive.

I did not alter the life expectancy target values, as I had previously
mentioned.

Table 1. I\'m not going to go through this, obviously, in detail, but
all I did is create an Excel spreadsheet with a formula. I set the
target at the end at 1,500, I set the percent drop per year, and I was
back-calculating the cells you would need to enter the study. That\'s
all it is. So I was trying to find out what cell count would you need at
age 21 in order to end up with a cell count of 1,500 at the time of
death for male or female, and then supplying the percent drop per year.

For that particular assumption, 1,500 cells at the time of death, 2
percent cell loss per year, I found, for example, age 21, you need 5,900
cells if you\'re female and you need 5,400 male. Not possible. We looked
at the normative data and those numbers exceed the normative data.

So the conclusion from that scenario is that if a 1,500 cell target is
desired at death, a 2 percent annual cell loss rate is not acceptable.
It\'s not possible to enter with a high enough cell count for all but
the very older age ranges. So everyone will fall below 1,500 because you
can\'t enter with a high enough cell count.

I did that same type of analysis trying to bracket what would be
inclusive of all ages in order to allow everyone to enter the study. A
1.5 percent cell lose rate, which is Table 2, they\'re still entering
with some very high cell counts. At age 21, for example, 4,300 for a
woman and 4,100 cells for a male.

The conclusion from that scenario with 1,500 target and 1.5 percent cell
loss is that no one could enter with a high enough cell density, except
those older than approximately 50. So that cell loss rate is
unacceptable, the 1.5, if you\'re targeting for 1,500, that target, of
course, having the advantage of allowing someone in the future an
intraocular surgical procedure.

It turns out a .9 percent cell loss rate per year allows all ages to
enter with a reasonable cell count that could be achieved based on the
normative data. The .9 percent cell loss per year on Table 3 shows all
the entry cell requirements, and they reasonably match or were below the
normative data for all ages, telling us that the cell density values
will approximate or exceed 1,500 at the time of death for all patients
entering the study.

So the .9, assuming you\'d want 1,500 to be your target, is the maximum
allowable rate that\'s inclusive of all ages, and that rate is
approximately 50 percent higher than the normal of .6 percent cell loss
rate per year. We\'ll later hear from our statisticians regarding the
feasibility of trying to read for that low level of cell loss rate in
the face of the variability and precision issues that Dr. Edelhauser
brought up, because it\'s my opinion, based on review of some initial
data, that the sample sizes would have to be unreasonably large.

Just as an example from the literature, an angle-supported phakic IOL
from Alio, 1999, has a cell loss rate of .72 percent from years 2 to 7
after experiencing a 6.83 percent loss from preop to year 2. So based at
least on something in the literature that the numbers are not huge,
it\'s doable.

Looking at it a different, looking at the target of 800, so running
right up to the edge of corneal edema, I can give you all the tables,
but the number that I am giving you is 1.9 percent cell loss rate per
year. That number of 1.9 percent cell loss rate per year would allow all
patients to enter based on the normative data.

So if you desire an 800-cell target value, a 1.9 percent rate of annual
endothelial cell loss is the maximum allowable rate of loss that\'s
inclusive of all ages, and that\'s about three-fold higher than the
normal .6 percent rate per year, and at least based on the Menezo 1998
Artisan lens data, I have an average cell loss rate of 2.28 percent from
years 1 to 4.

Based on all these analyses and review of the literature, I went ahead
and just prepared a bunch of different issues that I would want to see
or issues that I would want considered in phakic IOL studies regarding
the endothelium, and then we can back to the specific endothelial
questions. Most of the question issues I believe will be covered.

General issues that I would have for all phakic IOL studies is that
certainly endothelial cell density measurements are mandatory. We saw in
some of the published literature it did not report endothelial cell
densities whatsoever, which I think is unacceptable for a new product of
this design because it\'s a critical issue for the survival of corneal
health.

Certainly, a central count is mandatory. A peripheral count will be
important, especially if it\'s an anterior chamber lens. You\'d want a
cell density in the region near the IOL edge or in the area of minimum
distance between the IOL and endothelium. That was learned from early
lens design. So especially with an angle-supported lens, I would be
highly interested in reviewing the peripheral cell count.

It is my belief that morphometric analyses are mandatory. We know that
analysis of cell shape and size provides a more sensitive indication of
endothelial cell damage than cell density alone. I understand the
limitations of the issues, as Dr. McCarey and Dr. Edelhauser have
outlined, regarding the coefficient of variation and the reliability,
especially with the algorithms of the non-contact robo. Notwithstanding
those limitations, I still feel it\'s an important variable to consider
and may give us some additional information.

Just as a matter of course, corneal pachymetry, corneal functional
analysis, most certainly would be suggested.

The duration of the study that I would be interested in prior to that
study coming to panel would be three years. Based on the literature, it
seems like there is an initial larger decrease and subsequent next
decrease, and then stabilization after a year or perhaps two to three.
Depending on what is seen in panel, it would be my guess that there
would be discussion of postmarket surveillance of endothelial cell data
for possibly a year or two more.

There are some data that it may take four years to see the morphometric
data return to baseline levels and ensure stability, but I do not
believe, based on what I\'ve seen in the peer-reviewed literature and
based on my concern about the corneal endothelium, especially for
anterior chamber lenses, that I would be comfortable approving a lens
with only two years of data. So for me, three years would be the minimum
I would favor.

I would favor a longer endothelial study duration, perhaps
postmarket-mandated, for higher risk factors, such as angle-supported
lenses, which have a higher risk to culture the endothelium than
iris-fixated lenses, which are closer than posterior chamber lenses.

The same issue. Thicker lenses are closer to the endothelium than
thinner lenses. So we would want longer follow-up for those.

A shallower anterior chamber depth, such as hyperopic patients, would
have a higher risk than deeper anterior chamber depth, perhaps if the
IOL is closer to the endothelium, and certainly chronic anterior chamber
inflammation, as previously mentioned, would be a higher risk factor for
endothelial loss than a quiet anterior chamber.

Interestingly, in one early, approximately 50-page paper by Drews in
1991, he went over study parameters versus the FDA grid regarding what
he would expect for phakic IOLs, and he recommended a five-year study
duration. I certainly don\'t disagree with that, given the importance of
corneal endothelium.

With respect to anterior chamber phakic IOLs, we know that the
optic-endothelium distance plays an important role in potential
endothelial damage. Therefore, high-resolution ultrasound, as mentioned
by Dr. Werner, I believe would be mandatory to disclose the
optic-endothelial distance and distances between other eye structures
and the IOLs, such as the crystalline lens.

The peripheral endothelial cell density and morphometric measurements
would be mandatory in my opinion in the region of the IOL optic edge, in
addition to the central endothelial analysis, because if the examination
is limited to the central cornea, it may fail to detect significant
endothelial injuries, and then specular images can show significant
morphologic changes over the edge of the IOL in the absence of central
cell density changes.

I would caution that a preop history of eye rubbing may be a
contraindication for entry into the study, especially when we\'re
talking about such low tolerances between the distance between the IOL
edge and the corneal endothelium.

Depending on the IOL design, such as an angle-supported lens, a
manufacturer must specify a minimum anterior chamber depth that
contraindicates IOL insertion.

Because chronic inflammation is a known factor in endothelial damage and
because some studies have disclosed chronic anterior segment
inflammation after phakic IOLs using a laser flare cell meter, I would
recommend laser flare fluorophotometry to evaluate chronic anterior
chamber inflammation, and just raise the question would iris fluorescein
angiography be of any help if a lens were either rubbing the iris or
directly affixed to the iris? So that would be an issue that perhaps in
a small subset of patients in early studies may be relevant.

Posterior chamber phakic IOLs certainly would have advantages for
corneal endothelium. They would have a maximum distance between the IOL
and the endothelium. They would avoid optic-endothelial contact, but of
course, their location behind the iris would have a higher risk for
pigment dispersion and introduction of cataract. If these lens induce
chronic anterior segment inflammation, they certainly may have secondary
effects on the endothelium, so I do believe that endothelial studies are
also important for posterior chamber lenses, irrespective of the fact
that they\'re the furthest lens away from the endothelium.

As far as that table ‑‑ now getting back to the two questions, I added
these last two portions right at the end. Getting back to the table,
what would be the recommended minimum endothelial cell density to enter
these studies? And we saw that table put forth by the FDA.

I see two approaches to attack the problem. One is standard deviations.
You could look at accepted normative data and say you don\'t want anyone
entering the study outside of, let\'s say, lower than, let\'s say, two
standard deviations.

Let\'s talk about two standard deviations. Assuming the standard
deviations are reasonable and your studies are reproducible, you would
want to exclude anyone out in that 2.5 percent tail, and I went ahead
and just listed the values as they would range from age 20 at about
2,700 going down to 2,400 or so by age 60. That\'s sort of one way of
looking at it.

The other way to look at it would be the way that the FDA has approached
it. Look at do you have enough cells to make it near the age of death?
And that\'s the other way to look at it.

In reviewing the FDA Attachment B, the threshold values selected don\'t
exactly ‑‑ they do not likely allow a patient to undergo a secondary
ocular procedure such as cataract surgery or further phakic IOL
manipulation during the life of the patient. I would have concerns as a
clinician if a patient had a cell count of 1,000 with a moderately dense
cataract doing a phaco procedure. I have to be worried that I might tip
them over into clinical corneal edema.

So I think we have to understand that the chart values selected, and I
selected 1,500 and the FDA selected 1,200 and 1,000, are variable
depending upon what our expectations are for these patients to have
elective procedures down the road, and it\'s impossible to precisely
determine the minimum entry requirements without knowing the exact rate
of endothelial cell loss per year at the various sites that run these.
So when we discuss that particular table, I\'m certain all those issues
will come into play.

The issue that I haven\'t addressed, and I\'ll leave it to the
statisticians, is regarding sample size analysis. Drs. Edelhauser and
Bernie McCarey talked about that in the best case scenario, the best
precision they can get on endothelial cell measurements is 2 percent and
real-world data is at 9 percent according to Dr. McCarey. I wold like to
know how that translates into the standard deviation values that our
statisticians have calculated regarding sample sizes, if that\'s known,
to see what kind of numbers we would actually need if we wanted to
screen for the lower rates of annualized loss.

That would conclude my introductory comments at this time.

DR. WEISS: Thank you very much for a very thorough, as usual,
presentation.

DR. GRIMMETT: Thank you.

DR. WEISS: Dr. Matoba has a question. Then we\'ll go around.

DR. MATOBA: Mike, I might have missed this, but when you did your
calculations, did you assume any amount of cell loss from the actual
surgery?

DR. GRIMMETT: Yes. I assumed a 10 percent instantaneous loss at the time
of the surgery based on the (inaudible) of having 8.8 percent with a
phaco procedure.

DR. WEISS: Mr. McCarley, did you have a question?

MR. McCARLEY: I just had a couple of questions. The 9 percent that
you\'re referring to is what Dr. Edelhauser and Dr. McCarey were talking
about? Weren\'t those the controlled laboratory percentages and not
actual real data?

DR. GRIMMETT: I believe it was real data from a real study, but we could
probably have Dr. McCarey answer it, but Dr. Edelhauser\'s number of 2
percent precision was sort of in the best of hands what is the best
precision.

MR. McCARLEY: Right, exactly.

DR. GRIMMETT: And Dr. McCarey\'s number was in order to ‑‑ it might be
better to have Dr. McCarey answer, but I believe it was real data. I\'m
not sure how many eyes were in the study.

DR. WEISS: You can over there. As I recall, it was different centers,
with the variation 9 percent between different people reading the same
thing.

DR. McCAREY: Yes, it was real data from a clinical trial that
Medennium\'s working. It\'s the control data. There were 58 patients,
seven clinical sites. I just started to collect the data and asked the
question and came up with that answer.

MR. McCARLEY: Okay. I wonder is the FDA able to provide the panel,
especially the voting members and reviewers, with data that they
currently have on phakic intraocular lenses. In order words, the
endothelial cell data that has come already out of the studies? There
must be over 2,000 implants so far over ‑‑

MR. WHIPPLE: You mean the ones that are under IDE?

MR. McCARLEY: Pardon?

MR. WHIPPLE: Dave Whipple. You mean the ones that are already under IDE?

MR. McCARLEY: Yes, correct.

MR. WHIPPLE: We can summarize it.

MR. McCARLEY: In other words, we\'re reviewing the literature and making
decisions based on the literature, and a lot of these have been
recognized as being small studies. We don\'t know what methodology was
used to validate ‑‑ the validity of the methodology and so forth. A lot
of reference goes back to original studies that are even from the 1970s,
from Bourne and group, and of course, he did a later study, but he did
longitudinal study showing I think 10 years\' follow-up.

But I\'d be curious, one, is can the FDA provide the panel members with
the data that they have now to show them what the standard deviation is
right now?

MR. WHIPPLE: Yes. They\'re special government employees. As long as they
kept it amongst themselves, they could use it, yes.

MR. McCARLEY: Right. I would just say before a recommendation is made on
limits and so forth, I would say you have real-time data, real data on
real phakic intraocular lenses, that is up to date that you may want to
consider before you make a final recommendation.

DR. WEISS: Well, actually, the advantage of this sort of meeting is that
everyone\'s entitled to their opinion, there is no final vote, and there
has to be consensus. So basically, the FDA will use all the information
gathered here today, and including any other information we think would
be helpful to obtain in the future, to come up with some final
recommendations on their own.

Dr. Grimmett?

DR. GRIMMETT: Yes. Michael Grimmett. I alluded to it in my introductory
comments that while it would be wonderful to have the Phase III
endothelial cell loss data versus what is published in the literature,
we\'re not trying to set a threshold rate of what is acceptable to this
panel or what is not acceptable. That\'s not even the purpose of this.
But I approached the analysis in that fashion to show what the edges of
the approach would be, so that we can get some data on how many patients
would we need to screen in that range. That was my goal.

Understandably, the literature is not giving us that much guidance
regarding actual cell loss rates because most of the lens designs have
been just started and we\'re now on the newer lens designs. So we
actually don\'t know what the newer loss rates are.

DR. WEISS: Dr. Mathers?

DR. MATHERS: Yes, I want to compliment Dr. Grimmett on his excellent
analysis, and it may sound like it is rather strict, but I don\'t think
that using the actuarial tables as you have is in any way offbase. In
fact, it\'s probably ultraconservative because, as we have seen, as
medical advances continue, it isn\'t impossible to look at ages beyond
what you are saying, and we all know a lot of 80-year-olds who do not
feel like dying right now.

(Laughter.)

DR. MATHERS: And who are probably going to live longer as these issues
become more relevant. So 10 years from now, with one advance in cardiac
pathology, this would become not strict enough.

I would also like to ask who you think should do the reading and the
entrance qualification to get into a study like this, because clearly
the endothelium, which is actually quite accessible as the cell to
study, can be best read perhaps by a central office, and should the
entrance requirements be that a central group does the initial reading
to get in? What would you think of that?

DR. GRIMMETT: Michael Grimmett. Based on the comments of Dr. Edelhauser,
given all the variability that exists if the technician is not trained
properly and all the parameters to be analyzed, I obviously am in favor
of the highest trained, highest precision measurer because of the
critical nature of endothelial cell loss over time as our population
ages.

DR. MATHERS: It wouldn\'t be difficult to do this with digital capture.
You can transfer these images instantaneously and you can then decide
whether you have good images, because it would seem that a lot of this
depends upon having good images to start, so that you know how to get
good data afterwards, and that\'s certainly possible on an instantaneous
basis.

DR. WEISS: The way the document reads at the present time is that \"The
use of a reading center is strongly recommended. If the use of a reading
center is not possible, the sponsor should establish a protocol for
collection and analysis of images to be used by each participating
site.\"

Would you then change it from strongly recommended to required or you\'d
leave it as strongly recommended?

DR. GRIMMETT: This is Michael Grimmett again. I think there are always
multiple ways to skin a cat, and if a particular study or a sponsor can
demonstrate the reliability that they have internal mechanisms to
validate precision and validity and it appears to be equivalent to a
standardized reading center, I think there is always flexibility in that
regard.

DR. WEISS: Dr. Huang?

DR. HUANG: My first comment is that regarding Mr. McCarley\'s comment
earlier, using the FDA existing data is almost like using the soccer
player to be the referee. You know, that we are judging the safety of
the data and then using the data to be the reference for its own safety.
I think it\'s questionable.

The second comment I would like to make is also that Dr. Grimmett used a
very nice life table actuary to analyze this, but I think the endpoint
is a little bit strict because we don\'t do cataract surgery at the time
of the death. We do that cataract surgery maybe hopefully five or 10
years before the patient\'s life expectancy in order to improve their
quality of life.

So maybe we have two points that we can use. You know, maybe one at one
point is 10 years before death and then at the death point, and then to
find a reasonable middle ground for the starting point.

DR. GRIMMETT: This is Michael Grimmett again. Just a quick response. I
first attempted to do the cataract surgical procedure 10 years before
the age of death with an increased rate of annual cell loss. The table
became so complicated in the formula that I would have to do to change
the rate of cell loss midstream and back-calculate to the entry cell
data that I couldn\'t get the spreadsheet to work in that regard.

I took took the give-up approach. You know, I was on vacation.

(Laughter.)

DR. WEISS: Well, maybe in that case, the guidance could be to the FDA to
recalculate this with the average age of cataract surgery as the final.

Yes, Dr. Huang?

DR. HUANG: I\'m just joking. I say, you know, maybe he can take another
vacation to calculate that.

(Laughter.)

DR. WEISS: Dr. Burns?

DR. BURNS: Yes, but I think all things being equal, if you move the
cataract surgery earlier, you\'re going to actually end up with stricter
numbers because you\'ll have the loss from the surgery and then you\'ll
have an increased growth and you\'re going to come lower on the curve.
So I think that will only make things stricter.

DR. HUANG: Andrew Huang again. I think this is just a recommendation.
Not all the patients eventually are going to need cataract surgery, but
I certainly understand that there will be additional loss, and I don\'t
know which one is greater, 2 percent annual loss versus the 10 percent
initial loss. So statistics will tell us.

DR. WEISS: I think it would be up to the FDA to crunch the numbers both
ways to see what the differences are and if they\'re clinically relevant
or not.

Dr. Grimmett?

DR. GRIMMETT: I would just point out on the tables, you realize that it
is a 10 percent initial loss for the phakic IOL surgery. Please realize
there are some data on some of the more current studies that say that
that initial loss may at that rate, 5 to 6 percent. The earlier studies
did have a higher rate.

So I used a cataract surgery phacoemulsification initial rate that may
not exactly be true for phakic IOLs. I used the most conservative
approach to make sure that we leave people with enough cells at the end.

DR. WEISS: While we\'re on the endothelial cell topic, I just want to
pose one other question relating to this, and then perhaps Ms. Lochner
could come up and then we can go on with our other presenters and other
discussions.

The other question that I would pose to the panel, as I already did to
our experts, is what would you think would be the reasonable number of
months to tell a patient they would have to be out of contact lenses? If
you have an opinion.

Dr. Bullimore?

DR. BULLIMORE: None. I mean, I think keeping it ‑‑

DR. WEISS: Not even a week?

DR. BULLIMORE: Well, let me say less than a month.

DR. WEISS: Less than a month.

DR. BULLIMORE: I mean, I think trying to sort of take them out of
contact lenses with the expectation that the endothelium\'s going to
change in any meaningful fashion, based on my experience and what I
heard from the experts today, is futile.

DR. WEISS: So you would keep them out long enough to get a proper
keratometry or corneal topography?

DR. BULLIMORE: I mean, I\'d use the same guidelines that exist for
corneal refractive surgery.

DR. WEISS: Gee, I think we just eliminated two questions with that
comment.

Dr. Mathers?

DR. MATHERS: Yes, I strongly agree with that. Aside from the fact that
it would be really difficult to have patients go through that period of
time, since the polymegethism afterwards doesn\'t really evolve very
quickly and we don\'t know exactly the significance of it, I think that
it\'s not terribly relevant to have them out of their lenses a long
period of time, except to establish their refractive error issue.

DR. WEISS: Dr. Bullimore?

DR. BULLIMORE: And I think we need to be generalizable, and these
products and these procedures are going to be done on people who, to a
large extent, are long-term contact lens wearers. We saw yesterday that
something like 80 to 90 percent of the patients enrolled in a study for
low myopia or low to moderate myopia were contact lens wearers. So in
the high group, it\'s going to be probably even higher.

DR. WEISS: Another question, which I warn you in advance I\'m going to
limit the discussion on because it will come up again, is with this in
mind, would you only want one eye done at a time or one eye done and use
the other eye as a control for the endothelial cell study?

Dr. Bullimore?

DR. BULLIMORE: Again, I think you don\'t want to burden the patients too
much, and enrolling them in, say, a three-year study where they can only
have one eye done with a device and the other eye has to wait I think is
an unreasonable burden to be placed on the patient. We have a lot of
historical control data. It seems to me we have some historical data on
endothelial cell count as a function of age. We can use that, and what
we\'re looking for, I guess, are the extreme or the worst cases where
people really do loss a lot of endothelial cells within a relatively
short amount of time, and I don\'t think we need a control group to
necessarily look at those event rates.

DR. WEISS: Dr. Grimmett?

DR. GRIMMETT: Dr. Grimmett. My concern with a unilateral one-eye study
would be for quality of life for the patient. These patients would be
typically those that don\'t qualify for other refractive procedures, and
hence they have a higher range of myopia. There is significant
(inaudible) of emmetropia. So in a three-year duration study, I think
that would be unwieldy and probably not very reasonable for the patient.
So I\'m in agreement with Dr. Bullimore.

DR. WEISS: Dr. Mathers?

DR. MATHERS: Yes, I\'m also highly in agreement. I think we\'ll need to
discuss again the time delay between the first and second operation, but
three years is too long.

DR. WEISS: Then I would sort of conclude ‑‑ Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Yes, just very briefly. You know, statistically,
we\'d obviously like to have a contralateral, but I am absolutely swayed
by the quality of life considerations as long as we have good quality
control data. So that would include both a precise estimate of the rate
of loss, but also of the variability in rates.

DR. WEISS: Okay. So then I would conclude that the fact that the contact
lens issue in terms of the change and shape of the cells and number of
the cells might still be evolving after the implant was placed in will
be a confounding variable, but not objectionable by the panel. Fine.

Ms. Lochner, perhaps we can go on.

MS. LOCHNER: For analysis of the crystalline lens for lens opacity, we
currently recommend that \"The natural lens should be evaluated
preoperatively and at each of the postoperative intervals. The level of
evaluation should be commensurate with the risk of cataractogenesis or
lens changes identified by the risk analysis performed by the
manufacturer. For phakic IOLs where the design or surgical procedure may
lead to lens changes, a grading system or quantitative method should be
used to evaluate lens changes over time. For IOLs for which lens changes
are not an identified risk, qualitative observation may be adequate.\"

The analyses should include the number of patients with any change in
the appearance of the lens stratified by the type of change and the
number of patients with clinically significant lens opacities, and the
term \"clinically significant\" is as yet undefined.

We are asking for panel comments on whether you believe evaluation of
lens changes should be requested of all sponsors or whether this
evaluation should only be performed if the sponsor\'s risk analysis
warrants and whether you have any specific recommendations for defining
the term \"clinically significant\" lens opacities.

We\'re also asking for your recommendations about the use of
quantitative methods for measurements of lens changes versus the use of
grading systems, and finally we\'d like your thoughts on the duration of
the study and request that you specifically discuss the length of
follow-up you believe would be adequate for panel review of this
cataractogenesis outcome.

Now, Dr. Mathers will provide his review.

DR. MATHERS: Thank you.

Regarding the first question we are asked to address, the evaluation of
the lens changes, it is this reviewer\'s opinion that all phakic IOLs
need to be evaluated for any cataract or changes in the lens. Anything
that happens essentially inside the anterior chamber in front of the
lens is an issue here, and even something that would not touch the lens
or is known to be touching the lens would still be a problem. Certainly,
central touch is not the only issue nor is just peripheral touch.
There\'s anterior chamber inflammation, and all of this can affect the
lens changes over time. So any perturbation would be of interest and all
cataract processes need to be assessed.

In this direction, I think it\'s going to be important not just to look
at the lens itself, but to look at the source of the possible problem,
such as we have heard regarding flare assessment or anterior chamber
inflammation, and I think that it would useful to measure flare in these
patients with perhaps the laser flare system, and also, regarding the
evaluation of the cataract process, that the sizing and the structure of
the anterior chamber is going to be a key issue. So the use of
high-resolution ultrasound I think is going to be extremely important in
evaluating this.

Regarding the clinical significance of the lens opacities, this is a
more subjective area and we don\'t have very good data on this, but this
of course refers to vision changes, and in this regard we need I think
to be as precise as possible because when one measures vision under
various circumstances, you get very, very different results.

So if you have a central opacification of the anterior subcapsular area,
it will not show up in vision testing in a dim room. You\'re going to
have to do this with a small pupil under conditions that will induce
some glare, and in fact, the more glare, the better. This is not a
non-real-life situation. I mean, when people are in a high-light
environment, which they often are, this comes into play.

So I think glare testing is the most relevant, but the only way that
this should be assessed. For this, we need to have careful measurements
of the patients as they enter the study and a standardized method of
evaluating the glare, and that high-glare settings should be used.

Now, everyone will have some decrease in visual acuity with a high
setting of a glare. So we have to decide whether we think one, two, or
more lines of loss compared with the preoperative evaluation would be
significant. My recommendation would be two or more lines compared with
what they had in the loss before.

I think that all lens changes should be reported, not just the anterior
subcapsular fibrosis, but we also have anterior cortical changes which
may result from these anterior subcapsular processes.

The posterior subcapsular cataract is also an issue because the anterior
lens cells are not the only ones going to be involved. As you build
lenses that do not ride or touch the central lens, they may ride in the
periphery of the lens, and they are going to get closer to those cells
on the outside which can migrate posteriorally, and certainly may do so.
So that becomes an issue, and the possibility of inflammation that
occurs with the anterior chamber lens of this design may affect the
development of nuclear sclerosis, and this is going to be something that
is going to be harder to assess, but I think that we need to at least
monitor this.

In Part C, we\'re asked to comment on the use of quantitative measures
for the measurement of lens changes versus the more semi-quantitative
grading system, and by quantitative here, we mean the assessment or the
visualization, the optical visualization, of the changes underneath the
anterior capsule.

There is no standard way to do this and the examination of this is very
light-dependent. If the lighting system is a little bit off, you get a
little different view of this and it becomes harder to see, and Dr.
Werner\'s presentation on this was excellent, but even she could not
really tell us exactly how much better, say, a photographic system is
from a slit lamp system, which of course is going to be subjective. But
I believe that the backlighting and retroillumination of the lens with
high-resolution color photography probably offers us the most objective
and reliable way to follow this over time.

The development of a scale to do this has already been done. I don\'t
think this needs to be reinvented, but can be perhaps modified slightly.
The LSCS system can grade these opacifications and can be used for all
of this ‑‑ the anterior subcapsular, the posterior subcapsular, and the
nuclear ‑‑ and I think something like that would be appropriate.

I would strongly recommend the use of digital photography to perform
this process and I also think it is possible, as technology improves,
that we will have a better understanding through other means of
visualization, perhaps confocal microscopy of these cells now that this
becomes an issue and it becomes relevant to look at this. But there are
no standards for this now, and that would not necessarily be used in an
early study like this.

In Part D, we\'re asked to comment on phakic IOLs and the length of time
that it might be useful to evaluate this for, and here, as we\'ve heard
with the endothelium, when we\'re studying the endothelium, we have a
fairly clear endpoint. We have endothelial cell loss and we can follow
this fairly objectively.

With lens changes, it\'s much less objective, and one study, noted
recently, showed that there was some change in light transmittance with
these lenses, not necessarily based on cataract, but I think that with
the long time span that we\'re talking about and the possibility of
chronic inflammation associated with this that is subclinical, that at
least three years would be necessary to evaluate it. I think that the
monitoring of this perhaps should go on longer than that, but I think
the three years is probably enough to give us an idea of what is
happening.

The capsular process of cataract formation is tied to a number of
different other processes. Not just lens touch, but, as I said,
inflammation, and as the lens is redesigned to minimize the cataract
process, the other issues, such as iris touch and development of pigment
dispersion and glaucoma, become more of an issue, and I think that the
industry or lens manufacturers will be tempted to avoid the obvious
problems of lens touch by then shifting the burden to the back of the
iris. I think that this kind of monitoring is also going to be
important. I know it\'s not part of this particular issue, but I think
it\'s relevant because there are tradeoffs here. There is not much space
in this area and as you design the lens to perform in one way, you then
create other issues of significance.

That is my summary.

DR. WEISS: Thank you very much.

I just have just two questions on things which you\'ve already
mentioned, but I just want to clarify. What would you call a clinically
significant cataract?

DR. MATHERS: Clinically significant cataract refers to a loss of a
number of lines, but it\'s highly dependent upon that is assessed, and I
think that needs to be assessed not just with standard ‑‑ well, our
assessment of vision can be done in the standard way in dimly lit room
to optimize vision, but it needs to go beyond that. We need to have
glare testing as well because our standard measures of vision will not
be adequate to pick up the kind of changes we\'re going to see with
capsular opacification.

DR. WEISS: So then to just restate that, with glare testing, it depends
on sensitive you want to be to a very early cataract, and that\'s the
question I\'m asking, is how sensitive do you want to be? So if we said
let\'s it bring it to the glare testing realm and say, okay, we\'re
going to determine that by a loss of X number of lines by glare testing,
is there an idea you have?

DR. MATHERS: Certainly, it has to be more than one line, so I would say
two.

DR. WEISS: So would you prefer, if I was going to make you quantify it,
would you then say a loss of two lines by glare testing, rather than
just a straight loss of two lines without the glare testing or would you
want to say something else or it\'s totally unknown?

DR. MATHERS: I think without the glare testing loss of one line would be
important, would be significant. With glare testing, it\'s going to be
two, because the glare testing is much more sensitive.

DR. WEISS: And would you require contrast sensitivity data or that would
be optional?

DR. MATHERS: I think contrast sensitivity data also should be included.

DR. WEISS: Okay. So you\'d like to have both, but at least at this point
of the discussion, a loss of two lines at glare testing would be
considered significant.

Dr. Bradley?

DR. BRADLEY: Yes, just a comment on the means by which one does glare
testing and how that interacts with the underlying spatial distribution
of the cataract. We might think of two scenarios, one that was just
mentioned of a central cataract that is anterior or posterior. The idea
of most glare testing is you employ a bright light source and, in so
doing, the pupil constricts, and therefore the cataract fills a larger
proportion of the pupil, and therefore the scattered light becomes a
larger proportion of the retinal image, and that leads to an increased
visual effect.

Obviously, the converse is true. If you have a peripheral or marginal
cataract, as the pupil is constricted, a smaller and smaller proportion
of the pupil is covered by the cataract, and therefore a smaller
proportion of the retinal image is scattered light, and thus the visual
effects are decreased under those circumstances.

So I\'m not sure there is a single way one can do a glare test that
would sensitize the tester to the visual impact of a cataract, and it
may be necessary to employ more than one approach. Just an off-the-cuff
suggestion would be to employ the one suggested, which is the standard
approach, perhaps, where the pupil constricts in the presence of the
bright light and it\'s highly sensitive for picking up the visual impact
of a central cataract. I might also suggest performing the same test
under cycloplegic pupil dilation to emphasize the impact of a marginal
or peripheral cataract that, of course, would be visual manifest for the
patient under, for example, night driving circumstances, which arguably
are the most important ones.

DR. WEISS: The question, Arthur, has anyone done cycloplegic glare
testing? Do we have any data to know what the results are in the
normals?

DR. BRADLEY: I don\'t know.

DR. WEISS: Dr. Mathers?

DR. MATHERS: I would strongly agree with what you have suggested. I
meant that we should do standard testing, contrast sensitivity testing,
and glare testing, and I do not have any experience doing glare testing
in a dilated pupil, but it is similar to night driving, but we just
don\'t have any data on that, and I don\'t think that the visual
assessment is going to give us all of the answer. I think we\'re going
to see a lot more with the objective and quantitative than we do simply
with the vision changes.

DR. WEISS: Well, perhaps if we don\'t have that data, we could request a
subset. If panel thought that was helpful and so did the agency, we
could request a subset of patients when they have their initial entry
dilated exam to be glare tested while dilated and not dilated, so not to
be too onerous to any sponsors.

Dr. Grimmett, then Dr. Bullimore.

DR. GRIMMETT: Dr. Grimmett. Just a quick comment. If my memory serves me
correctly, I think I\'ve seen some dilated glare testing data in an ARVO
abstract by Arthur Ginsberg out of California, San Ramon. He does
functional driving tests and other activities and has some data on that
kind of stuff. He\'s a contrast sensitivity guru. I think I\'ve seen
that data before, so I think it could exist.

DR. WEISS: Dr. Bullimore?

DR. BULLIMORE: My impression is we\'re going to come to contrast
sensitivity in a minute and glare testing, but since it\'s on the table,
this is a real sticky area, and anybody who a few years ago was involved
in the Eye Care Technology Forum knows that agreement was quickly
reached on some areas, like measurement of intraocular pressure and
visual acuity and visual fields, but contrast sensitivity and glare
testing became a thorn in the side of the organizers of that meeting,
and Morris Waxler was the point person on that and Arthur was involved
in the panel as well. It was very difficult.

As far as assessment of cataract, I think one of our speakers put
forward a number of mechanisms by which a standardized grading system
could be used. I think the panel should consider whether the FDA should
strongly recommend a reading center for cataracts or for lens opacities
in the same way they\'re recommending it for endothelial cell density.

It becomes difficult because in the case of endothelial cell density,
you have a standardized instrument that can capture the image.
Photographing lens opacity, since you want to capture the different
features of the lens, is a much more difficult and sophisticated
procedure.

So I think using standardized grading systems is appropriate, paying
attention to the kind of opacities that are likely to occur. Anterior
and posterior capsular opacities I think are appropriate, and cortical
opacities maybe, but I\'m not in favor of requiring a reading center in
the same way that it\'s currently recommended for the endothelium.

DR. WEISS: If there are no other comments on this section, Ms. Lochner,
if we could proceed to the third and last question.

MS. LOCHNER: At the most recent ANSI meetings, a consensus appeared to
be reached on the general parameters of the contrast sensitivity
substudy that\'s outlined in Section 8.3, and Dr. Bullimore, you might
be interested to know that we had Dr. Ginsberg, who\'s the contrast
sensitivity guru, and we had Dr. Jack Holiday, who\'s advocated contrast
acuity testing, actually agreeing on this point. So it was a red letter
day.

(Laughter.)

DR. BULLIMORE: For the record, I never called him a contrast sensitivity
guru. That was Dr. Grimmett. I want to strictly go on the record on
that.

(Laughter.)

MS. LOCHNER: And I think that the use of the contrast sensitivity
systems, rather than contrast acuity, was recommended because of
contrast sensitivity\'s ability to capture the full range of spatial
frequencies and contrasts, and it was felt that the contrast acuity
charts would potentially miss significant contrast losses because of the
unpredictability of the spatial frequency at which these losses may be
seen. Of course, we will have letter recognition performance under low
light conditions assessed by the best-corrected visual acuity testing.

The contrast sensitivity testing, as proposed, includes mesopic and
mesopic with glare conditions. Please comment on the clinically
significant decrease being set at .3 log units, and also on whether this
decrease should be at one or two or more spatial frequencies to be
considered significant.

Next, should charts with the minimum contrast at each spatial frequency
be used to minimize the problem of missing data, and perhaps first of
all, are these charts commercially available?

Please also comment on the recommended analyses of these data, including
how missing data should be handled, and by missing data, we mean when
the patient is unable to see the target at a particular spatial
frequency at any of the available contrast levels.

Last, please provide any additional comments, particularly any
recommendations you may have to improve the quality of the data
generated from this testing.

Dr. Bullimore?

DR. BULLIMORE: Can you go back to the first slide? I want to take these
questions one at a time with panel input, if that\'s okay, Madam
Chairman.

DR. WEISS: Anything you want.

DR. BULLIMORE: Wow. I guess lunch is not on the table.

(Laughter.)

DR. WEISS: That\'s true.

DR. BULLIMORE: Let me paraphrase my comments by saying that I have a
long and distinguished record of being a fan of letter charts over
grating, so anything I say should be taken in that context.

That notwithstanding, I think first of all, the statement about .3 log
units being a clinically significant decrease in contrast sensitivity is
reasonable. Just to put that in context, we\'ve come to accept two lines
of visual acuity on a logMAR chart as being a meaningful decrease and
representing a complication or an adverse event or, to put it more
broadly, an unsatisfactory outcome of a refractive procedure. Here,
we\'re talking in the contrast domain of an equivalent of three lines,
and I think this is reasonable and conservative.

I think saying that the drop should be at two or more spatial
frequencies, again, we get into the martial end of contrast sensitivity
testing pretty quickly. One of the limitations and reservations that
some people have about these tests is that unlike letter testing, for
example, where the patient has to name a letter, the patients is asked
either whether they can actually see the grating or not or is asked to
say is the grating on the top part of the chart or on the bottom part of
the chart? So the opportunity for a bias based on shifts in criteria if
you use the first approach or the opportunity to sort of guess correctly
when it\'s just a one in two chance compound the analysis of some of
these data.

But again, in the interests of the goodwill exhibited between Dr.
Holiday and Dr. Ginsberg, I think this again is a reasonable, practical
approach, and with a letter chart, of course, you might not have the
problem with then having to say, well, is it one or two spatial
frequencies, but really I think the panel at this stage should be
presented with the data when it\'s available and let the panel decide,
so to speak.

Does anyone want to comment on that first thing? I\'m sure Arthur would.
I\'d appreciate Dr. Owsley\'s input anytime she wants to say something.

DR. WEISS: Dr. Bradley? Or Owsley. Whoever.

DR. OWSLEY: Why don\'t keep going and then I can probably just make a
few comments at the end?

DR. BULLIMORE: Okay. Arthur, can I keep going for you as well or do you
want to interject?

DR. BRADLEY: I really appreciate the opportunity to interject.

(Laughter.)

DR. WEISS: So why don\'t you?

DR. BRADLEY: Mark raises an interesting sort of comparative analysis to
try and decide, well, is .3 log units, obviously a factor of two
changing contrast sensitivity, clinically significant? And he draws the
parallel between what people decide is clinically significant in terms
of logMAR for visual acuity change, and two lines, obviously that\'s .2
log units on a logMAR chart, and I question, Mark, that that is somehow
equivalent to .3 log units in contrast sensitivity. Was the equivalence
based upon some sort of Z score change, Mark, or ‑‑

DR. BULLIMORE: I didn\'t mean to imply that they were equivalent, but I
said it sort of parallels the change.

Now, you could say, well, if we\'re doing .2 log units of visual acuity,
we should use .2 log units for contrast sensitivity. Unfortunately, most
of the commercially available tests for contrast sensitivity go in steps
of .15.

Again, we\'re going to have the data. We\'re going to be able to look at
the number of patients that have lost .3 or more log units at one or two
spatial frequencies. We\'ll have mean contrast sensitivity data for each
spatial frequency and for each lighting condition. There will be a
colossal amount of data that we\'ll be able to sort of chew over in
depth when the opportunity arises.

DR. BRADLEY: Yes, I think we\'ll have the data, but we\'ll still be left
with the question about what\'s going to be significant.

Just as a suggestion, then, I would make that if there is consensus that
a .2 log unit change of visual acuity is clinically significant, would
you think it reasonable that we convert that into some sort of acuity Z
score change ‑‑ say, two, three, four standard deviations, whatever it
is ‑‑ and propose that an equivalent Z score change in contrast
sensitivity be considered significant. Does that make any sense at all?

DR. BULLIMORE: It makes sense, but I don\'t think it\'s an approach that
I would advocate at this stage.

DR. WEISS: Dr. Owsley?

DR. OWSLEY: This is Cynthia Owsley. I think one of the ‑‑

(Telephone rings.)

DR. OWSLEY: Could somebody get that?

DR. BULLIMORE: I think it\'s Art\'s.

DR. WEISS: It\'s probably Pizza Hut returning someone\'s surreptitious
call.

(Laughter.)

DR. OWSLEY: I mean, I think both Mark\'s approach and Arthur\'s approach
are reasonable approaches. The problem for me, when I think about this,
is when you decide how much decline on a visual function test is bad in
some sense, clinically significant in a bad sense, you have to ask
yourself what is it you\'re trying to prevent.

Answering these questions in vacuo without looking to see how much of a
loss you need in contrast sensitivity or acuity or glare or whatever the
visual field causes a problem in functional performance, without looking
at it in that way, I just don\'t see how you could answer the question.

I\'m not suggesting that we propose all kinds of ‑‑ whatever they\'re
called ‑‑ substudies to answer that, but I think it\'s an important
dilemma, because when it\'s considered on its own, it\'s abstract. For
the patient, it\'s in terms of their everyday life. What implications
will a .2 loss in logMAR acuity mean? What implications for their
everyday will be a .3 loss in contrast sensitivity?

So I haven\'t proposed any answers to this, but I see it as a very
sticky dilemma that we might just have to kind of go with something that
feels like it has some face validity sort of on a clinical level.

DR. WEISS: Mr. McCarley, Dr. Mathers, Dr. Bandeen-Roche, and then Dr.
Bradley.

MR. McCARLEY: Yes, just one question. Is this the first time contrast
sensitivity testing has been required by the panel? My understanding is
that manufacturers of refractive lasers also collected this data. I
mean, the question behind that is is there a standard for contrast
sensitivity or are we now making the standard?

DR. WEISS: Well, we\'re making a standard for phakic IOLs, so even if it
wasn\'t required for anything else, it really ‑‑

MR. McCARLEY: In my understanding, it was. Maybe I\'m wrong.

DR. WEISS: Well, I\'ll defer to Mr. Whipple.

MR. WHIPPLE: Yes, I believe we have required contrast sensitivity for
LASIK studies.

DR. BULLIMORE: Yes, and the current guidance document says that either
you have to measure it or basically to say that you didn\'t measure it.

MR. WHIPPLE: Right, and I\'ll defer also if Donna and Malvina ‑‑

PARTICIPANT: That sounds definitive.

DR. BULLIMORE: I\'m paraphrasing a little bit, but that\'s the general
spirit of it.

DR. WEISS: Donna?

MS. LOCHNER: Well, it\'s not the first time it\'s been required. As you
point out, the LASIK example, and of course the panel has reviewed
extensive contrast sensitivity data in the multifocal IOL example.

I think it\'s also important to point out this question about the
clinical significance because I think what Dr. Bullimore was saying
about, you know, you\'re going to have to look at the data and make some
judgements when it\'s received, but this question is backing up to the
sample size calculations. It\'s not backing up that if it\'s .3, the
device is approved and if it\'s .29, it isn\'t. It\'s really more is
this a reasonable effect to be looking at the sample size calculations,
et cetera.

I think also, as Dr. Owsley said, the meaning of this is really not
going to be clear to many of the panel members, as well as to the
patients, unless this were there were this daily living-type testing
required, which we really have not ‑‑ we\'re not suggesting that, but I
think it\'s a point well taken. So really, if you think of this in the
context of the sample size.

DR. WEISS: I think Dr. Bullimore ‑‑

DR. BULLIMORE: Yes, I mean, you can look at a .3 loss as being
clinically significant two ways, whether it occurs in a subset of
individual patients or in one individual patient or whether it occurs in
the population as a whole, and in terms of sample size, you\'re
interested in the population as a whole. In terms of the safety of a
device, you might say, well, if a two-line loss of visual acuity sets
off alarm bells and appears on some summary statistics for safety, then
should there be an equivalent here?

I\'m not comfortable doing the later. You know, we heard from a speaker
this morning who has a lot more experience with phakic IOLs than the
rest of us, and he was advocating that the IOLs be held to the same
standard visually as LASIK, and we have some historical precedent here
with these tests being done on everybody and I think we should carry on
with that.

In terms of the sample size for the entire cohort, I think it\'s much
more likely to be driven by endothelial cell density considerations than
anything visual.

MS. LOCHNER: So it\'s your recommendation that this testing be performed
on all individuals?

DR. BULLIMORE: Yes. That would be my recommendation.

DR. WEISS: I think we\'re going to go along this time even if it\'s out
of order I originally said.

DR. BULLIMORE: I\'m not asking that everybody flies to Iowa for a
driving simulation. I mean, this a test that should be reasonably easy
to incorporate into a protocol and I would like to see data on as many
patients as possible.

MR. CALOGERO: Don Calogero. Right now, it\'s set up as a substudy, and I
believe the sample size is somewhere between 60 and 100 patients, and
that gives us the ability to detect down to .15 log units. So you\'re
saying that in spite of perhaps having sufficient precision to the
study, you\'d like to see it on the entire population?

DR. BULLIMORE: Well, I think where Dr. Mathers was going with this is
that he would like to see data on contrast sensitivity with and without
glare that would give you clues, maybe not definitive decisions, as to
whether significant cataractogenesis had occurred in these patients.

MR. CALOGERO: Okay. So you\'re also using it for that purpose, then.

DR. BULLIMORE: Exactly. Now, if my memory serves me correctly, I mean,
yesterday\'s presentation for an intraocular ‑‑

DR. WEISS: Wavefront.

DR. BULLIMORE: Wavefront. That was it.

DR. WEISS: How quickly we forget.

DR. BULLIMORE: A good dinner.

For that, we had data on all the patients. Am I correct?

MR. CALOGERO: I believe so, yes.

DR. BULLIMORE: Yes. So I would have thought, with a newer technology,
which, let\'s face it, these phakic IOLs are, and I think increased or
elevated safety concerns in terms of lens opacities, I\'d want to have
that data on as many patients as possible.

Now, I realize we may be into latter phases of some PMA investigations,
and that\'s fine, but I think it\'s going to inform at this stage
whether the patients have indeed developed anything that may cause
concern in the lens opacity department.

MR. CALOGERO: Thanks for clarifying that.

DR. WEISS: Dr. Mathers, then Dr. Bradley, and we\'ll move our way
around, and then come back to Dr. Owsley.

Dr. Mathers?

DR. MATHERS: Yes, I agree with Dr. Owsley that it\'s difficult to assess
how this impacts the patient, but what we need to do is have reasonably
high resolution of the data that we\'re picking up. When we\'re talking
about whether this is actually a good thing, you have to contrast that
with the struggles the patients have with enormous myopia and their
tremendous problem and the alternative of clear lens extraction and
other significant issues, but we want to have reasonable resolution and
an ample sample size so that we can tell what\'s going on, and it may be
that two or three lines is a reasonable expectation considering the
other struggles that they have. But we would determine that later. We
need to have the data now, and I think the contrast sensitivity not only
gives us something about the visual function of the system, but also the
cataractogenesis process.

DR. WEISS: I think that probably most people here are in agreement that
we need the data and whether or not someone postulates that they know
what the data means upfront versus whether they don\'t know what the
data means upfront really won\'t affect the FDA. They can just tell you
after the fact whether you were right or not.

So if anyone has any comments not related to their opinion on that
particular topic, we can proceed with them.

Dr. Bradley?

DR. BRADLEY: Yes, I think just because this is a new product doesn\'t
necessarily mean we have to measure contrast sensitivity. We really need
to have sort of underlying theoretical rationale for why contrast
sensitivity measurement might or might not be useful in this particular
case.

I think the primary concern we have here is degradation of optical
quality, whether it be in the cornea due to endothelial problems or
primarily in the lens due to cataract development. The likely optical
and visual consequences of that are related to scattered light, and they
have fairly predictable optical effects. Indeed, they will have some
effect on our ability to see fine detail, which ought to be revealed by
some visual resolution task.

In addition to that, they will have impact on the image quality for
larger targets, and the primary impact will be on contrast reduction.
One method for assessing this is to examine contrast sensitivity.

That said, as Mark alluded earlier, there are devotees of letter
contrast sensitivity testing and there are devotees of grating contrast
sensitivity testing. One of the arguments in favor of grating testing is
that one can test at many spatial frequencies, which academically might
be quite interesting, but unless one can come up with a reasonable
theoretical argument for why a measurement at a single low spatial
frequency might not provide the same information, I think one is wasting
one\'s time measuring at lots of different spatial frequencies.

Therefore, I wonder about most grating tests for that reason, and I
think Dr. Owsley might be able to comment on that.

DR. OWSLEY: Yes. I very much agree with the perspective or the question
you\'re raising. I would not describe myself as a devotee or a guru of
any test.

The reason I favor letter tests in situations like this is that I know
of no convincing evidence in the peer-reviewed literature that shows
that letter tests are worse than grating tests or grating tests are
better than letter tests, however you want to say it.

I think that there are a lot of us who do clinical studies, clinical
intervention evaluation studies, including bodies like the National Eye
Institute, who go the way of letter tests not only based on the evidence
that they\'re not worse than the grating tests, but because of two
things. One, if you\'re getting a measure of high-resolution visual
acuity, and then you do a contrast sensitivity letter test, say like the
Pelly-Robson, which has large letters, you\'re basically getting
information about the entire shape of the function.

Then the second reason is that we\'re talking about ‑‑ I don\'t know
which specific test the sponsor would be using or any sponsor would be
using, but if you\'re doing spatial frequency testing in the kinds of
things we\'re talking about in this kind of study, you\'re doing those
spatial frequencies for topically, mesopically, with glare and without
glare, before and after surgery. This is a long testing time, okay?

And then I think ‑‑ what was my last point on this? Well, I\'ll just
leave it like that, but I know that this issue has been visited by this
panel before and I\'ve heard about it. I\'ve never been to the panel to
hear it argued as a panel member, but I think that it\'s an important
point that sponsors should hear, the public should hear, and the FDA
should hear that there really are really sound arguments for not, in
every case, doing all the spatial frequencies. You need to ask yourself,
what are you doing with that information? What\'s it really providing
for you that high-contrast acuity in a single measure on a large letter
contrast sensitivity chart would not provide?

DR. WEISS: Dr. Swanson?

DR. SWANSON: I agree with both sets of comments and wanted to add one
other thing. I\'ve used letters and spatial frequencies. It depends on
what the task is.

The point that Dr. Bullimore raised becomes important for sample size
calculations as well as for the amount of time that goes on,
particularly if we\'re looking at this question of glare, but as Dr.
Bradley mentioned, in general, these effects should be in a range of
spatial frequencies.

If you are using a grating and you have a two-alternative forced choice,
basic researchers who use those things do lots of trials because that\'s
the only way you can reduce test/retest variability. For letter testing,
where there\'s going to be between 10 and 26 options that the person\'s
guessing amongst, a much smaller number of trials is needed.

So in order to have a significant change, you need to have a test where
the test/retest variability is low. For a small number of trials, which
needed to run all these conditions in all these people, a multiple
alternative, 10- or 20-alternative forced choice test, is going to be
much better than a two-alternative forced choice, and there aren\'t any
commercially available 10-alternative forced choice grating tests and
it\'s going to be very difficult to create on given the response demands
on the patients. So a letter type of acuity test is going to be much
more suitable in terms of gathering a fair amount of useful data in a
short period of time.

Then the questions that come up, such as, well, do we have to have two
spatial frequencies down or three spatial frequencies or one spatial
frequencies down, those become quite complicated by the high test/retest
variability of a two-alternative forced choice with just a single
endpoint.

DR. WEISS: So let me get to a bottom line. What do you want?

DR. SWANSON: I\'m just trying to hammer home all the points they made
about letter charts being superior for this purpose. I understand there
was agreement before.

DR. WEISS: So you would like a letter chart for this purpose.

DR. SWANSON: For the purpose, a letter chart is going to allow a much
smaller sample size and a much larger ‑‑

DR. WEISS: And Dr. Owsley, you agree, and Dr. Bradley?

DR. BRADLEY: Yes, I agree, a letter chart. I think Donna asked us if
such charts were available. There certainly is a letter contrast
sensitivity chart, as I think it\'s been referred to. Sometimes it\'s
called a Pelly-Robson chart.

One thing I would alert the FDA to is if you are to request use of that
chart, it doesn\'t have to be used at the standard distance at which it
was originally designed, and there are reasons to pick your distance,
depending upon the scale or size of target for which you wish to study.

DR. WEISS: Dr. Bullimore, your comment?

DR. BULLIMORE: I mean, the spirit in sort of guidance documents before,
whether for this issue or others, was that the sponsor or a potential
sponsor would be able to speak with the FDA and the FDA, in terms of the
guidance document, wouldn\'t specify a given test, but there would be
some scope. I was just a little surprised that this was so specific,
even naming spatial frequencies. I mean, you come pretty close to naming
a test or naming a couple of tests, and I\'d just like to see some
statement that other tests could be considered if the sponsor in
consultation with the agency would be able to agree that these were
acceptable.

DR. WEISS: Don Calogero?

MR. CALOGERO: I can provide a little background. At the last ANSI
meeting, we sort of discussed this issue, and there was a presentation
and the basic summary of the presentation was that it\'s really not
possible for us to predict where the largest effect is going to be in
terms of the spatial frequencies. We went through the literature
containing some information ‑‑

DR. BULLIMORE: But Don, the panel\'s telling you that that\'s not an
appropriate ‑‑ well, not necessarily a widely held view of the world.

MR. CALOGERO: Well, this was from the literature and this is from sort
of the internal data we have. Some devices, depending on the type, had
the largest effect at 1.5 cycles per degree, others 12 cycles per
degree, and the committee felt that if we had recommended the letter
charts, based on sort of the spatial frequency domain that they
evaluate, you\'re essentially just simply getting the highest spatial
frequencies, maybe 12 cycles and above, whereas we could potentially
miss large drops at other spatial frequencies, and with our current to
predict where the effect is, we felt it would be judicious to recommend
that the entire contrast sensitivity function be defined.

DR. OWSLEY: Can I make a comment?

DR. WEISS: Yes. Make a comment, Cynthia, and then also if we could
direct it at, from what I understand from the vision scientists on this
panel, they don\'t agree, and is that the case or is that not the case?

DR. OWSLEY: The vision scientists on this panel I think do agree the
letters would be better.

DR. WEISS: No, you agree that letters would be better, but are you
agreeing with what\'s been put forward by the FDA?

DR. OWSLEY: Well, let me put it like this.

DR. WEISS: That\'s what I\'m asking.

DR. OWSLEY: And that\'s exactly what my comment is on. I\'ve been
reading this literature for 20, 25 years, like Arthur ‑‑ Mark\'s a
little younger ‑‑ and Steve.

DR. WEISS: He\'s thinking a lot younger.

DR. OWSLEY: I would be happy as a consultant to the panel to look at
those peer-reviewed papers. Of course, if you have internal data you can
or cannot share with me, that\'s your decision, but I have not seen any
convincing evidence that measuring all these different spatial
frequencies would matter in any of the decisions that you would be faced
with at the FDA regarding these types of devices. But I\'m openminded. I
just haven\'t seen those papers.

DR. WEISS: So I see sort of agreement by Dr. Swanson.

Dr. Burns has a comment.

DR. BULLIMORE: I mean, my overall view is that these ‑‑

DR. WEISS: Dr. Burns has a comment.

(Laughter.)

DR. BULLIMORE: This ‑‑

DR. WEISS: Well, I guess Dr. Bullimore has a comment.

(Laughter.)

DR. BULLIMORE: Since it\'s my ‑‑

DR. WEISS: Dr. Burns is deferring to you, Mark, so why don\'t you give
your comment?

DR. BULLIMORE: I have no problem with gratings being used. It was just
having a sentence in there that other avenues could be pursued if ‑‑

DR. WEISS: So you don\'t like the rigidity of it, but you don\'t have
a ‑‑

DR. BULLIMORE: It\'s more the rigidity, and I mean, as I said before,
you\'re almost sort of saying you\'ve got to use this test or this test,
and those of us who work in other arenas, and we\'ve already spoken
about the limitations of certain types of tests, we just find that a
little offensive, I think.

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

DR. BURNS: Yes, I just want to chime in that I also believe that the
combination of the high contrast and the low contrast letter chart will
give us enough sensitivity both for some of the safety issues, such as
contrast degradation from cataracts combined with glare, and remember
also, this is a refractive procedure. So we do want to get general
decrement information. But I do believe that a contrast letter chart
combined with a high contrast letter chart will be acceptable.

DR. WEISS: Mr. Whipple?

MR. WHIPPLE: Yes, Dave Whipple. I just wanted to address Mark\'s comment
about the rigidity of the guidance. We may recommend certain tests or
prefer certain things, but a guidance is exactly that. It\'s guidance.
It always carries with it the option of using other tests, other test
methods, and making arguments why the recommended tests aren\'t
appropriate for that particular device. So that\'s inherently built into
the guidance document development.

DR. WEISS: We\'ll go on to the other two comments if they\'re not
related or they don\'t change what my next statement is going to be.
It\'s from why I understand, the members of the panel prefer a letter
chart and Dr. Bullimore would also prefer that the wording doesn\'t
sound so restrictive, even if it actually isn\'t.

Having said that, do you have anything else to add to that, Dr.
Bandeen-Roche or Mr. McCarley?

DR. BANDEEN-ROCHE: My comment was a brief one on a different topic, so
should we finish this?

DR. WEISS: If it\'s related to this question ‑‑

DR. BANDEEN-ROCHE: It\'s related to clinical significance in terms of
functional performance.

DR. WEISS: Well, why don\'t you just proceed?

DR. BANDEEN-ROCHE: I just wanted to mention that there is detailed data
from the Salisbury Eye Evaluation Project on glare, contrast, et cetera,
with many measures of functional performance. So I don\'t think we\'re
completely in the dark. I think that there are some data that can inform
that question, albeit it is a sample of older adults.

DR. WEISS: Good. Thank you.

Mr. McCarley?

MR. McCARLEY: Yes, just very quickly. I\'d like to understand or get
clarified for me the intent. My understanding, at least from the ANSI
side of it when we\'ve been discussing this for the last several years,
was that doing contrast sensitivity was to see if the combination of
optical components in the eye degraded, similar to what the intent was
when they did LASIK studies. Now, it seems to be that\'s what\'s being
used to determine whether or not the patient\'s undergoing a degradation
as a result of cataract, for instance. So one would be a sample size and
one would be all patients, I think.

DR. WEISS: Dr. Bullimore, did you want to address that?

DR. BULLIMORE: No.

DR. WEISS: No one wants to address that. I guess we have no takers?

DR. BURNS: If you\'re measuring a visual performance like this, you\'re
tapping the whole system, and the degradation can come about from
optical imperfections or from what are actually just very high-order
optical imperfections of scattering and tissue turbidity. So it probes
the whole system.

DR. WEISS: I think we\'ve beat this one into the ground and it\'s no
longer even gasping. So why don\'t we go on to the next one?

DR. BULLIMORE: The next one I think is very easy to deal with.

DR. WEISS: We\'ll hold you to that.

DR. BULLIMORE: Again, we\'re asking people to be very specific about the
tests, and I think the FDA have enough savvy and flexibility to deal
with this, but if somebody can\'t read or can\'t see the highest
contrast on the chart, I think their contrast sensitivity has to be
scored as zero. One would hope that preoperatively the test was
sufficiently intelligently designed such that they could read well above
that bottom level.

Certainly, recalling some of the data we were presented with yesterday,
we were dealing with contrast sensitivities of one or above most spatial
frequencies. So as long as we have something down at the 40 percent or
60 percent, which of course is .3 or so contrast sensitivity, we should
be okay.

But if they can\'t see it, it shouldn\'t be counted as missing data. We
should assume that their contrast sensitivity is zero or some other
intelligent value based on the range of the test.

DR. WEISS: So can the transcript reflect there are about six heads
bobbing up and down?

Next question.

DR. BULLIMORE: And the next question, please, Donna?

I think this is kind of tied in with the last one. If I can answer, I
think tests are available and if a patient can\'t see a targeted spatial
frequency at any contrast, it should be scored as a contrast sensitivity
of zero.

MR. WHIPPLE: That is information.

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

DR. BRADLEY: I\'m having a bit of trouble with the question. I mean,
we\'re not anticipating these patients are going to have horrible
vision, are we?

DR. WEISS: Before or after the implant?

(Laughter.)

DR. WEISS: Sorry.

DR. BRADLEY: I mean, we\'re talking about some serious methodology here.
We\'re trying to ascertain something fairly subtle, and I don\'t think
in any of these cases we\'re going to have the problem that people
can\'t see the target at all.

MR. CALOGERO: I think why we\'re asking the question is under the
mesopic test conditions. Under the mesopic test conditions, we do in
fact have cases where at the higher spatial frequencies, the patients
are unable to perform anything, and so you might have 20 or 30 percent
of the population that you\'re testing that essentially has a zero,
let\'s say, 12 or 18 cycles per degree. So we wanted some sort of
standardized way of handling all of those zero data points.

DR. BRADLEY: Well, I think the panel has given you our suggestion on
that, which is that you should not do these grating tests. Particularly,
don\'t try to find out if people can see fine detail in the dark. We
know they can\'t.

DR. OWSLEY: This is Cynthia Owsley. It\'s very unusual to find a patient
who can\'t see the first triplet of the Pelly-Robson chart, and I see
Karen Bandeen-Roche from the SEE Project nodding.

DR. WEISS: But in that case, I think we have the answer to this
question. We may not like the question, but I think Dr. Bullimore has
already given an answer to it, which I assume you would agree to, but
you don\'t think it\'s going to even come up.

Fine. Next?

DR. BULLIMORE: Beaten to death. Beaten to death.

I really have nothing to add on this one at the moment. I\'ll read it
again. \"Please provide any additional comments on the contrast
sensitivity substudy\" ‑‑ now it\'s a substudy ‑‑ \"including any other
guidance that could be provided to enhance the quality of the data that
are generated from this testing.\"

Use a good test would be my recommendation.

(Laughter.)

DR. WEISS: That\'s why we call the experts to figure this out.

DR. BULLIMORE: And use it well.

DR. WEISS: So is that the end of your questions?

DR. BULLIMORE: I\'d like to hear what Dr. Owsley has to say.

DR. WEISS: Dr. Owsley?

DR. OWSLEY: I think the test should have the best test/retest
reliability as possible and should be brief.

DR. WEISS: And brief is always dear to my heart.

Yes?

DR. BULLIMORE: This is Dr. Bullimore again, not wanting to shut up. I
think it would be ideal and preferable and maybe mandatory that for any
test that\'s going to be used that normal data are available on a wide
range of age ranges and for the measured conditions.

DR. WEISS: Dr. Bradley?

DR. BRADLEY: I think just to reiterate what everybody has said here and
maybe to put the comment that Bill Swanson made earlier, what we\'re
arguing for regarding the quality of a contrast sensitivity test can be
thought of by thinking of an analogy with a visual acuity test.

Imagine you had a visual acuity chart, one letter per line, and it was
either A or B. Would we consider that an appropriate test? And clearly
not, and all we\'re saying is let\'s hold the contrast sensitivity test
to a similar standard psychophysically in terms of rigor and test/retest
reliability that we are quite comfortable demanding from our visual
acuity tests, and it turns out at the moment the only convenient one out
there that we know of is a letter chart.

DR. WEISS: Dr. Bradley, we get the idea you like the letter chart.

DR. BULLIMORE: He is so proud that he can read.

DR. WEISS: He likes that letter chart.

DR. BULLIMORE: He is so proud.

(Laughter.)

DR. WEISS: If there are no other comments on this, what I\'d like to do
then is move on to panel discussion on remaining issues, and I have
three issues, and then we\'ll introduce if the agency has any additional
issues or if any members of the panel want to introduce any additional
issues.

One issue, which has been alluded to and discussed, but I would like to
see if we can give as many opinions as possible, is duration of study
before it\'s presented to the panel. Somewhere between two and three
years has been mentioned. Perhaps any of those of you who would like to
give your opinions can raise your hand and just give me a number and
tell me why.

Dr. Burns?

DR. BURNS: From what I see of the endothelial cell measurements and
their likelihood of accuracy in this population, I think three years is
a minimum.

DR. WEISS: So Dr. Burns feels three years.

Dr. Bullimore, had you ‑‑ three years. We have a sign. We\'re going to
signs now. Okay. So we have Dr. Matoba at three, Dr. Grimmett at three.
Dr. Bradley likes the number chart.

(Laughter.)

DR. WEISS: Dr. Huang, three. Dr. Mathers is three. Dr. Owsley is three.
Dr. Swanson is three. So I think we have actually, even though we\'re
not looking for a vote, essentially it\'s almost unanimous, if not
unanimous, for three years.

DR. BANDEEN-ROCHE: Madam Chair?

DR. WEISS: Yes?

DR. BANDEEN-ROCHE: May I make a very brief comment?

DR. WEISS: Yes.

DR. BANDEEN-ROCHE: And that is that I believe it\'s important, based on
Dr. Grimmett\'s comments, that at least one, preferably two, evaluations
be scheduled between two and three years because he suggested that
linearity was not beginning to be achieved until then.

DR. WEISS: Okay. So one to two endothelial cell counts should be
performed between the two- and three-year mark.

Dr. Grimmett?

DR. GRIMMETT: Dr. Grimmett. I couldn\'t agree more with Dr.
Bandeen-Roche that the data that is present in the peer-reviewed
literature do not show a linear approach. We don\'t have enough data
long enough. So that is correct. In an intermediate point.

DR. WEISS: Dr. Mathers?

DR. MATHERS: I would not end the data collection necessarily with three
years because I think that ongoing data could be important.

DR. WEISS: That\'s an important question in terms of a postmarket study.
It could be brought to panel at three years, at least from the
recommendations from this panel today. After that, a postmarket study of
what duration of time would you like to see, Dr. Mathers?

DR. MATHERS: Another two years.

DR. WEISS: Another two years.

Dr. Grimmett?

DR. GRIMMETT: Dr. Grimmett. I would agree with Dr. Mathers\' sentiments,
but that decision would be made more accurately with the data in hand
with the PMA at three years obviously, but I would feel certainly
comfortable with probably a postmarket study.

DR. MATHERS: Yes.

DR. WEISS: Dr. Bullimore?

DR. BULLIMORE: This is endothelium only?

DR. WEISS: It can be whatever you want.

DR. MATHERS: Cataract.

DR. WEISS: And you don\'t have to define it now. Basically, what the
agency would like is your opinions.

DR. BULLIMORE: My opinions will be more well-informed once I have some
data, but I have considerable concerns about the long-term safety of
these intraocular devices. As the lens continues to grow, as it gets to
cohabit with the phakic IOL for a long period of time, I don\'t think
any of us can predict with any accuracy or precision what that\'s going
to do to the crystalline lens on a long-term basis.

You know, these devices we can expect to be better than some of the
first-generation phakic intraocular lenses, but they haven\'t been
around long enough for us to tell, so I could foresee a substantial ‑‑
i.e., five-year ‑‑ postmarket study to track these patients and see, for
example, how many people develop significant lens opacity, whatever that
may be, how many people have to have a cataract extraction and
conventional IOL implantation, how many of those patients have
complications from that procedure, and it can be nothing more than
fairly straightforward head counting, but I think tracking these
patients long-term, given what we know happened with, for example,
extended wear contact lenses in the \'80s and anterior chamber
intraocular lenses, I think it would be prudent.

DR. WEISS: So the impression I get ‑‑ and if there\'s something you
would like to add, then we\'ll add it ‑‑ is that the panel members would
like to see postmarket studies from two years on up, maybe even to five
years, but pending what the data shows.

DR. BULLIMORE: Once we have a PMA before us, we can make a more informed
decision, but certainly, given the fact that this is an intraocular
device that\'s cohabiting with a lens that\'s continuing to grow and
function, I would ‑‑

DR. WEISS: You want to see a postmarket study.

DR. BULLIMORE: Well, I would anticipate the possibility of this
requirement.

DR. WEISS: Dr. Mathers?

DR. MATHERS: We have not focused on pigment dispersion, but in the
literature there are a number of papers that do. Not so much that
they\'ve had a lot of glaucoma yet, but they often have pigment
dispersion in the range of 30 percent, and therefore gonioscopy and
pressure measurement.

DR. WEISS: Actually, that\'s an excellent point. I don\'t recall if
that\'s in the document, gonioscopy, and then how often ‑‑

DR. MATHERS: It is.

DR. WEISS: And how often should postop.

DR. MATHERS: It\'s in there now and it hasn\'t been focused on, but
it\'s in the literature, and I think it\'s an important issue.

DR. WEISS: So we haven\'t defined here, but there is concern in terms of
follow-up as far as not only the cataract and the endothelium, but also
gonioscopy and how frequently that would be done and what the postmarket
would be would be defined in terms of when some of the data comes in.

Another question is what is an independent entity? Is the subject an
independent entity or is the eye an independent entity?

For example, classically, for intraocular lenses, each patient has been
an independent entity. Each subject has been an independent entity. So
if the FDA statistically said that 300 data points were required, then
each patient would be considered separately an entity whether or not
they had one or both eyes treated.

On the other hand, for LASIK, each eye has been considered an
independent entity in the same patient, so that if 300 data points were
required, then you might only need 150 patients.

So this is a very important point for sponsors to know whether they need
300 patients, and we\'re going to be getting to sample size as well, but
if the sample size is determined to be necessary to be 300, should that
be 300 patients or can it be 150 patients with both eyes treated?

Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Yes, I mean, statistically speaking, from a strict
point of view, sites are the independent entities. Now, obviously,
we\'re not going to base sample size on that, but methods are available
to account for correlation of eyes within individuals, and in turn, of
individuals within sites if necessary in computing power.

So one doesn\'t necessarily need to go to the extreme of saying, for
instance, we\'re going to count people as entity. One can still account
for the information provided by two eyes within an individual, yet
accounting for the correlation in that information that two eyes
shouldn\'t count as much as two separate people, and indeed that perhaps
two people within a site shouldn\'t count as much as two people in
different sites.

I actually have a figure that I brought on this, but if you prefer to
save it, we can.

DR. WEISS: No, sure.

DR. BANDEEN-ROCHE: I need the overhead. So can I just quickly set that
up?

DR. BANDEEN-ROCHE: Sure. Maybe while you\'re setting that up, we can go
on to a comment by Dr. Burns, and then to Dr. Matoba.

DR. BURNS: Yes, I just want to support that strongly because we\'re
talking here a lot about biological reactions to a foreign body. So
there will be a significant amount of correlation, I assume, between
eyes, and so the studies should explain how they\'re going to handle it
statistically in the design, and not in post-hoc analyses.

DR. WEISS: So I want to understand. Would you feel that an eye should be
an independent entity or a subject?

DR. BURNS: I think Karen is going to explain the statistical way to
handle it, but it\'s important that it be handled that way from the
outset, that you\'re accounting for the correlation between eyes.

DR. WEISS: Now, we\'re going to go along with other comments, but we
also need to look at this not only statistically, but from a safety
standpoint because this is a new device.

Dr. Matoba?

DR. MATOBA: Yes, in regard to the safety standpoint, since we\'ve
already decided that because of the issues of quality of life we\'re
going to allow patients to have both their eyes done instead of limiting
it to one eye over a three-year period of time, we might as well get
data from both eyes, and so fewer people would have to be involved in
the initial study.

DR. WEISS: Dr. Mathers?

DR. MATHERS: Yes, I strongly agree with that comment. I think we should
have both eyes, but we should account for the correlation, and that
allows us to get over this quality of life issue, which is going to be
very, very important to the patient because only doing one eye is not
going to work.

DR. WEISS: Well, we\'re not talking about only doing one eye. We\'re
talking about whether you need 300 subjects who can both have both eyes
done or 150 subjects who can still both have both eyes done.

DR. MATHERS: I think we shouldn\'t throw away the data on the second
eye, but we should use it with an appropriate correlation.

DR. WEISS: So you basically want to count it and not require another 150
patients.

DR. MATHERS: We\'re about to hear how we can account for the
correlation.

DR. WEISS: Okay.

DR. MATHERS: In estimate.

DR. BANDEEN-ROCHE: Yes, and so certainly one can just state what is the
expected design, including eyes within patients, patients within sites,
et cetera, and then do power and all other statistical analyses
accounting for that correlation. So what I had diagrammed here was
thinking of people within sites, but it could equally well apply to eyes
within people. There might be several levels.

So here, M is referring to the larger level. So let me just stick to
people within sites because that\'s the way that I did it. So M is the
number of sites and N is the number of individuals within sites.

So for instance, if it were people and eyes, it would be M people, and
for two eyes, N would be two eyes per person, and so what I\'m showing
you here is the standard deviation of the mean ‑‑ say, a rate, say, a
safety rate ‑‑ or I guess to simplify things, this was meant to be a
continuous measure. So it would be something more like an acuity measure
that\'s measured on a continuous scale.

So you can see that the standard deviation depends both on the overall
number of units, either people times eyes or sites times people, and the
symbol rho, which I\'ll point to here, that\'s the correlation between
outcomes within a person ‑‑ so two eyes within a people ‑‑ or between
visual acuities within a site, and then sigma is just the standard
deviation of the measurement that\'s being taken in the population.

So one thing to point out is that if N equals 1, then this top term goes
away, and you just get the usual standard deviation of the mean.

So what I\'m showing you here is how the standard deviation varies for
the ‑‑ I assumed the FDA sample size of 300, but what\'s varying here is
the number of clusters, and so here\'s where this is really more
relevant to sites and people within sites, because the FDA guidance for
the number of sites says something like at least 20 per site and no more
than a quarter being accounted for by any one site, and so if we had
four sites, then that would just be meeting no more than a quarter by
any one site. Then here, up at 300, you only have one patient per site,
so that\'s the outer limit.

So the bottom line here, the straight line, is what you get if there\'s
no correlation. That\'s just the standard deviation of the mean. If
there\'s no correlation, then it doesn\'t matter how you distribute
people by sites.

The other three curves, just to save time, the bottom one here assumes a
correlation of .05. That\'s small. That\'s assuming that 5 percent of
the total variation in outcomes is accounted for by variation between
sites.

So even with that minimal amount of correlation, notice how much bigger
the standard deviation is. I apologize that the scale on this isn\'t
better, but that\'s twice as high. It\'s approximately twice as high as
your analysis ignoring correlation says that it should be.

Incidentally, we were about here yesterday. We had five sites yesterday,
and I think two of them accounted for more than 50 percent of the data.

The one point is that I would encourage going to more sites than no more
than allowing any one to be up to a quarter of the data, but the second
point is that if we were just talking about eyes within people, it would
be straightforward to do this calculation and just account for it in
calculating power and doing the analyses and what have you.

DR. WEISS: Thank you very much.

I\'m going to ask Donna Lochner to speak with us a little bit more about
this issue.

MS. LOCHNER: Well, I think this is helpful, but the kind of
recommendation we need clinically is what factors do we base the
correlation on and what is the correlation that would be plugged
prospectively, as you\'re stating, into this equation?

DR. WEISS: And I should also add with information from you already is
the precedence to date, is that LASIK is a little unusual because each
eye has been considered a separate entity, but the history has basically
been for intraocular lenses one patient, whether or not they had both
eyes done or one done, was a separate entity. Viscoelastics, whether
they had one eye or both eyes done, was a separate entity. So there\'s
been a little bit of a history of using patients as separate entities,
as opposed to eyes.

MS. LOCHNER: Right, and I mean, we want to get a feel for clinically how
you would assign this correlation factor for all the various variables
that you\'re looking at outcomes.

Now, we, of course, in our guidances, have not addressed this method of
potentially using the second eye, and so all of our calculations and
sample sizes and whatnot are based on independent people, but if we were
to allow this approach, we would have to have some sense of what would
the panel consider acceptable for how correlated are the two eyes for
the various safety outcome variables and effectiveness outcome
variables.

DR. WEISS: Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Yes, so certainly the approach of calculating it for
people is conservative.

MS. LOCHNER: Right.

DR. BANDEEN-ROCHE: That would essentially be it, and so I have a hard
time arguing with that, although I know that others would raise we
can\'t afford to waste any data or money or what have you.

So in terms of getting a sense of the correlation, I would think that if
you have decent pilot data, that the correlations I\'m talking about
could be estimated in a straightforward fashion.

DR. WEISS: Could you perhaps have a subset of the first 20 patients, 50
patients, to draw whatever those correlations are to see whether you
could then use separate eyes as separate subjects or the same patient
with two eyes as separate?

MS. LOCHNER: I mean, my general impression is that for most sponsors,
developing this pilot study and determining this correlation ‑‑ I mean,
I\'ve seen nobody suggest that to us, first of all, and secondly, how
would they do it if at the end of the study they want to use both eyes?

But I\'ve never seen it presented. I\'ve never even seen a suggestion
for what this pilot study would be, and in fact probably what we\'ve
recommended in terms of the slow phase in to not put eyes at risk for
unproven phakic IOLs ‑‑ I mean, if they have foreign experience, we do
allow them to phase in quicker, but I kind of suspect that given the
slow phase in, doing the pilot study, it\'s going to be complicated. I
mean, it\'s going to take a while for them to gather that information.
I\'m not sure how many you typically see in a pilot study to establish
these correlations.

DR. BANDEEN-ROCHE: And so, you know, certainly I would be perfectly
happy with the conservative approach, but my question to the panel, and
I have no idea what the answer to this would be, would one expect the
data to be so different in these particular studies that a good sense of
reasonable correlation could not be obtained from either ‑‑ I mean,
LASIK data, that\'s probably ridiculous, but aphakic IOL trials or is
there historical data that are similar enough in nature that a
reasonable estimate of the correlation of outcomes in a subject could be
done?

DR. WEISS: I mean, I always wonder, if this is new technology, I wonder
in terms of we heard about if the IOL is too small, it can induce
cataract by sitting on the lens. How often is that phenomena happening
and is it correlated between the quality of the measurement, a vagary of
that individual and their eye, and is it the quality of the surgery? So
I think some of these may be unknown factors.

Dr. Burns?

DR. BURNS: I mean, I\'d be happy with the conservative approach, too. I
wouldn\'t be happy with getting the final analysis coming back suddenly
treating the eyes as 600 eyes at the end.

MS. LOCHNER: Oh, no. No. That maybe needs to be clarified. In the sample
size calculations that we\'ve done, we\'ve recommended 300 individuals,
their first eye, and we require that they collect data on the second
eye. The second eye data is not combined in with the first. It\'s just a
separate analysis that\'s provided to the panel that\'s really more of a
confirmation check that the outcomes are holding up in the second eye
and giving you a little bit more numbers. But no, we don\'t combine them
into a 600 sample size and improve the precision.

DR. WEISS: Dr. Mathers?

DR. MATHERS: I was just concerned that there was some thought of holding
up doing the second eye for the three-year period.

MS. LOCHNER: Oh, no. No.

DR. MATHERS: But if that\'s not the issue, then you can afford to be
conservative in your statistical approach if that\'s what you want.

MS. LOCHNER: And I think that basically, without the detail and the sort
of clear way you\'ve just presented it today, Dr. Bandeen-Roche, we\'ve
basically given this advice to sponsors that, should they want to use
the second eye, they need to determine the correlation between the two
eyes and relook at their sample sizes.

So I think just getting this out on the table is important, and I think
the point that Dr. Weiss made is probably where most of us sit in the
FDA of there\'s some unknown information and how do you determine the
correlation? Perhaps a pilot study, but there\'s just so much unknown,
and it\'s helpful for us to hear you reiterate what we\'ve basically
told sponsors is determined on how the two eyes interact.

DR. BANDEEN-ROCHE: And the only thing I would add to that is that at the
end of the study, the data itself provides an estimate of the
correlation, and that should be accounted for in any analyses of two
eyes.

MS. LOCHNER: Right.

DR. WEISS: Dr. Mathers?

DR. MATHERS: We are saying, though, that the data on the second eye will
be collected. Is that correct?

MS. LOCHNER: Oh, yes, and will be reported to the panel.

DR. MATHERS: Fine.

MS. LOCHNER: But it will not be combined with the first eye to get a
bigger sample size. It will be reported separately.

DR. MATHERS: Yes, that\'s key.

DR. WEISS: Mr. McCarley?

MR. McCARLEY: Yes, just quickly. What are the ISO standards? What are
the requirements in ISO right now?

MS. LOCHNER: Well, again, all the sample sizes were based on a
straightforward calculation not taking the second eye into account, so I
believe that the ISO is basically asking for 300 individuals as well.

You know, it\'s a little different with a standard in terms of ‑‑ I
mean, you still can go to the notified bodies and present whatever you
want, but certainly with the FDA, we would allow companies to propose
alternate proposals, but taking into account what\'s been discussed.

DR. WEISS: Thank you very much.

The other question that I wanted to answer, and we would probably need
your input on this as well, is the question of sample size. The 300 is
what was put forward by the FDA. Of course, it depends very much on the
issues that have been discussed by the three panel reviewers, but does
anyone have any comments on that 300 number?

Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Dr. Grimmett was kind enough to hand me a set of
analyses yesterday, and I believe they were done at FDA. Are they going
to be presented?

MS. LOCHNER: Well, I don\'t know if now\'s the right time to bring it
up, but we did have a bit of a question about the endothelial cell
density discussion that went on earlier, and that is based on some of
Dr. Grimmett\'s questions, we prepared that table, which is a table of
different potential rates of cell loss due a phakic IOL in sample size,
and also different standard deviations in the measurement.

DR. WEISS: Why don\'t show it now, because that is probably ‑‑

DR. GRIMMETT: Why doesn\'t Don Calogero just go over some of the salient
points?

MS. LOCHNER: And let me just, before he does that, say that from the
earlier discussion, we heard the 1,500 cells and we heard that using the
actuarial data, and even perhaps backing the age of cataract and
calculating different point on. We heard all that, but what we didn\'t
get from the earlier discussion was what rate do you want to be able to
detect? And that essentially is what Don will present. I mean, just
before giving you a clinical impression, of course, you have to see what
the sample size is. We\'re talking about what really kind of seems
reasonable. It\'s a combination of your clinical judgement along with
the sample size is that translates into you arrive at a rate that seems
reasonable.

So Don\'s passing that out, and I\'ll let him explain that to you,
because we really didn\'t walk away understanding whether you felt the 2
percent rate that we\'ve set up is reasonable.

DR. HUANG: Can I make a comment? Donna, I think the sample size itself
is not just for statistical analysis. It also has to be considered for
practical matters. You know, as we mentioned earlier, in some of the
aniridia patients, you may not be able to get all those patients, and so
you cannot mandate that 300 eyes.

DR. WEISS: This is very relevant to the slide you\'re about to see.

MS. LOCHNER: And let me also say that the 300 sample size actually
didn\'t originate from the endothelial cell density study. I mean, way
back when we started some of studies, it originated from the IOL work
and being able to detect low rate of complications, and then, as we
developed the statistical analysis for the endothelial cell density, et
cetera, it was a reality check to that sample size and it coincided very
nicely, but originally we carried over a lot of the assumptions from
aphakic studies in what we wanted to be able to detect in the
complication arena.

DR. HUANG: But also the current discussion is really limited to the
phakic population, and then we are probably targeting towards a higher
myopia patient, and those are patients more difficult to come by as
indicated from yesterday. For the wavefront technology, they could only
recruit 130 eyes with a -7.

MS. LOCHNER: That\'s true. However, I think most of the studies that are
ongoing in the U.S. go down as low as a diopter. They aren\'t
necessarily limiting ‑‑ beyond the initial stages, when some of the
preliminary safety data is being gathered, in later stages of the study,
they are going down to 1, 2, 3 diopters.

DR. HUANG: But if this were to be limited to the higher myopic
patients ‑‑

MS. LOCHNER: You wouldn\'t have the problem you\'re discussing. Right.

DR. HUANG: Yes.

MR. CALOGERO: Okay. As Donna said, we need some additional guidance in
terms of the sample size. The sample size that we have in the document
now of approximately 300 subjects is probably powered to detect
endothelial cell loss rates of maybe 2 percent and maybe as low as 1.5
percent, but it\'s not going to get down to the .9 percent, which was
the lower extreme that Dr. Grimmett brought up.

In terms of this document that I passed around, what it looks at is it
looks at sort of a true yearly loss. The left column is the yearly loss
from .9 percent up to 2 percent, and then the next three columns on the
right are the sample size that you need with an observed, allowable rate
per year, which is the fourth column, to give you 90 percent confidence
that the true rate is up to the yearly loss rate in the lefthand column.

Like in the first one, if you want the true yearly loss rate to .9
percent, if you in your data you have a standard deviation of 10
percent, you would need a sample of 296 subjects, and your allowable
observed rate could be as high or as low as .63 to meet that level.

So it becomes important to first get a sense of what the true standard
deviation is in this data, and then secondly, to have a sense of what
the panel members would like to see in terms of defining a true rate
associated with endothelial cell loss for these devices.

I simply generated the numbers, and we\'d like some feedback.

DR. WEISS: I think Dr. Grimmett has a question.

DR. GRIMMETT: Drs. McCarey and Edelhauser put forth precision numbers
for those, 2 percent and 9 percent, and I want to know how those
correlate over the standard deviation numbers.

PARTICIPANT: Put up the slide. Are they the same?

DR. BANDEEN-ROCHE: No, they\'re not quite. They\'re not quite, and so as
I understand it, the numbers that were presented this morning were
essentially the absolute difference in two measurements over the maximum
of those two measurements. I read that off of the handout from this
morning.

So what that means is the numerator is the difference in two
measurements, and so essentially what you need to do with that, each one
of them has a variance. Each one of them contributes one of those
standard deviations from your table, except it has to be done in terms
of variance.

So to make a long story short, the conversion is that the FDA percent
standard deviation is the percent variation that was reported this
morning divided by the square root of 2, and that division being that in
the numerator of the statistic this morning, there were two measurements
being subtracted. So if you approximate no correlation between them,
they each contribute a variance, and then take the square root of that
because it\'s a standard deviation, rather than a variance.

So that\'s where that square root of 2 comes from, and so if you do
that, then I just sketched out on a thumbnail sketch what the 5 percent,
10 percent, and 15 percent on the table in front of you corresponds to
in terms of what we hearing this morning. So respectively, that would be
7 percent, 14 percent, and 21 percent. That\'s just multiply by 1.4, the
approximation of square root of 2.

One more number would be that if you went down to 3.5 percent on the FDA
table, that would correspond to 5 percent in terms of the figures that
we were hearing this morning.

DR. GRIMMETT: This is Dr. Grimmett. If I interpret that correctly,
that\'s actually good news, because that means the numbers that were
quoted this morning may be achievable because they actually translate
into lower standard deviations.

DR. BANDEEN-ROCHE: I interpret it the same way. Yes, and it seems
important to me that ‑‑ I mean, measurement, good quality of
measurement, is where we stand to gain precision and power, and however
that can be absolutely pushed for people to up their standards, it\'s
important.

DR. GRIMMETT: Dr. Grimmett again. So in Dr. Edelhauser\'s best case
scenario, though, the 2 percent precision factor could be achieved.
Assuming that could be done, then we\'re talking a standard deviation of
just slightly higher than that. For example, 3 percent or something like
that, whatever the number is.

DR. BANDEEN-ROCHE: Well, even lower, right? Yes.

DR. BURNS: Excuse me. Just a clarification. That\'s the precision of the
measurement, but not the standard deviation of the population, is it?

DR. BANDEEN-ROCHE: Right, but that\'s what I understood this to be. We
were talking about the precision of the measurement, right? Yes. So that
is what appears in the FDA Table 2. Those standard deviations refer to
standard deviation of measurement in a single person.

DR. WEISS: So with this information before us and your extra analysis,
I\'d like some opinions as far as what numbers of subjects we\'re
looking at and what yearly loss.

MR. CALOGERO: Don Calogero. Can I just mention one thing? I believe that
data was on the KeraVision rings, and those were sort of low myopia
patients. I believe they went up to 3 or 4 diopters. The population that
we\'re looking for with these devices is going to be higher.

I\'ve actually had my endothelial cell counts taken and I\'m 4 diopters
without my glasses. It\'s correct what they\'re saying. It\'s very
difficult to focus on that green light. I can imagine if you\'re 8
diopters or 12 diopters. So I suspect in the populations we\'re actually
looking at, that\'s a very conservative estimate.

DR. BANDEEN-ROCHE: There was a number being cited of 9 percent this
morning. I mean, again, just purely interpolating that would put us at
about 7.5. I mean, it\'s in-between the 5 and 10 percent on this table.

MR. CALOGERO: Okay. That\'s the KeraVision number.

MS. LOCHNER: So I think what Don is saying is that 9 percent figure came
from the KeraVision, which puts you in-between the 5 percent standard
deviation and the 10 percent. Maybe it would be prudent to go up at
least to the 10 percent standard deviation because the population these
will be used in will be a much more difficult population than the
KeraVision.

DR. BANDEEN-ROCHE: If I could ask one more question, these calculations,
were they based on just a three-year minus three-month difference?
That\'s what was being analyzed?

MR. CALOGERO: Yes, yes.

DR. BANDEEN-ROCHE: Because ‑‑

MS. LOCHNER: No, they were repeated measures.

DR. BANDEEN-ROCHE: All four measurements?

MS. LOCHNER: Yes, repeated measures, not ‑‑

MR. CALOGERO: Okay. As Ashley said, we established linearity with the
four measurements, but in terms of this particular calculation ‑‑

MS. THORNTON: Don, please speak into the microphone.

MR. CALOGERO: In terms of this particular calculation, it\'s I believe
the three-month value, the 36-month minus the three-month, and then you
simply divide by 2.75. The actual method and equation is right in the
information that we provided to you. I simply used the equation that\'s
in that document.

DR. BANDEEN-ROCHE: Right, and so certainly I would expect that some
precision could be gained by using all four measurements, rather than
just the difference between the last and the first, and so that would
impact this table.

Go ahead. Interject, interject.

DR. BRADLEY: This is Dr. Bradley. Could somebody clear up for me, the 9
percent that we\'re talking about from this morning, if I recall the
presentation, was the difference that would have to occur in a single
eye to confirm with 100 percent certainty that in fact a change had
occurred. Therefore, that was an estimate of the overall range, not the
standard deviation in that distribution. Perhaps the speaker from this
morning can clarify that.

PARTICIPANT: I agree with what you just said.

DR. BRADLEY: But I think it\'s being treated here as a standard
deviation.

DR. BANDEEN-ROCHE: Well, let me just clarify. So the overall range ‑‑
now, let me see if I read the wrong thing off of your handout, but the
way that I understood it was two measurements, maximum minus minimum
over maximum?

DR. McCAREY: If you\'re referring to the graph ‑‑

DR. WEISS: Can you identify yourself first for the transcript?

DR. McCAREY: My name is McCarey. If you\'re referring to the 9 percent
one, that was simply a subtraction of baseline and three months for each
individual.

DR. BANDEEN-ROCHE: Right, but that\'s an absolute difference.

DR. McCAREY: Yes.

DR. BANDEEN-ROCHE: Yes, and so you can approximate an absolute
difference by the square root of the squared difference, and so in turn
‑‑ I admit there are multiple approximations here, but it\'s not a bad
approximation. The square root of the square, then expectation of the
square is a variance, and that\'s how that enters in.

Yes, but I agree. It\'s worth doing this more carefully than on my
thumbnail.

DR. WEISS: So I think we could actually ‑‑ I think you\'ve given us the
data to look at and try to balance what we\'re willing to detect as a
yearly loss versus what we\'re willing to balance against as a maximal
amount of endothelial cell loss, and then we can choose the numbers we
want.

I would ask Dr. Grimmett if this is basically and opinion-type thing at
this point, but that\'s basically all you want right now. So do you have
an opinion as far as what you would wish for a yearly loss and an
allowable rate?

DR. GRIMMETT: Sure, but I\'m taking into account that some of these
numbers have largely varied. For example, in the .9 category of the
study of 669 patients, to have good accountability over three years is
pretty incredible, and which I don\'t think is really achievable or
reasonable.

Keeping that in mind, the higher numbers I guess at this point are 1.9,
2 percent loss. I would be extremely disappointed and worried if a
phakic IOL actually achieved that rate. I think it would indicate that
patients would actually develop corneal edema during their lifetime,
especially if they need cataract surgery. I would hope that they\'d have
a lower rate of cell loss.

What would I like to detect versus what is reasonable? Based on the data
here, I suppose if we could be at the worst, assure it\'s not higher
than 1.5. I\'d still hope it\'s a little lower than that. I think a 2
percent threshold is too high based on the actuarial tables that I ran.

Even for some of these lower numbers, even the 1 percent, if they have a
250 sample size ‑‑ 244 in this example with a 10 percent standard
deviation ‑‑ you know, they would be allowed to see a rate of .7 to be
sure with 90 percent confidence is not higher than 1. You could still
determine other factors, just not with this much precision. It\'s going
to be much harder at the lower rates, and then we admit the normal
endothelial cell loss rate is .6 percent per year or so. So we have to
account for that factor, and then there will be zero differential
between what he phakic IOL is actually doing versus normal cell loss
rate. The 1.5 is what I\'m looking at.

DR. WEISS: So I think perhaps you could say the 1.5 percent and
allowable rate being ‑‑

DR. GRIMMETT: Yes, just straight off the table. I mean, once we set the
sample size, it\'s going to lock this in to what their allowable rate is
to be sure of a 90 percent confidence is not higher than our threshold.

Given the difference ‑‑ for example, let\'s look at the 1.5 percent
category. Given the difference between the smallest number, the 243
sample size, and the unwieldy 542 independent patients over three years,
that\'s a huge number and it would cost probably a fortune to even try
to do it.

So I\'m still, I think based on statistics and ‑‑ I see I was looking at
the 15 percent standard deviation. But looking at the statistics and
stuff, I think that the sample size that we\'re actually asking for is
somewhere in the neighborhood of 250 or so. That\'s what it looks like
on this table. Whatever the number happens to be, but I think asking for
higher precision than that is not reasonable.

DR. WEISS: So I think from what I understand you\'re saying, yearly loss
would somewhat be dependent on the fact that most ‑‑ I would also agree.
You don\'t want to ask for than 250 to 300 patients. So that already
locks us into what we want our yearly loss to be.

DR. GRIMMETT: My hope is that with the precision and the careful
techniques that Dr. Edelhauser described, if they can actually be
implemented with care, is that by lowering the true standard deviation,
we\'ll have much better precision than we would want, and that\'s got to
be hopeful. Controlling technicians is so important to lower that
standard deviation to give the power of the study better precision.

DR. WEISS: Dr. Mathers?

DR. MATHERS: And our precision is going to improve with time because as
we monitor afterwards, presuming that is the case, then monitoring for a
longer period of time improves our data on the loss rate. It\'s not part
of this table, but this doesn\'t get worse over time. It gets better if
you continue to monitor.

DR. WEISS: Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Yes, I would just like to bring up a little something
about the safety and effectiveness precision given a sample size of 300.
This was Attachment A, Section A.1, and by my calculation ‑‑ you know,
of course, zero events is the least that you can have ‑‑ with a sample
size of 300, that gave a 95 percent upper confidence bound of .01.

Now, so that\'s a 1 percent, say, adverse event rate, and I would just
submit that for the panel\'s consideration. I don\'t think that that can
be argued as meeting the .001 standard that was cited in the attachment
in the way that I feel is honest and candid.

DR. WEISS: What sample size would allow you that rate?

DR. BANDEEN-ROCHE: Well, unfortunately, it\'s very large.

DR. WEISS: Well, what is very large?

DR. BANDEEN-ROCHE: Three-thousand.

DR. WEISS: So in other words, we have to change the rate. We might want
that rate, but none of us believe that a study with 3,000 patients can
be done.

DR. BANDEEN-ROCHE: That\'s right, but maybe it just supports the
importance of postmarketing data.

DR. WEISS: Okay. So it supports our concern for stringency.

Dr. Bullimore?

DR. BULLIMORE: And one of the continuing limitations of the data we
consider is we\'re presented, bombarded, with event rates and, give
complication rates or adverse event rates, we choose to ignore the
confidence intervals or we\'re not presented with the confidence
intervals that you give you an indication of the precision of those
estimates, and if you really truly want to ensure that the event rate
is, say, less than 1 percent, you would have to do as Dr. Bandeen-Roche
suggested, enroll considerably more patients, as was done, say, in
recent continuous wear contact lens studies.

We choose to ignore information, we sort of try and meet targets, and we
keep in the back of our minds often what the precision of the estimate
might be, but it\'s not something we consider on a regular basis, and
maybe we should, but I\'m not sure that we\'d like the answer that we\'d
get if we were presented with those on a regular basis.

DR. WEISS: Dr. Bandeen-Roche?

DR. BANDEEN-ROCHE: Well, just stating it another way, I mean, is the
panel willing to live with 5 percent of studies claiming an event rate
of .001 or less when in fact it\'s higher than 1 percent? I mean,
that\'s the ramification.

DR. WEISS: I think the difficulty is in the real world, if we required
the number of patients we would like to get the answer, it would take so
many years by that point the technology would be archaic.

Mr. McCarley?

MR. McCARLEY: Just one comment. There is always an ongoing postmarket
surveillance on products. Every year we have an annual report in all
products, and especially implants, where we essentially divide the
number of adverse events we\'ve had by the number of implants that have
taken place. So if we saw any increase in it, the FDA would immediately
take action or we\'d have to justify why that would be.

So I agree for the purpose of making an initial decision for a PMA, you
might not have all the information, but you certainly have the mechanism
in place to continue to monitor any higher rates.

DR. WEISS: Dr. Grimmett?

DR. GRIMMETT: Dr. Grimmett. I would counter that by saying that
postapproval, there is probably significant underreporting of adverse
events.

DR. MATOBA: We\'re going to collect data on both eyes, right? So for
events, specific events, that would become available to the FDA,
wouldn\'t it? On twice as many eyes potentially as 300?

MS. LOCHNER: Right, but the statistical assumptions that, for example,
would be inherent in this table would then have to be adjusted.

DR. MATOBA: From a practical point of view, but in terms of missing
something terrible, it\'s not as bad as she says.

MS. LOCHNER: I think from a practical standpoint, I hear you. I mean,
you will have more eyes from a practical standpoint.

But I think the issue with phakic IOLs isn\'t missing something
catastrophic early on, but missing a slow bleed that\'s occurring over
time and approving it without understanding that the rates could be
higher.

DR. WEISS: Dr. Bullimore?

DR. BULLIMORE: Reasonable assurance of safety. That\'s what we\'re asked
for.

DR. WEISS: I guess that\'s the difference between the 300 and the 3,000.

DR. BULLIMORE: Exactly.

I have one other issue on the endothelial cell count which I\'ve hinted
at before and I\'ll come back to. When these data are presented, I think
it will be appropriate not only to have the mean rate of loss, whether
you give that annually, but I think over a three-period, knowing the
proportion of eyes that have lost 10 percent, 20 percent, and 30 percent
of endothelial cells ‑‑ I mean, I\'m sure a reviewer\'s going to ask for
that information, but prospectively it should be at the forefront of the
analyses.

DR. WEISS: I wanted to find out if the agency had any other questions
for the panel at this point.

MS. LOCHNER: No, just if there are any other comments on any other
sections of the guidance.

One of the things that I think I took away from the earlier discussion
on contrast sensitivity is that we may need to provide to vision
scientists some of the data upon which we came to this conclusion about
contrast sensitivity, and so we may follow up with a homework assignment
to look at that because it\'s possible, first of all, that we\'re
misinterpreting what we\'re looking at, and so we took those contrast
acuity comments especially to heart if we are in fact doing that.

DR. WEISS: Dr. Matoba had a comment.

DR. MATOBA: I had a question about the guidance. Number 5, study
population. This is phakic IOLs for myopes, specified minimum
uncorrected visual acuity 20/40 or worse, meaning you could have myopia
uncorrected visual acuity of 20/40 and then be eligible to get into the
myopic phakic IOL study? Twenty/forty doesn\'t seem compatible with high
myopia.

DR. EYDELMAN: Dr. Eydelman. This is for all phakic IOLs. As Donna has
mentioned previously, current studies are not limited to high myopia. So
we have phakic IOLs for -2 and -3.

DR. WEISS: So would any members ‑‑ and I\'m going to regret asking this
question.

(Laughter.)

DR. WEISS: Briefly, would any members of the panel ‑‑ or actually, even
more importantly, does the FDA care whether the panel wants it to be
20/40 or not or it\'s irrelevant?

MS. LOCHNER: We care.

DR. WEISS: You care. That\'s too bad.

(Laughter.)

DR. WEISS: So do any members of the panel have any disagreement with
doing a phakic IOL for someone who\'s 20/40?

DR. BULLIMORE: I\'m having a senior moment. You were talking about
excluding patients with entering visual acuity of worse than 20/40?

DR. WEISS: Twenty/forty uncorrected. It\'s uncorrected visual acuity of
20/40. I want my 20/40 ‑‑

DR. MATOBA: Would make you eligible to get in the study.

DR. WEISS: Would make you eligible to have a phakic IOL at this point.

DR. GRIMMETT: This is Dr. Grimmett. You\'re using the 20/40 as a marker
for your refractive error.

DR. WEISS: It\'s about a -1, isn\'t it?

DR. GRIMMETT: Yes. You\'re really asking the question should patients
with low myopic or low refractive errors be entered into trials that
have significant risks that we\'ve discussed today of cataracts,
endothelial cell loss, pigment dispersion, glaucoma, et cetera?

DR. WEISS: And at the present time, they are being entered into this.

Dr. Mathers?

DR. MATHERS: I think they should not be entered into this study. We
should have a cutoff that is much higher than that for patients to enter
the study.

DR. WEISS: Okay. So what would your cutoff be?

DR. MATHERS: Minus 8.

DR. WEISS: That\'s pretty high.

DR. MATHERS: Maybe -6. I mean, -6 is very treatable with most LASIK
procedures.

DR. WEISS: So you would come down to a -6.

DR. MATHERS: Yes.

DR. WEISS: Dr. Swanson, do you have an opinion on this?

DR. SWANSON: Well, I have an opinion on most things, but I agree that
we\'re talking about something that has ‑‑ we want to determine what the
risks are, so it makes sense to look at the population that\'s
supposedly to be served by this risky procedure.

DR. BULLIMORE: I have a question related to the question. I think if we
start prefacing entry criteria and say, well, this population can be
adequately served by other technology, we\'re actually entering a very
dangerous bias zone.

A question for the folks who do this kind of thing. In terms of the
safety of the device, are there any a priori reasons why endothelial
cell count, contrast sensitivity loss, and lens opacifications would
expect to be greater in a low myope compared to a high myope or vice
versa?

DR. WEISS: I don\'t think they would be, but I think the concern is why
make the cutoff at 20/40? Why not do it at 20/25?

DR. BULLIMORE: Yes. Well, I agree that -1 is perhaps a little too
conservative, but I don\'t think we should say, well, we approved LASIK
up to -6. That should be our cutoff.

DR. WEISS: You know what? I think what you\'re hearing, and obviously
this discussion could go on for a while, but I think some members of the
panel have a concern that the low myopes, the risk/benefit ratio might
not be the same as in the high myopes, and where you would draw that
line would be up to discussion. Perhaps it would it be appropriate for
these IDEs to first do a higher group of myopes, and when there is
proven to be some sort of clinical safety and efficacy, then expand the
trial to the lower myopes.

Dr. Eydelman?

DR. EYDELMAN: Malvina Eydelman. That is exactly what I was trying to
make a point of, that we usually allow brand new phakic IOLs only in the
higher degrees of myopia, and once the sponsor obtains enough safety
information on the high myopes and submits it to FDA, then internally we
review it and decide that is sufficient, and we allow lower ranges.
Again, depending on safe we assess it to be, that\'s the degree of
myopia that we allow it to go down to.

DR. WEISS: Mr. McCarley?

MR. McCARLEY: Just very quickly, I agree with it. I think that it\'s
prudent to study higher myopes, develop a level of confidence and
safety, and then move down, but I would ask I guess a question about
LASIK, another refractive technology that apparently is now safe and
effective, though from what we heard yesterday morning or at the
beginning of this session, it may not be completely true when you have
large numbers of patients.

Aren\'t there lasers approved right now for -15, for instance? I think
so.

DR. WEISS: There are, but I don\'t think they\'re being used for it.

MR. McCARLEY: They\'re approved for it. That\'s what I\'m saying. So
it\'s sort of a double standard and I agree we all think of phakic
intraocular lenses as treating high myopia, and in fact, if you look at
the means of the data that\'s presented at the American Academy of
Ophthalmology and ASCRS, you\'ll see that that\'s up around the 12, 13.

But in fact, this may be a replacement technology. There may be benefits
we don\'t know over LASIK.

DR. WEISS: Dr. Swanson?

DR. SWANSON: Good. Thanks. I\'ve been promoted.

Well, I think the one question to consider there is, in terms of
effectiveness, one of the effectiveness criteria is percentage of eyes
that achieve uncorrected visual acuity of 20/40 or better. So if there
are a lot of people enrolled that are just worse than ‑‑ that are 20/50,
that effectiveness is not going to mean as much. So that\'s something in
terms of study design. The safety may not be different across eyes, but
the effectiveness should be considered.

DR. WEISS: Does the agency have any other questions?

(No response.)

DR. WEISS: I want to thank the panel and the presenters and the agency
for all their work and excellent preparation, and Sally will have some
closing comments before we end the meeting.

MS. THORNTON: I, too, would like to add my thanks to the panel, and to
Drs. Werner, Edelhauser, and McCarey for being with us today. It\'s been
quite a contribution you\'ve given to our proceedings, and I thank the
panel for all their hard work for yesterday as well.

I will be letting you know about mid-September what the story is for the
November 14-15 tentative panel meeting schedule. So stay in touch with
your website.

DR. WEISS: The meeting is closed.

(Whereupon, at 2:03 p.m., the meeting was adjourned.)