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      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
                                                            2

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
                                                          3

                         C O N T E N T S

                                                       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
                                                            4

                         C O N T E N T S

                                                         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
                                                                    5

1                          P R O C E E D I N G S       (8:30 a.m.)

2                DR. WEISS:    I'd like to call this meeting of

3    the Ophthalmic Devices Panel to order, and we will have

4    introductory remarks from Sara Thornton.

5                MS. THORNTON:    Good morning and welcome to the

6    104th meeting of the Ophthalmic Devices Panel.   Before we

7    proceed with the agenda, I do have a few short

8    announcements to make.

9                I'd like to remind everyone who is new to the

10   sessions today to sign in on the attendance sheet in the

11   registration area.    I'd actually like everyone to sign in,

12   but I know some of you have heard this announcement before.

13    But please do sign in right outside on the registration

14   table.

15               All handouts for the meeting are available out

16   there on the table, and we'd like, if you have messages for

17   the panel members, the FDA participants, if you need
18   information or have special needs, they should be directed

19   to Ms. Annmarie Williams, who's over here by the door, and

20   Ms. Jennifer Weber.    They're both available also at the

21   registration area.

22               The phone number for calls to the meeting area

23   is (301) 977-8900, and in consideration of the panel, the

24   sponsor, and the agency, we ask that those of you with cell
25   phones and pagers please turn them off and put them on
                                                                    6

1    vibration mode while you're in this room.

2                 Lastly, will all meeting participants please

3    into the microphone, directly into the microphone, less

4    than four inches away, according to my instructions, and

5    give your name clearly, so that the transcriber will have

6    an accurate recording of your comments and others will be

7    able to hear you.

8                 Now, at this time, I would like to announce to

9    those new to the session today the confirmation of the new

10   Ophthalmic Devices Panel Chair, Dr. Jayne Weiss, to my

11   left.   We also have three newly appointed voting members,

12   Dr. Anne Coleman, Allen Ho, and Timothy McMahon, who are

13   regrettably unable to be with us today.     However, we look

14   forward to their attendance at future meetings.

15                I'd also like to extend a special welcome and

16   introduce to the public, the panel, and the FDA staff three

17   panel consultants who today are with us for the first time.
18    Dr. Stephen Burns, on my left, who comes to us from

19   Boston, Massachusetts, where he is a senior scientist at

20   the Schepens Eye Research Institute and an associate

21   professor at Harvard University.   Dr. Cynthia Owsley, to my

22   right, is from Birmingham, Alabama, where she is a

23   professor of ophthalmology in the School of Medicine and

24   co-director of the Center for Research on Applied
25   Gerontology at the University of Alabama.    Lastly, Dr.
                                                                   7

1    William Swanson, on my right, is a senior research

2    scientist in the Department of Clinical Sciences at the

3    State University of New York College of Optometry in New

4    York, New York.

5                  I'd like now to read the conflict of interest

6    statement for this session of the 104th meeting.    "The

7    following announcement addresses conflict of interest

8    issues associated with this meeting and is made part of the

9    record to preclude even the appearance of an impropriety.

10                 "To determine if any conflict existed, the

11   agency reviewed the submitted agenda for this meeting and

12   all financial interests reported by the committee

13   participants.    The conflict of interest statutes prohibit

14   special government employees from participating in matters

15   that could affect their or their employers' financial

16   interests.    However, the agency has determined that

17   participation of certain members and consultants, the need
18   for whose services outweighs the potential conflict of

19   interest involved, is in the best interests of the

20   government.

21                 "Therefore, waivers have been granted to Drs.

22   Mark Bullimore and Stephen Burns for their interests in

23   firms that could potentially be affected by the panel's

24   recommendations.    The waivers allow these individuals to
25   participate fully in today's deliberations.    Copies of
                                                                     8

1    these waivers may be obtained from the agency's Freedom of

2    Information Office, Room 12A-15 of the Parklawn Building.

3                   "We would like to note for the record that the

4    agency took into consideration other matters regarding Drs.

5    Arthur Bradley, Michael Grimmett, and Jayne Weiss, who

6    reported interests in firms at issue, but in matters not

7    related to today's agenda.    The agency has determined,

8    therefore, that they may participate fully in all

9    discussions.

10                  "Lastly, we would like to note for the record

11   that Drs. Henry Edelhauser, Bernard McCarey, and Liliana

12   Werner, all invited guest speakers today, reported

13   interests with firms at issue.    Dr. Edelhauser reported a

14   personal financial interest, a consulting relationship, and

15   a professional relationship in the form of contracts and

16   research grants.    Drs. McCarey and Werner reported

17   professional relationships in the form of contracts,
18   grants, or research.

19                  "In the event that the discussions involve any

20   other products or firms not already on the agenda for which

21   an FDA participant has a financial interest, the

22   participant should excuse him or herself from such

23   involvement and the exclusion will be noted for the record.

24                  "With respect to all participants, we ask in
25   the interest of fairness that all persons making statements
                                                                   9

1    or presentations disclose any current or previous financial

2    involvement with any firm whose products they may wish to

3    comment upon."

4                Thank you, Dr. Weiss.

5                DR. WEISS:    Thank you, Sally.

6                We're going to have some comments at this point

7    by Mr. David Whipple.

8                MR. WHIPPLE:    Thank you.

9                I only had one comment that I wanted to make

10   this morning.    I wanted to thank this panel for yesterday's

11   discussion of the labeling for the wavefront technology

12   LASIK device.    I know it was long and difficult, but a very

13   important discussion for us in the agency.    Not only will

14   we use your comments and recommendations as guidance in a

15   framework for building labeling for devices of this type,

16   but we will also use it for monitoring the promotion and

17   advertising when they go to market their products as well.
18    So thank you for that discussion yesterday.

19               DR. WEISS:    Thank you very much.

20               We're going to proceed to the open committee

21   session and start with the FDA presentation.     Excuse me.

22   I'm out of order.   We're going to start with the open

23   public hearing session and Dr. John Vukich of the

24   University of Wisconsin is going to make his presentation.
25               DR. VUKICH:    Thank you and good morning.
                                                                     10

1                 DR. WEISS:    Would you be able to start by --

2    just start by identifying yourself and your conflicts, if

3    any.   Thank you.

4                 DR. VUKICH:    Okay.    Thank you.

5                 My name is John Vukich.      I am an associate

6    professor at the University of Wisconsin in the Department

7    of Ophthalmology.   I'm an investigator and medical monitor

8    for Staar Surgical, and it is from this experience that I

9    draw the information from which I form my opinions that I

10   will be presenting this morning.

11                My testimony today, however, is as an private

12   citizen.   I have not received support or reimbursement for

13   my visit today, but I'm here to speak on behalf of phakic

14   IOLs as a segment of the refractive industry and as an

15   option for the correction of myopia.

16                Right now, LASIK is gold standard by which we

17   need to compare all future refractive technologies.      We're
18   clearly trying to improve the outcomes of LASIK, and I

19   believe the decision yesterday to allow custom ablations is

20   a step in that direction.    Any new technology that comes

21   along certainly is going to be compared to LASIK, and what

22   I'd like to do is present some information on the

23   comparison of LASIK and phakic IOLs.

24                We have looked at this in my practice.      I am
25   primary a refractive surgeon.       Most of my practice revolves
                                                                    11

1    around this.    We looked at 198 phakic IOLs with a mean

2    myopia of -10.     We compared this to a similar number, 219

3    LASIK patients similarly high myopia of between -9.5 to 12.

4     The mean was -9.5.     Predominately female and younger

5    patients in their mid-30s.

6                   When we looked at the percent of patients who

7    achieved 20/20 or greater, again, in this relatively highly

8    myopic group of patients, we found that about 32 percent of

9    patients on their treatment achieved 20/20 or better with

10   LASIK -- again, with a mean correction of close to -10 --

11   and close to 50, or 48.5 percent, were able to achieve

12   20/20 or better with phakic IOLs, and this was

13   statistically significant.    The curve did fall off towards

14   the end and this was due to an early in the clinical trial

15   difference in the nomograms, and this curve has in fact

16   stayed the same all the way out and has remained consistent

17   for this difference.
18                  So we believe that phakic IOLs, at least as a

19   single procedure, offer an alternative to LASIK in the

20   quality of vision that a patient might expect in the higher

21   ranges.

22                  We know that recovery of visual acuity is an

23   important issue.    Ultimately, patients need to retain their

24   visual acuity, but the rapidity of recovery is also an
25   issue, and the length of disability is an important issue,
                                                                   12

1    of course.

2                  When we look at lines lost or gained early in

3    the recovery at one week, we see that with LASIK, again in

4    the higher ranges, it is not uncommon -- almost 28 percent

5    of patients lost two lines or more of acuity early on, and

6    we can explain this because of epithelial irregularities,

7    surface irregularities, or edema in the early postoperative

8    period.   We contrast that with phakic IOLs, in which not a

9    single patient in this clinical trial lost two lines or

10   more of visual acuity at week.

11                 When we look at six months out, of course, we

12   would expect the epithelial changes to have recovered, and

13   in fact that is the case.   However, there still were 6

14   percent of LASIK patients who had lost two lines or more.

15   This predominately fell from 20/15 to 20/25.    Nevertheless,

16   this is a demonstrable loss of quality of vision that has

17   persisted through six months.    Again, contrasting with
18   phakic IOLs, in which there was not a single patient who

19   had lost two lines of visual acuity.    So in terms of

20   preservation of acuity, we believe that phakic IOLs offer a

21   good alternative, and perhaps superior, to corneal ablative

22   procedures.

23                 We have anecdotal reports that patients prefer

24   the quality of vision with phakic IOLs.    There have been a
25   limited number of patients who have had a phakic IOL in one
                                                                  13

1    eye and LASIK in the other, and we have heard in fact that

2    at least one clinical trial from a prominent researcher in

3    Greece was discontinued because of the strong preference of

4    the phakic IOL eye and it was felt that continuing on that

5    did not make sense for them.

6                  So based on this, we felt that perhaps maybe

7    there was something we could do to demonstrate a

8    difference, and what we have done is we have looked at

9    wavefront analysis as an objective assessment of optical

10   quality, and have now looked at comparison of the induced

11   aberrations in patients who have either received a phakic

12   IOL or LASIK.

13                 These were 10 patients, 20 eyes, two eyes in

14   each patient.   The mean myopia in the phakic IOL group was

15   -12 ranging to -15.    The LASIK group ranged up to -10.5

16   with a mean myopia of 8.75 or a few diopters less.

17                 When we looked at coma group means square
18   values, for phakic IOLs the average value was .22 or less

19   than half of the amount of coma observed in LASIK patients

20   postoperatively, and this was highly significant at the

21   .001 level.

22                 We can do image convolutions to demonstrate

23   this difference looking at the standard Snellen chart.

24   This is what a patient might expect to see in simulation
25   with this much induced coma in LASIK, and this is what they
                                                                   14

1    might expect to see with this much induced coma from a

2    phakic IOL.

3                  We can do the same image convolution with a

4    photograph.   Again, with LASIK and with the phakic IOL, and

5    we believe that there's a demonstrable difference in the

6    quality of the images that the patients see and what we can

7    demonstrate mathematically.

8                  We looked at spherical aberration as well as an

9    isolated fourth-order higher term, and we see that there

10   were three times as much induced, or at least three times

11   as much observed, RMS of spherical aberration in the LASIK

12   compared to the phakic IOL.   Again, significant at the .001

13   level.

14                 When we look at the image convolutions of this,

15   we see the LASIK image compared to the phakic IOL image,

16   and again we can look at photographic convolutions with

17   LASIK and with the phakic IOL.
18                 All of these images again demonstrate what we

19   have heard anecdotally, and that is that the patients with

20   phakic IOLs seem to be very pleased with the quality of the

21   image that they receive.

22                 These images or these RMS values do combine and

23   it would probably make more sense to look at the

24   combination of terms.   When we look at spherical and coma
25   RMS combined, we see LASIK versus phakic IOL, and once
                                                                  15

1    again the image with phakic IOL.

2                Well, custom corneal ablation is not ideal

3    option for high myopia.   The approval up to -7 yesterday I

4    believe is a step forward in our ability to correct myopia,

5    but one of the issues that I think will limit this

6    application is the fact that it can remove up to 20 microns

7    of tissue per diopter with larger ablation zones and with a

8    custom application.   I believe this will ultimately limit

9    custom ablations to ranges that are already approved, at

10   least from one manufacturer, but in fact the simple physics

11   and the simple anatomy may eliminate this as a possibility

12   for higher corrections.   So it would certainly be

13   beneficial to have a noncorneal alternative.

14               There is in fact a limit to how much corneal

15   tissue can be removed.    This is a macroscopic view of a

16   cadaver eye that has had corneal tissue removed down to a

17   level of 100 microns.    This is clearly thinner than what we
18   would do clinically, but it does demonstrate grossly the

19   elastic character of the posterior surface of the cornea

20   and again is consistent with what we can observe with

21   advanced imaging technologies.

22               Corneal ablation is certainly not appropriate

23   for some patients no matter what the correction achieved.

24   Patients with keratoconus, as demonstrated here, clearly
25   would not be suitable for corneal reshaping, but there are
                                                                     16

1    certainly many more patients who have subtle changes that

2    come to our attention when we screen them for refractive

3    surgery, changes of mild elevation, changes on the

4    posterior surface elevation, or keratometric changes that

5    are subtle variants of what we would consider an abnormal

6    corneal topography or corneal anatomy, and in fact a

7    noncorneal alternative may be a superior alternative for

8    these patients as well.

9                The fact remains that there are few options

10   available to patients who have high myopia.      This has led

11   to some options being employed that are not approved and in

12   fact may pose dangerous situations for patients.     We have

13   certainly seen clear lens extraction as an unapproved use

14   of an approved IOL for cataract surgery, but again used in

15   a refractive manner.    This is controversial.   However, it

16   is being done.

17               With one anecdotal report from a clinical trial
18   center in the United States of a refractive-based practice,

19   we looked at the incidence of clear lens extraction before,

20   during, and after the availability of phakic IOLs in this

21   individual practice.    The white bar beneath represents the

22   time during which enrollment was available for phakic IOLs,

23   and we can see that there was a significant decrease in the

24   total number of clear lens extractions performed as a
25   refractive procedure.    At the conclusion of enrollment,
                                                                     17

1    there was an over doubling of the number of clear lens

2    extractions.

3                   Again, this is consistent with the researcher's

4    or with the investigator's observation that given an

5    alternative, this particular researcher would shy away from

6    clear lens extractions, and we believe that this is a

7    better alternative and perhaps something that I think would

8    offer our patients perhaps a better, or we hope safer,

9    alternative.

10                  In conclusion, I would like to suggest that

11   corneal refractive surgery is an excellent opportunity for

12   patients.   Many of them enjoy -- most all enjoy -- the

13   benefits of this, but I believe that a noncorneal

14   alternative is an important step forward.      I believe that

15   the safety and efficacy of phakic IOLs needs to be

16   demonstrated, but certainly the opportunity to provide

17   quality of vision seems to be quite high.
18                  DR. WEISS:    Thank you.

19                  Do any of the members of the panel have any

20   questions for Dr. Vukich?      I would actually start off with

21   one question myself, which is how would you weigh the

22   potential risks of intraocular surgery -- namely,

23   endophthalmitis, albeit rare, and corneal edema -- against

24   the benefits of the visual recovery and quality of vision?
25                  DR. VUKICH:    Well, certainly, any time we go
                                                                   18

1    inside the eye, we have to hold a different standard than

2    we would on the surface.    We know that infection is an

3    option, or at least is a problem, with LASIK, albeit rare,

4    but it's somewhat devastating when it does occur.    It is

5    something that needs to be looked at very carefully in

6    terms of the real incidence.

7                 I think the bigger issue in my opinion is the

8    potential for removability of these devices, and that is

9    that there is an alternative to restore the eye perhaps not

10   exactly to what it was preoperatively, but to remove

11   whatever the patient may not have liked about the quality

12   of vision.   If there is edge glare or halos or night vision

13   problems or decentrations with LASIK, the remedies are

14   typically not satisfactory, and in fact with the phakic

15   IOL, at least the opportunity to reverse that or remove the

16   offending treatment certainly I believe offers a

17   significant advantage.
18                DR. WEISS:    Depending on if the offense is

19   irreversible endothelial cell loss or infectious organisms

20   or cataract formation.

21                DR. VUKICH:   Very clearly, those are things

22   that have to be looked at.    Endothelial cell counts are a

23   critical issue, as are the potential for infection.

24                DR. WEISS:    I think Dr. Bradley had a question,
25   and Dr. Bullimore as well.    Let's start with Dr. Bradley.
                                                                     19

1    Dr. Bradley, Dr. Bullimore, and then Dr. Mathers.

2                  DR. BRADLEY:    I was just looking at your slide

3    where you showed visual acuity as a function of time after

4    the procedure, and I didn't quite follow your explanation

5    of why the phakic IOL percent of patients achieving 20/20

6    fell off at 12 months.      You sort of ran through some sort

7    of excuse it sounded like.

8                  DR. VUKICH:    I'd like to think of it as the

9    reason.    The early nomograms for calculation of power will

10   be represented at the last data point collected as time

11   goes on.   So the first several phakic IOLs that were

12   implanted in this clinical trial systematically

13   undercorrected all the patients, and mid-course adjustment

14   or early-course adjustment and the attempted correction

15   versus achieved correction became substantially better.       So

16   that dip between six months and 12 months, which was the

17   two data points at six months and 12 months and there was
18   no in-between visit, remains something that between 12

19   months and two years we have seen that seem dip, and now

20   between two years and three years we see that same dip.       It

21   is just simply the leading edge representing the earliest

22   patients who were enrolled, but the remainder of the line

23   stays as it has been with the improved nomogram.

24                 DR. BRADLEY:    Thank you.
25                 DR. WEISS:    Dr. Bullimore?
                                                                  20

1                DR. BULLIMORE:   Yes, this is Mark Bullimore.

2    If my memory serves me correct, one of the issues discussed

3    by the panel at previous visits to this phakic IOL guidance

4    document was whether these devices should be held to the

5    same standard as LASIK.   What's your impression?

6                DR. VUKICH:   To the same standard in what

7    regard?

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

9                DR. VUKICH:   In terms of quality of vision?

10               DR. BULLIMORE:   Yes.

11               DR. VUKICH:   I believe that that is both

12   appropriate -- I don't know that we would want to see a

13   step backward in the evolution of any technology, and so

14   holding to the same standard I believe makes sense.

15               DR. BULLIMORE:   So in the absence of any other

16   information, you would argue that we should use the same

17   criteria for uncorrected visual acuity and corrected visual
18   acuity and loss of visual acuity that is currently used for

19   refractive lasers?

20               DR. VUKICH:   I think that makes sense.     I think

21   that it would also make sense to stratify the data into the

22   various ranges of power that you're looking at, knowing

23   that the standard for LASIK at -12 diopters should be

24   different than the standard at -1 or -2, and that the
25   outcome at that level could be a different expectation.
                                                                      21

1                 DR. BULLIMORE:    You mean in terms of safety or

2    efficacy or both?

3                 DR. VUKICH:   Both.

4                 DR. BULLIMORE:    So you would expect your LASIK

5    patients in your -10 group to be not doing as well as

6    patients with lower degrees of myopia?

7                 DR. VUKICH:   I would expect higher enhancement

8    rates.   I would expect potentially higher levels of

9    reported edge effect, glare, and those sort of symptoms in

10   the higher ranges.   We might also anticipate that the

11   higher ranges of LASIK may in fact become lower as we

12   implement custom corneal ablations limited by the tissue

13   effect that needs to be removed.       We simply don't do -12

14   LASIKs anymore.   At least, I don't, and many reputable

15   surgeons or high-volume surgeons have lowered the upper

16   limit at which they will perform LASIK, and that number I

17   believe is still going down.
18                DR. BULLIMORE:    But clearly there are some less

19   than reputable people doing a lot of clear lens exchange.

20                DR. VUKICH:   Again, I can't speak to the

21   decisions that other surgeons make.

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

23                DR. VUKICH:   In the face of not having an

24   alternative, it seems to be happening.
25                DR. BULLIMORE:    Yes.    And one final question.
                                                                       22

1    I mean, you presented data on 200 patients who had phakic

2    IOLs and LASIK.   Were they all from your practice?

3                  DR. VUKICH:    Yes.

4                  DR. BULLIMORE:    And where these people who had

5    the phakic IOLs, were they single device?

6                  DR. VUKICH:    Excuse me.    The phakic IOLs were

7    part of the multicenter trial.      Excuse me.    All the LASIK

8    patients were from my practice.

9                  DR. BULLIMORE:    Okay.   Thanks very much.

10                 DR. WEISS:    Dr. Mathers?

11                 DR. MATHERS:    Do you have any information about

12   observation of cataract formation that might have occurred

13   later?   I mean, these lenses have been implanted for some

14   time now, but we don't see any data on three years, four

15   years, or whatever, and certainly something was implanted a

16   little bit longer than we have seen data for.

17                 DR. VUKICH:    Yes, and we are collecting data
18   and do have a substantial amount.       In fact, all of the

19   patients in at least one of the clinical trials is

20   submitted.    Not submitted, but is through the two-year

21   point, and we're about halfway through the three-year

22   collection of data.   So yes, that data does exist on the

23   formation of cataracts in all of the safety and efficacy

24   parameters that were approved in the protocol that's been
25   undertaken.   Again, I am not prepared to do a thorough
                                                                      23

1    disclosure or presentation of that information, other than

2    to say it is going to be submitted and we believe

3    represents a standard that we believe is acceptable.

4                 DR. WEISS:    Dr. Huang?

5                 DR. HUANG:    Given the known potential

6    complications of cataract, glaucoma, and retinal

7    detachment, are you implying that this phakic IOL device

8    should be limited to the higher myopias?

9                 DR. VUKICH:    Ultimately, the complication rate

10   is something that is going to determine whether or not

11   phakic IOLs will be appropriate.    The quality of the optics

12   and the ability to correct a refractive error I believe is

13   intuitive and has been demonstrated and will be

14   demonstrated.   Ultimately, how safe they are is going to be

15   the issue as to where they should be used.

16                If a product can be demonstrated to be safe at

17   any range, I see no reason that it should be limited only
18   to the higher myopic patients.    I believe initially it

19   would make sense to offer this as an alternative for higher

20   myopic patients in which we know LASIK has limitations or

21   may not even be appropriate.

22                DR. WEISS:    Dr. Grimmett?

23                DR. GRIMMETT:    Dr. Michael Grimmett.    Is your

24   experience with phakic IOLs mostly of the posterior chamber
25   type?   You don't have any other experience or data
                                                                  24

1    otherwise regarding anterior chamber, either angle-

2    supported or iris clip?    Is that correct?

3                 DR. VUKICH:   All of my personal experience has

4    been with posterior chamber phakic IOLs.

5                 DR. GRIMMETT:   Okay.   Thank you.

6                 DR. WEISS:    Just one follow-up question in

7    terms of the standards that the IOL should held to

8    visually.   In a LASIK patient who has higher myopic error,

9    we can easily lift up the flap and enhance, but with a

10   phakic IOL, the risk of entering the eye again is higher

11   than a flap relift.   With that in mind, would you still

12   hold them to the same visual results postoperatively?

13                DR. VUKICH:   I think comparisons would need to

14   be made based on a one- or two-procedure comparison.     I

15   believe that all of the trials for LASIK have been as a

16   single procedure without enhancement, and I think the

17   ability to enhance we understand is real and people can do
18   that, but I believe that all the submissions have been on

19   primary treatment, not enhanced data.

20                Now, the ability to do a minor -- or not minor.

21    To do a corneal treatment on top of a phakic IOL certainly

22   exists, although the answer to question is yes.    Going back

23   in for a small refractive error probably could easily be

24   done on the corneal level, perhaps more appropriately so
25   than exchanging the implant.
                                                                   25

1                DR. WEISS:    Any other questions from the panel?

2                (No response.)

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

4    your presentation.

5                DR. VUKICH:    Thank you.

6                DR. WEISS:    Are there any other comments from

7    anyone else for the open public hearing session?

8                (No response.)

9                DR. WEISS:    If not, we will now -- obviously, I

10   was anxious for the FDA presentation.   So now, we will have

11   it.

12               MS. LOCHNER:    I'm just going to make a few

13   introductory comments before we actually present the

14   questions to the panel.

15               Today we plan to discuss with the panel

16   clinical study design for phakic intraocular lenses.     We

17   have prepared for your review a document entitled "Phakic
18   Intraocular Lenses:   Clinical Guidance for Ophthalmic

19   Devices Panel Discussion, August 2, 2002," which is a

20   compilation of several activities in which the FDA

21   participates.   It generally represents a composite of the

22   American National Standards Institute standard, the

23   International Organization for Standardization standard,

24   and the FDA's guidance document for phakic IOLs.
25               We last received the panel's recommendations
                                                                  26

1    for phakic IOL studies in 1998 and so we thought it

2    important to receive updated recommendations from the

3    panel.   We will then compile your recommendations and

4    present to the ANSI and ISO Standards Committees and update

5    FDA's guidance document accordingly.   By having this

6    discussion today, we believe sponsors of these studies will

7    gain valuable information to successfully prepare

8    investigational device exemption and premarket approval

9    applications for their phakic IOLs.

10                We will begin this morning with presentations

11   from our invited speakers on two topics.    First, Drs. Henry

12   Edelhauser and Bernard McCarey from Emory University will

13   discuss methodology and analysis for endothelial cell

14   density specular microscopy measurements.   Next, Dr.

15   Liliana Werner from Storm Eye Institute will provide

16   background for the measurement and analysis of lens

17   opacity.
18                Following the invited speakers' presentation,

19   we will focus the panel's discussion on three areas.

20   First, the endothelial cell density study with Dr. Michael

21   Grimmett as the primary reviewer; second, measurement of

22   lens opacity with Dr. William Mathers as the primary

23   reviewer; and third, contrast sensitivity with Dr. Mark

24   Bullimore as the primary reviewer.
25                Questions have been provided to each of these
                                                                    27

1    panel members for these topics to help to generate

2    discussion.   However, we hope the panel will allow the

3    discussion to move to any area of significance to them.        We

4    hope to step through each of the three areas -- endothelial

5    cell counts, lens opacity, and contrast sensitivity -- one

6    by one, opening each topic to full panel deliberations

7    after each of the primary reviewers' comments.     After these

8    three primary areas have been discussed, Dr. Weiss will

9    open the discussion to comments on any section of the

10   clinical study guidance.

11                 Unless there are any questions about the

12   agenda, I would like to move on to the invited speakers.

13   First, I'd like to express my gratitude to Drs. Henry

14   Edelhauser, Bernard McCarey, and Liliana Werner for taking

15   time from their schedules to present to us today.    We are

16   honored to have people of their caliber providing their

17   insights to these important topics.
18                 I would like to introduce the first two invited

19   speakers.   Dr. Henry Edelhauser is professor of

20   ophthalmology and director of ophthalmic research at Emory

21   University University School of Medicine in Atlanta.      He

22   received his Ph.D. from Michigan State University and

23   joined the faculty of the Medical College of Wisconsin.        In

24   1989, he became the Ferst Professor of Ophthalmology and
25   director of ophthalmic research at Emory.   He has served as
                                                                   28

1    president of ARVO and has received the Honor and Senior

2    Achievement Award from the American Academy of

3    Ophthalmology.   He also has received the Castroviejo Medal

4    and the Alcon Research Award.   He presented a keynote

5    lecture at the 55th Congress of Clinical Ophthalmology in

6    Japan entitled "Cataract and Refractive Surgery:     The

7    Effect on the Corneal Endothelium."      His research interests

8    include surgical pharmacology, corneal physiology, drug

9    delivery, and ocular toxicology.

10                And Dr. Bernard McCarey is professor of

11   ophthalmology at Emory University School of Medicine and

12   affiliate scientist at Yerkes Regional Primate Center at

13   Emory.   He received a Ph.D. from Marquette University and

14   joined the Department of Ophthalmology at the University of

15   Florida College of Medicine.    He joined Emory in 1979 and

16   has served as chairman of their Institutional Animal Care

17   and Use Committee.   He has received the American Academy of
18   Ophthalmology Section Honor Award, the Barraquer Award, the

19   Alcon Research Award, the CIBA Vision Research Excellence

20   Award, and Everett Kinsey Lecture Award at CLAO.     His

21   research interests include corneal physiology, refractive

22   surgery procedures, ocular toxicology, and contact lenses.

23                And so, without further ado, I'll turn it over

24   to Drs. McCarey and Edelhauser.
25                DR. McCAREY:   Thank you.
                                                                   29

1                  My name is Bernard McCarey.   As you've been

2    told, I'm at Emory University.    I have been interested in

3    specular microscopy as a laboratory science and also as a

4    clinical science.    At present, I am a reading center for

5    Medennium.

6                  What I'd like to discuss today with you is --

7    whoops.    We're not moving forward.   It's hooked up, but it

8    doesn't move.

9                  DR. WEISS:   I'd just mention at this point,

10   after all the speakers give their presentation, they can

11   actually sit at this table over here with your names there,

12   so the panel has an opportunity to ask you questions.

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

14                 There are several specular microscopy units on

15   the market presently and they break into two categories,

16   contact and non-contact.     I present this as a list for your

17   handout.    You can look at it later, but what I would really
18   like to do is to express to you the major differences

19   between the contact and non-contact.

20                 Obviously, contact means you have to use an

21   anesthetic.     You have to applanate the surface of the eye,

22   but you also are flattening the surface of the eye, and

23   when you do this, you generally can look at a larger field.

24    So generally, the contact units are considered large-field
25   specular microscopy.    The non-contact has a smaller field.
                                                                  30

1                You can see on the very bottom of your slide

2    we're talking about 700 or 800 cells can be visualized with

3    a contact unit, whereas only 160 or so for the non-contact,

4    and this has to do with the height of the slit.   If we had

5    time, we'd go into specular glare, but basically the slit

6    in both of these instruments is the same width.   It's just

7    a different height.

8                We are going to be collecting data about the

9    cell morphology, cell area, cell density, polymegethism,

10   which is an order of variation in size, and pleomorphism,

11   which tells you about how many sides there are on a cell.

12               I add this slide just for your notes.   It

13   expresses the calculation for cell density and coefficient

14   of variation.

15               I also add this for groundwork.   It gives you a

16   feeling as to what people would say at middle-age the

17   number of cells would be on a corneal endothelium, and it
18   varies with age.   This is well-known in the literature and

19   we can find many references in the literature towards these

20   numbers.

21               But what I'd really like to show you is that

22   these numbers are from linear regression lines.   They are

23   not a number.   A person doesn't have a 2,700 cell density

24   because they're the age of 50.   Rather, there's quite a
25   wide spread, as illustrated from this data from Dr.
                                                                   31

1    Edelhauser in 1985.   You can see a person of age 50 can

2    have anything from 2,200 on up to 3,300.   So there is quite

3    a spread.

4                We also have a convention, an issue, that I'd

5    like to mention.    That is, polymegethism is often referred

6    to in the literature as a value like .27 for a normal young

7    adult, but you can also see 27.   Don't be confused.   It's

8    just a literature convention.

9                The spread in coefficient of variation is

10   sometimes even larger in the normal population, as

11   illustrated here.   So please don't expect to find one

12   number.

13               The major question that we're going to have

14   here is if you do a surgical trauma or something else to

15   the eye, how representative is a central endothelial cell

16   density to the information of what happened to that tissue?

17    If you cause local damage in one area of the cornea, how
18   fast does it affect another area, what does that time

19   duration spell, and can you really look at central

20   endothelium and get a feeling for what trauma occurred?

21               I reached back in the literature back to '79,

22   and I use this not as an example of what a surgical

23   technique may do to the tissue, but rather as an example of

24   how the tissue responds to a surgical event.
25               In this case, there was phacoemulsification and
                                                                   32

1    extracataract extraction, and what the person did was

2    they're obviously making an incision in the superior area,

3    going into the eye, potentially damaging endothelium in the

4    superior zone, and if we look at the control tissue, we can

5    inferior, central, and superior clustered together.     After

6    the surgery, we see superior has dropped considerably,

7    central has less, and inferior less.

8                So the question is will this spread of damage

9    rapidly congeal to one point again?    And if you look at

10   this data, for 24 months there was only slight difference,

11   and it took on up to five years or more before all three

12   zones expressed themselves with the same value.    So these

13   things go slowly.

14               DR. BULLIMORE:    Before we move on, am I correct

15   in assuming there's only three people in that last data

16   point?

17               DR. McCAREY:     I'm glad you mention it.   No.
18   There are three people, but what this data did was he

19   collected the data at one time point.    So he had 28

20   patients and some of them were out five years and some were

21   out four years or whatever, and he just collected the data

22   in that manner.   Yes, there are very few data points in

23   each one of these, but I show this as an illustration as to

24   what can occur.
25               As another example, we're looking at data from
                                                                  33

1    intracapsular cataract extraction, and if I point just to

2    mean cell area, you look at rapid changes going on for the

3    first four months and then some kind of a linear response.

4     Now, this is characteristic, if we looked at keratoplasty,

5    where you'll see much the same kind of event, rapid changes

6    -- in this case, six months -- and then a progressive

7    change.   So this gives you a feeling as to when you might

8    want to collect data because of the kind of tissue

9    response.

10                If we reach back into the literature from Dr.

11   Bourne, we can see that he chose to follow patients for 10

12   years after cataract extraction.   It doesn't matter if it's

13   with or without an implant.   The point is that he followed

14   the patients for 10 years and he saw a rather in form cell

15   loss of 2.5 percent per year.

16                We often are referring to what a normal patient

17   would lose as far as endothelial cell density over time
18   simply because of aging, and we can refer to a paper by

19   Bourne.   He says he followed them up for 10 years and he

20   has .6 percent, plus or minus 5 percent.   I feel that's a

21   rather conservative number, but this is a number that's in

22   the literature.

23                One of the things we must realize is that we're

24   often using patients in clinical trials, such as refractive
25   surgery clinical trials, and these patients have a history,
                                                                  34

1    and the history may often be contact lenses.   So we're

2    entering patients in that are not "pure normal" patients,

3    but somebody that has a history of some kind of possible

4    trauma to the endothelium, and we can definitely say in the

5    literature that there are both transient problems with

6    contact lens wear, but also chronic problems in which we

7    have pleomorphism and polymegethism shifts in the tissue

8    over time.

9                 So these patients will often look like this,

10   and I point these three examples out because you'll notice

11   that the cell densities are all fairly high and all fairly

12   much the same.   Cell density is not going to give you the

13   full answer as to what that history of the patient was.     We

14   have to look at the coefficient of variations, and we'll

15   see that they vary from 45 on up to 76.   They can be quite

16   high, and that's expressing the fact that we have some

17   large cells interdispersed among the smaller cells.
18                The way we're going to analyze this tissue is

19   by multiple methods out there in the literature.   The first

20   one is a comparison method.   Look at a picture, look at a

21   honey comb, and how many cells do we have?   It just tells

22   you cell density.

23                The frame method is another method.   Just cell

24   density.
25                The next two methods, corner method and center
                                                                   35

1    method, are going to give you actual cell area, and from

2    that we can calculate coefficient of variation and other

3    values.

4                  Let's take a moment to look at the frame

5    method.    The technique is, on the screen or from a

6    photograph, you put a box, and then you simply count the

7    cells within the box.    The box is a small portion of a

8    millimeter.    You adjust it up to a full millimeter, and

9    that's going to be the answer.    So you just simply get cell

10   density.

11                 One of the really easy pitfalls in this is that

12   in this example I've made a blue box, and the data over

13   here is in blue, and a yellow box.    The blue box is twice

14   the surface area of the yellow box, even though it may not

15   look it, and if you give somebody an opportunity and tell

16   them to put a box on a field, they're going to make a small

17   box.   What this means is that if it's twice the surface
18   area, if you counted 90 cells within the blue box, you have

19   to multiply it by 27 in order to get it up to a full square

20   millimeter.    If you had the yellow box, you'd count 45 --

21   it was half the size -- and you'd have to multiply it by

22   55.    So right off the bat, you have a two-fold error

23   magnifier in your calculations simply by the size of the

24   box, and most people make small boxes.
25                 The other method is the center method.   In this
                                                                    36

1    one, we put dots in the center and calculate what the

2    nearest neighbor is, and from this you calculate a polygon,

3    which is the cell, and so forth.   Dr. Edelhauser will

4    discuss the patterns of this method in a few moments.

5                  One of the things we must worry about is if you

6    put the dot offcenter, does it louse up the calculation?

7    And with the Konan software, you have a very nice

8    opportunity of simply a dot and then asking for this

9    analysis.   Come back, move another dot, ask for the

10   analysis.

11                 So I did this for 10 different cells, and you

12   can see that the error is fairly small.     It's less than 1

13   percent.

14                 I then dropped a cell.   That is, took a dot

15   away, and tried it with various sizes of cells, and it

16   didn't seem to matter.   I even used a hexagon pattern,

17   which was a perfectly uniform pattern, and it looked like
18   each cell that you missed the dot on, you lost about a

19   percent in the accuracy of the answer.

20                 Another question is how many cells do we need

21   to count?   This is the classic one you see in the

22   literature.   If you count more cells, you get a more

23   accurate answer.

24                 So I got a large field like this, divided it up
25   into multiple boxes, and then counted 10 cells, 20 cells,
                                                                     37

1    30 cells, and so forth to create a series of lines, as

2    illustrated on this.   So each one of these is an effort of

3    increasing the number of cells in the count.

4                  You'll notice if you have a uniform, low

5    coefficient of variation cell pattern, you can get a fairly

6    good answer right off the bat.   It improves when you get to

7    about 50 and it's a slight improvement beyond that.      So you

8    don't need to count an awful lot of cells.

9                  Coefficient of variation?   It's a little bit

10   noisier.   You certainly want to be over 50 cells counted in

11   order to get a reasonably uniform answer, but there's

12   always a spread in the answer.

13                 This is more real life.   This is a patient that

14   may have had a contact lens or some history of something or

15   simply an older patient with a higher coefficient of

16   variation, 45.   Do the same kind of analysis.   Now look at

17   the spread.   It's tremendous.   If you counted 25 cells, you
18   could have anything from 2,000 to 3,200 for cell density.

19   It gets better over 50 or 100 cells, but it never gets

20   really tight.

21                 Coefficient of variation is even worse.    This

22   is just summarizing.   You can look at this on your handout,

23   but basically it says that if you have a large coefficient

24   of variation, you're going to get a larger spread and you
25   can't get away from that.
                                                                 38

1                 Also I want to mention some of things that are

2    pitfalls in the analysis.   That is, when you ask the

3    clinical site to count 100 cells, they may tap 100 cells on

4    the cell pattern, as illustrated here on your right, but

5    the analysis using nearest neighbor -- for instance, if

6    this was seven dots and you asked for the calculation to be

7    performed, you'd only see that you actually counted one

8    cell, the one in the center.   The others were just nearest

9    neighbor in the analysis.

10                So if you want somebody to count 100 cells,

11   coming down we have to count actually about 140 cells in

12   the analysis.   Now, that sounds like a small point, but

13   when you have a limited field to look at, you may not be

14   able to achieve that because there simply aren't enough

15   cells on the field.

16                This shows data from a Medennium clinical

17   trial.   These are strictly the control eyes, 123 good
18   images plotted out after the counting, and we had

19   everything from 900 or so on up to 3,600.

20                You'll notice that if you had asked for 100

21   cells in the analysis, we'd have to have a field of about

22   2,400 cell density.   Less than 2,400 cell density, there

23   simply aren't the cells to look at in the specular

24   microscope field if using the Konan specular microscope.
25                Then every once in awhile we'll get poor
                                                                  39

1    images, which we are unfortunately forced to used because

2    maybe the control data wasn't better than that, and you're

3    really using very few cells in the analysis.

4                 Another issue is how uniform is the surface of

5    the eye.   This happens to be my eye, and what I did was I

6    looked at the central target, I looked at a little bit

7    further out -- 1 millimeter, 2 millimeters, and 4

8    millimeter zones -- and then I took pictures as I looked in

9    various spots on the field, as you can see here.

10                Then I asked the question, statistically, is

11   this dot the same as this dot and so forth?    And it came

12   out to no.   So my surface, even though I have no history of

13   contact lenses and so forth, has a lot of variability, and

14   if you took answers from all over the place, you are going

15   to look like multiple patients.   It's not going to look

16   like one patient.

17                Narrow the field down, still the same problem.
18    Narrow it down, still the same problem.   Get down to about

19   a millimeter out and it's certainly better, but it's really

20   good if you look at the dead center.   If I looked at that

21   green target very carefully and took 10 pictures in a row,

22   they would really look like the exact same patient.

23                There is a little trick involved in this, and

24   that is I happen to be an emmetrope -- these are reading
25   glasses -- so as I look off at the target inside the
                                                                    40

1    machine, I see what you see on that screen, a red circle

2    with a green dot.   If a person is a myope with 2 or 3

3    diopters off, he sees a blur, and so asking him to

4    cooperate to look at dead center becomes an increasing

5    challenge.

6                 One more piece of data.    What I did was I

7    looked at the control data from the Medennium group that I

8    have and there's a single reading group, which is me, but

9    there are 58 subjects at seven clinical sites.     So this is

10   real life.   The patients had a real-life coefficient of

11   variation, 36, not the nice normal of 25 or so, and what we

12   did was we had data collected at baseline and three months,

13   and I asked the question on that patient is the baseline

14   the same as the three-month data?      And what it showed me in

15   a paired T-test was a .7, which is pretty good.

16                But there's a little more to the story.    If I

17   then looked at the data and massaged it a little bit
18   further and graphed out the percent difference between

19   these two time periods for each of the patients and then

20   made a cumulative graph on your Y axis, I can then ask if I

21   have a spread of 2.5 percent, how many patients are going

22   to fall in that group?   And this said 50 percent.    So you'd

23   have to have less than 2.5 percent difference between these

24   two numbers to have 50 percent of your patients in your
25   group.   If we wanted all of the patients, we'd have to go
                                                                    41

1    up to 9 percent to get 100 percent.

2                 So it's really quite surprising, and there are

3    references in the literature that support these kinds of

4    numbers.   We're not looking at 1 or 2 percent spread in the

5    data between these two time periods.   In this group, we

6    were looking at 9 percent.   So we'd have to have a 10

7    percent change in the event in order to be 100 percent sure

8    that it was caused by the event, rather than just the

9    spread.

10                Some guidance for setting up clinical trials.

11   You certainly want to have careful control of the criteria

12   of your study, which specular microscope you're using, your

13   experience, and the data capture.   Who's doing the capture

14   and how often does he do it and how much experience?     How

15   many sites are located?   Each time you add a site, you're

16   increasing the variabilities.

17                So let's go right down to the final slide and
18   what I would suggest.   First of all, I would suggest we all

19   have the same microscope, and I like the non-contact

20   specular microscope simply because it means you're asking

21   for less skill from the technician.

22                I prefer one technician, I prefer to train that

23   technician, and I'd like to check on the training of that

24   technician to see if they really are doing it frequently
25   enough that they have kept their skills up.   Most of these
                                                                  42

1    people have lots of other things to do and they kind of get

2    soft on their skills.

3                I think a central reading center to limit some

4    variability is also a very good idea.

5                Thank you very much.

6                DR. WEISS:   Thank you very much.    You can take

7    a seat when you're done, Dr. McCarey, at the table.

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

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

10               DR. EDELHAUSER:   While Dr. McCarey's doing

11   that, I'm Dr. Henry Edelhauser, and I'm at Emory.    My

12   laboratory has been a reading center for KeraVision and

13   Staar, and I do a number of research contracts with Alcon

14   on intraocular irrigating solutions.

15               What I'd like to summarize for everybody today

16   is a very practical summary now of what Bernie talked about

17   and a little bit of the theory, and Dr. Ramzy Azar was the
18   one that helped out and was one of our major reading center

19   individuals, though he's presently in the Navy right now

20   down in Bethesda.

21               The purpose of what I'd like to summarize today

22   is using the robo non-con specular microscope, which seems

23   to be about the best specular microscope to run a clinical

24   trial, and particularly when you're thinking about
25   refractive surgery, because you're not applanating onto the
                                                                   43

1    cornea.    So we want to understand the variable issues that

2    may be found in specular microscopes.     So our objectives in

3    this 10-minute presentation are to provide good examples in

4    good and poor photography, illustrate the variability, and

5    illustrate the variability within a single image that data

6    has to be obtained from.

7                  What is a good image?   I think Dr. McCarey

8    showed you.    This is typical panel that one would receive

9    from the robo non-con.     You notice on here you can find

10   distinct cells.    You can identify at least 150 cells.     The

11   cells can be grouped in a very uniform manner.

12                 Then you may have to say, well, what may be

13   good for clinical purposes may not be good for research.

14   For example, in many clinical times, they'll only count 15,

15   20 cells, but for a research study, particularly where

16   you're quantitating endothelial cells over a long time, you

17   want to try and put a dot in every one of these corneal
18   endothelial cells.

19                 Things to consider that may affect the optical

20   image.    Dry eye, contact lens use, wrong specular

21   microscope settings -- you can go into the manual mode with

22   the non-contact -- and patients with keratoconus are very

23   difficult to get endothelial specularscopes.

24                 Patient compliance.   This is a real issue if
25   the individuals can't see that little green circulating dot
                                                                   44

1    and you have to work with the patient.    So training becomes

2    very important.

3                 Age of the patient, a little bit more

4    difficult, and then training and experienced photographer,

5    and as I emphasize over and over again for individuals and

6    companies that are trying to under specular microscopy, you

7    have to train the individual out in the field.

8                 Poor quality images are something that are an

9    issue, and particularly with preoperative because if your

10   preoperative photos are poor quality, this is going to

11   carry through the whole study.

12                Here is an example where you have just a panel

13   over here, and here's another panel here.    So really what

14   was happening is that the patient was moving his eye when

15   this picture was captured.

16                Another type of poor quality image.   Very

17   difficult.   Here you might be able to obtain 30 to 40 cells
18   in this particular panel.    If this was a preop, this

19   patient is lost because there's identifiable cells that

20   could be measured.

21                Again, poor quality images where it's very,

22   very difficult, and I can tell you from being involved in a

23   reading center and looking at over 10,000 of these with the

24   laboratory, you get photos like this that are preoperative
25   and when you want this as a preoperative photo, how do you
                                                                     45

1    start a baseline for this particular individual?      This is

2    where training of the photographer or the individual

3    running the specular microscope out in the field is very

4    important because that image will come up on the screen,

5    and if it's this one, they should sit the patient down

6    again and retake the photograph.

7                   Conditions that potentially increase

8    variability.    Patients that have Fuch's, polymegethism,

9    pleomorphism, injury, and low cell density.    Particularly,

10   there are some patients that do have a low cell density.

11                  Here's an example of a patient that has guttata

12   or Fuch's, and notice you see these black spots here.

13   Actually, these black spots are covered by a very, very

14   thin part of the corneal endothelial cell and the

15   refractive index is different here.    Well, how do you

16   analyze this photograph?    Well, you'd have to group here or

17   you'd have to group here.
18                  So capturing the best image is very important.

19    You have to make sure the patient is comfortable.      You

20   have to instruct the patient to blink.    You have to

21   instruct the patient not to move and to open his eyes wide.

22    You have to instruct the patient to focus on the green

23   light, and as Dr. McCarey said, it's difficult for somebody

24   who has type of disease or is extremely myopic because you
25   can't see the green light as well as somebody who's an
                                                                     46

1    emmetrope.    You have to be patient.   You have to work with

2    that patient and use of the manual setting to improve the

3    quality of the cornea is -- sometimes the corneas are

4    thicker than the normal setting, so you have go to the

5    manual.

6                   Things to consider when you analyze images.

7    You have to locate the best and most representative area,

8    the number of cells, you have to look at the quality of

9    cells, and you have to use the area with the fewest

10   distortions, as I'd shown in the very early aspect.

11                  Here is an example of the best image.   Well,

12   the best image on this specular here would have to be here,

13   and this one you'd have a very hard time finding the best

14   image.    It may be somewhere along in this area.

15                  Dotting cells.   You have to dot all the cells

16   in the center and you have to remain accurate and

17   consistent throughout.     We always recommend dotting at
18   least 150 cells if there are 150 or more than that on the

19   photograph because at least you'll get an analysis of 100

20   cells, 110 cells, and as Dr. McCarey showed you on the

21   graph, the more cells you can dot, the better the

22   statistical analysis will be.

23                  Where to group the analysis?   Now, this is

24   interesting.    Well, if you could dot every one of these,
25   this would be the appropriate way to go, but if you dot
                                                                  47

1    here, if you would look here, you'd have a lot of big cells

2    up in this area and small cells here.    So certainly, the

3    diversity in the cell count would be very large, and this

4    is one of the disadvantages of having specular microscopy

5    done out in the field and have the technician because the

6    technician may just pick this area and then that will be

7    the preop, or they may pick this area, and then you come

8    back and your three-month data or six-month, they're going

9    to analyze up here in this area.   So having a reading

10   center or having one person do all the analysis is very

11   important.

12                What's wrong with this analysis?   Well, here's

13   an example of analysis done in this area, just localized

14   down in this area.   Only 71 cells were counted, but it

15   still had an endothelial cell density of 2,639.   So the

16   analysis really is not representative.    It's introducing

17   bias because you're looking at a population of a lot of
18   small cells here, you're not likely to be able to repeat

19   this analysis, and really we say that you have not counted

20   enough cells.

21                It is very important to group the analysis like

22   this or as illustrated here, and when you look at your

23   grouping analysis, notice the box that we've drawn here.

24   This is an improper grouping that you would see here
25   because you're doing this nearest neighbor analysis as the
                                                                   48

1    algorithm of the specularscope and may only end up with 50

2    cells or something like this, whereas if you group the

3    whole group, you'd end up at least putting a dot in 150

4    cells.   But see, technicians have to be trained if they're

5    going to do this, or your reading center.

6                 Patients that have guttata.    You may have some

7    of these in a study group, grouping here, here, here, or

8    here.

9                 DR. BULLIMORE:    This is Mark Bullimore.   Excuse

10   me interrupting.   You've talked about guttata twice and you

11   seem to infer that you should count around them when

12   estimating cell density.

13                DR. EDELHAUSER:    Right.

14                DR. BULLIMORE:    So you don't include that area

15   at all in your analysis, even though there are no cells

16   there.

17                DR. EDELHAUSER:    Well, there's just usually one
18   large cell that covers that area, but we have found that in

19   doing patients like that, if they're part of the study

20   group, the best analysis is to just use the cells without

21   including that guttae in there.    The reason is is that if

22   you put that one large cell, you're multiplying this by

23   such a large factor that your cell number is extremely

24   variable.   See, you're wedded to the algorithm of the
25   specular microscope.
                                                                   49

1                 DR. BULLIMORE:    Thank you.

2                 DR. EDELHAUSER:    And hopefully, in doing a

3    study, you would not have many of these patients in there,

4    but I can tell you from the studies that we have done with

5    LASIK and things, you do find some patients that do have

6    guttata.

7                 To analyze the cells, you need to be able to

8    visualize the cells.   You have to identify a pattern.      And

9    would it be appropriate to take this endothelial cell that

10   has shown some damage?

11                Where the image is analyzed can create a great

12   degree of variability, as illustrated here.    The old way

13   which we used to do specular microscopy with contact

14   specular microscopy is take a wide field and then we'd have

15   to trace the corneal endothelial cells, put a number in,

16   and then we would digitize each one of the corners.    This

17   is very accurate, but again, notice the grouping of the
18   cells.

19                Here are examples of variability.   This is one

20   specular image here.   If you analyze the endothelial cells

21   in the lower portion, you'd up with a cell density of

22   2,976.   If you analyze the endothelial cell density in the

23   upper portion, you'd end up with a cell density of 2,873, a

24   difference of 103 cells and a 4 percent difference.      So you
25   can see the variability that can occur and this can very
                                                                    50

1    easily occur if the training of that individual is not

2    appropriate.

3                   Here are examples of variability within

4    readers, and this occurred out at our center when we were

5    training the people out of our Vision Correction Center to

6    do this.   Endothelial cell density 2,531 here and 2,358

7    here, a 7 percent difference just on the same pattern.

8                   Here are examples of variability between

9    readers, with having different readers.     So in this case,

10   we had five different readers put dots in each one of the

11   cells, and you can see they varied from 2,531 up to 2,631.

12    So this is really a degree of variability.    So training

13   not only needs to occur with the photographer, but also the

14   person doing the analysis.

15                  Just to show you this, the consequences of

16   overcounting, if you skip two cells, you have a significant

17   difference.    If you overcount three cells, you have a
18   significant difference.    So this is where the training is

19   extremely important for the individuals.

20                  Well, just to put this into a little

21   perspective on this, and this is a graph that we've

22   recently put together, the first study that was done that

23   we did back with Richard Yee, et al., this is what happens

24   with contact specular microscopy.     Notice, from age groups
25   from 10 up to 89.    Notice, this is the distribution of
                                                                   51

1    endothelial cells here.

2                Okay.   We recently went back and did 125

3    patients through the various decades with the non-contact

4    robo, which is illustrated in the yellow line, and notice

5    that the lines overlap.   Very early, we published a paper

6    in the AJO and I took the preoperative data from our LASIK

7    patients, which varied from 20 to 50, and notice those

8    lines overlap.

9                There are two areas of outliers, and this was a

10   mixed Asian group of patients that we had in Emory when we

11   looked at this, and notice the Asian patients have a higher

12   endothelial cell density, and a number of years ago we had

13   access to a Japanese population in Osaka when Dr. Matsuda

14   was with us, and in this population, notice that the

15   Japanese population in Osaka had many more endothelial

16   cells than a Caucasian American.

17               So this becomes a very interesting point of
18   view when one wants to look at endothelial cells in grouped

19   patients if you're doing a study, say, in the West Coast

20   compared to, say, in the South or the Midwest.

21               Mike?

22               DR. GRIMMETT:   Just a quick question.   I hope

23   you don't mind the interruption.

24               DR. EDELHAUSER:   No, not at all.
25               DR. GRIMMETT:   The non-contact robo data, is
                                                                    52

1    that published somewhere?     Is that an abstract?

2                  DR. EDELHAUSER:   No, that's published, Mike.

3    That's the original data from Richard Yee's paper we

4    published in Current Eye Research.

5                  DR. GRIMMETT:   In '85.

6                  DR. EDELHAUSER:   In 1985, yes.

7                  DR. GRIMMETT:   Is there an updated one?

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

9                  DR. GRIMMETT:   Oh, I see.

10                 DR. EDELHAUSER:   It's in the process of being

11   written up.   We just completed that within about two months

12   ago.

13                 DR. GRIMMETT:   Thank you.

14                 DR. EDELHAUSER:   But I thought it was a very

15   interesting comparison because much of the data in the

16   literature is from the contact scope, and this is really

17   the first longitudinal study with the non-contact.
18                 Just to give you an example of the variability

19   in the best of hands, this was taken from our LASIK paper,

20   where Ramzy Azar took all of the photographs of the

21   patients, and he then used his own eye throughout a three-

22   month time period where he took the pictures of his right

23   eye and his left eye.   So this is 36 different photos, 18

24   of the OD and 18 of the OS.     His endothelial cell density
25   is 2,545 and 2,600.
                                                                  53

1                 Notice the standard deviation, 45 cells.   So

2    the precision in the best of hands with this, and this is

3    from this AJO paper, is 1.7 percent and 1.5 percent.

4    That's with one person looking and taking all the photos,

5    and I think this is very important.

6                 A recent study that we've done and reported at

7    ARVO, which I think is very important as we think about the

8    endothelial cells, we measure central endothelial cells,

9    but peripheral endothelial cells are going to become of

10   interest, too, particularly when you think about phakic

11   IOLs.

12                These are three graphs where lyserine red-

13   stained human corneas, something like 71 human corneas that

14   we looked at.    You can see the N listed here.   This line is

15   the endothelial cell density in the center, the paracenter,

16   and the far periphery, about 4.5 millimeters from center.

17   You can see there is a progressive decrease of roughly a
18   half a percent per year all the way across the line, but

19   still you do have a higher cell density in the periphery

20   that could aid in the sliding of endothelial cells to the

21   periphery.

22                So just to summarize this, then, what are the

23   sources of variability?   It's difficult to return to the

24   same location.   When we were a reading center for
25   KeraVision, we did a reproducibility study with 10 patients
                                                                     54

1    at three different sites where they took three consecutive

2    readings, and we ended up plus or minus 56 cells, very

3    similar to what we measured in the LASIK study.     So you

4    have an inherent error, just the reproducibility, of 2

5    percent.

6                   Poor image quality.   We suggest trying to get

7    at least 100 cells.

8                   Training error.   Training, and you have to have

9    consistency.    Reading analysis.    Training and consistency,

10   and equipment calibration and alignment is another very

11   important issue that has to be.

12                  So in summary, what the ideal situation might

13   be is it could be a company, it could be an independent

14   reading center, it could be you need your specular sites,

15   and this data then should be sent to a reading center.       You

16   should not have the sites do their own analysis.     Then the

17   data in a mass fashion, which would be received to the
18   reading center, would be sent to the data processing

19   center, and then for statistical analysis then to the

20   technology company, and obviously then on to the FDA.

21                  So I hope this little bit of a summary was

22   important and I was able to show you some of the

23   variability of the technique.     It's a good measurement,

24   it's a hard measurement to get, and what is very important
25   is that you do certainly want to see what the state of the
                                                                  55

1    corneal endothelium is.

2                  Thank you for your attention.

3                  DR. WEISS:   I'd like to thank you both for

4    excellent presentations.     Perhaps you could come up to the

5    table and the panel could start their questions.

6                  I would just like to ask you a couple of

7    elementary ones.   What would you suggest as the minimal

8    time of follow-up in order to detect endothelial cell loss

9    after phakic IOL implantation?    So what's the shortest

10   study?

11                 DR. EDELHAUSER:   Well, I think certainly a

12   three-month time period, that's a reasonable approach to

13   take it.   I mean, are you trying to say how soon after --

14                 DR. WEISS:   Two years, three years, five years?

15    What would your wish list be?

16                 DR. McCAREY:   If the literature is any

17   indicator, I would imagine that the most active changes are
18   going to occur probably within the first six months, and

19   then afterwards you're probably going to level out into

20   some kind of a steady effect.    So the initial trauma of the

21   procedure, let's say the first six months you need the

22   data.    Afterwards, you might need data every six months for

23   maybe two years, and then hopefully you're going to see

24   some kind of a level line that you're dealing with.      If you
25   don't, you're just going to have to go further.
                                                                      56

1                 DR. WEISS:   So just to clarify if I understand

2    you correctly, you would say two and a half years from

3    implantation?

4                 DR. McCAREY:   Certainly two years.

5                 DR. WEISS:   Two years from implantation as a

6    minimal, unless there is anything else that you can tell.

7                 DR. McCAREY:   Correct.

8                 DR. WEISS:   If a patient is a contact lens

9    wearer before, that's an evolution of what is occurring

10   with the endothelium as well.      Before they have their

11   phakic IOL, how long should they be out of contact lenses

12   so you get a stable specular microscopy before they can be

13   entered into a study?

14                DR. McCAREY:   Yes.    That's almost a

15   presentation on its own as to how the patient is able to

16   return from this polymegethism state from contact lens

17   wear.   It looks like it's very, very, very slow, if at all,
18   there is a correction from that polymegethism change.       So

19   it means that you could look at a patient one, two, three

20   years, five years out of having not wearing their contact

21   lenses and they would still have the effect of wearing the

22   contact lenses.

23                The next part of the issue is does this mean

24   that the eye is a little susceptible to further trauma?
25   And the literature would indicate that these eyes are more
                                                                       57

1    susceptible to trauma.     They respond more negatively to

2    trauma than a person who had a normal CV and no contact

3    lens history.

4                  DR. WEISS:   So should that be an exclusion

5    criteria then?

6                  DR. EDELHAUSER:   No, I wouldn't think so.     It

7    shouldn't be an exclusion criteria if somebody has

8    polymegethism.

9                  DR. WEISS:   No, I mean contact lens wear,

10   because it sounds like it's such a confounding variable

11   that you --

12                 DR. EDELHAUSER:   It is, but I think there is

13   variability within the degree of polymegethism because if

14   you're thinking of phakic IOLs and everything, basically

15   all these people have worn contact lenses.

16                 DR. McCAREY:   I agree with Dr. Edelhauser.

17   That's the problem.   You're going to lose an awful lot of
18   your patients.

19                 The second part of the story about

20   polymegethism is it's a stress from oxygen.    If you are an

21   old-fashioned PMMA lens wearer, you have the most stress.

22   If you have the more modern, let's say the silicone

23   materials or a high-water content hydrogel, you'll probably

24   have less stress.   So it's a sliding scale as to how much
25   stress they have had from their contact lenses.
                                                                   58

1                I think what I want to point out is that the

2    endothelial cell density is not alone an indicator as to

3    the history of that patient.       You'd also want to know

4    what's going on with their CV, the spread in the cell

5    sizes, and I think good data collection is probably more

6    important a statement than eliminating these patients.

7                DR. WEISS:   If I had to put you on a spot and

8    ask you to give a bare minimum -- not the range, but the

9    bare minimum -- you think that someone would have to be out

10   of contact lenses, would you be able to give me a number?

11               DR. McCAREY:    It would just be a wild number

12   and I would certainly --

13               DR. WEISS:   A wild number might still be

14   helpful.

15               DR. McCAREY:    Certainly six months, but I don't

16   really know for sure.

17               DR. WEISS:     Okay.    Six months.
18               Would Asian corneas then have to be grouped

19   differently because they're starting out with more

20   endothelial cells?

21               DR. EDELHAUSER:    I would think that would be a

22   subset that should be analyzed separately.        From past

23   experience with that, all Asians that we've looked at have

24   a very higher cell density, and it depends upon where the
25   study is going to be conducted, but I wouldn't use an
                                                                     59

1    exclusion.   I'd just use it as an added subset.

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

3                 DR. McCAREY:    Could I add one more thing on

4    this?

5                 DR. WEISS:    Yes.

6                 DR. McCAREY:    I think that the contralateral

7    eye is a goldmine, that a lot of these issues that you're

8    referring to can be lessened as far as you're concerned if

9    you know the history of the contralateral eye.       Follow both

10   eyes and make the data relevant within the patient

11   themselves, rather than some kind of a standard regression

12   line from a group.   I think will solve a lot of problems.

13                DR. WEISS:    So in this case, you would suggest,

14   at least from the endothelial cell portion, that it would

15   be very helpful only to do unilateral phakic IOL surgery.

16                DR. McCAREY:    Yes.   Unfortunately, that's what

17   I would state.
18                DR. WEISS:    Thank you.

19                We're going to go around.     Dr. McCarley, then

20   Dr. Burns, then Dr. Bullimore, Dr. Matoba, Dr. Grimmett,

21   and then we'll go on down the line.

22                MR. McCARLEY:    This is Rick McCarley.   I knew

23   if I waited around long enough, I'd get a degree, too.         So

24   thank you.
25                (Laughter.)
                                                                   60

1                MR. McCARLEY:    It's just Rick.

2                DR. WEISS:    I think I'm going to start with

3    first names and go back to the first names.

4                (Laughter.)

5                MR. McCARLEY:    There you go.   Thank you.

6                You'll see my eyebrows going up several times

7    today because obviously I'm involved in a clinical study on

8    phakic intraocular lenses in the U.S. that's been going for

9    about five years now, and in fact 15 years in Europe.     So I

10   have a lot of -- I'll call it practical experience, and

11   boy, I wish I knew then what I know now.     We do have a lot

12   of data and I wanted to share some of this because it

13   applies to all of us.    These discussions have happened in

14   the ANSI standards, so I'm pretty well up to date on what

15   has happened in the industry and what data we've collected.

16               But a couple of the comments, one is the

17   patients not only wear contacts.    Most of these patients
18   that we've seen have polymegethism, but many of them, we're

19   talking about -15 to -20.

20               DR. WEISS:    Actually, I'm going to interrupt

21   you for a moment.   Because of the time constraints, what

22   I'd like to do is use the benefits of our experts'

23   expertise, and I would prefer the comments get directed to

24   the comment portion.
25               MR. McCARLEY:    That's okay.
                                                                    61

1                  DR. WEISS:   And if you have any questions to

2    direct to Dr. McCarey or Dr. Edelhauser, use this time for

3    that.

4                  MR. McCARLEY:   Okay.    Then I will ask the

5    question directly.   Have you ever studied a population of

6    high myopes individually and compared that to the normal

7    population?

8                  DR. EDELHAUSER:   No, we haven't.    The only high

9    myopes that we've really looked at were part of our study

10   that we published on LASIK, where had 100 consecutive

11   patients that we looked at and there were only, I think,

12   eight to 10 at the most that were high myopes.

13                 MR. McCARLEY:   I see.    And when you're

14   analyzing the endothelial cell data over a large

15   population, the comment about the subgroup of Asian eyes,

16   are we looking at percent changes, so it really doesn't

17   matter what their beginning or ending is?      So looking at a
18   subgroup really doesn't matter.       If they start off with

19   more, we'd expect them to end up with more.

20                 DR. EDELHAUSER:   I think that's how the study

21   design is set up and how the statistical analysis is done.

22                 MR. McCARLEY:   Right.

23                 DR. EDELHAUSER:   I mean, as an independent

24   reading center, we want to be masked in that.       So the
25   criteria would be in the early study design and how you're
                                                                       62

1    going to do that.

2                  MR. McCARLEY:   Thank you.

3                  DR. WEISS:   Dr. Bandeen-Roche?

4                  DR. BANDEEN-ROCHE:    Yes, I have maybe three

5    related questions.   The first one is both of you alluded to

6    cell density not being uniform over the surface of the eye.

7     Would you think it would be worth some sort of a dynamic

8    sampling strategy to try to isolate the maximum cell loss

9    or is that relatively reliable in the center?     I'd just

10   appreciate your thoughts on that.

11                 DR. McCAREY:    I think you'd be opening up a can

12   of worms if you approached it that way.     I think you're

13   probably best trying to get central readings, and with

14   instruments like the Konan, hopefully the patient can

15   cooperate and look at the target and you're getting the

16   same field.

17                 On my own eye, I could take 10 pictures, and
18   every one of us having slightly different patterns and you

19   can see an odd cell here and there, and within the 10

20   pictures, I could see the same little couple of cells.        I

21   can come back two or three months later and do that again

22   and once again see those same little odd cells.

23                 So I think that the key here is training and

24   cooperation from the patient and the central cells, and
25   that gets rid of some other cans of worms.
                                                                 63

1                 DR. BANDEEN-ROCHE:   Thank you.

2                 DR. EDELHAUSER:   Let me just add one other

3    thing.   I think in order to get a representative, it is

4    recommended, and we certainly have recommended this, that

5    if you're going to take specular photographs, at least try

6    and get three photographs, and then at least have the

7    reading center or whoever is doing the analysis try and

8    then analyze the best one of this, or in the early training

9    of your individual, if you have them take three, and then

10   take the average to see where they are.     So again, it comes

11   back to teaching the photographer to get a representative

12   photo.

13                DR. BANDEEN-ROCHE:   Thank you.

14                The second question goes to variability over

15   repeated readings, say, over a three-month time period, and

16   you alluded to in the best case percentage variability of

17   1.7 and 1.5 percent.   I'm curious.   How much of that is
18   variability in the reader versus natural variability in

19   cell density over three months?   And when you refer to

20   those rates being the best, I tend to say, well, suppose

21   somebody just counted more cells?     Couldn't it get better?

22    If you could respond to that.

23                DR. EDELHAUSER:   In this particular case, I say

24   it was the best because we had one person taking the
25   pictures of his eye and counting as many cells as possible
                                                                    64

1    to come up to do this, and I think that what you're dealing

2    with in this particular case is the variability of the

3    machine and the algorithm.    Because don't forget, in this

4    particular case, you're, say, dotting 150 cells.     At best,

5    160 maybe is all you can put on there.     Then you push the

6    button and the algorithm pops up here, and what you're

7    dealing with is that's what you're left with, the analysis

8    of those particular cells that you're dealing with.

9                  DR. McCAREY:   I kind of take a little bit

10   different approach to that.     I think the math is the math.

11    It's not changing.   The computer's not changing.    The

12   machine is hopefully focusing the same and keeping the same

13   magnification.   So your variation isn't in the equipment.

14   It's in either where the picture was taken -- well, that's

15   probably the heart of it, where the picture was taken,

16   because there is a variation across the surface.

17                 Now, you mentioned the best answer and the
18   worst.   I showed you 9 percent of a spread in order to get

19   all the patients in the group.    That's with seven clinical

20   sites, 58 patients, and no expectation that I was going to

21   do that analysis.   That's the hardcore reality.

22                 Whenever you look at a paper that comes from a

23   given site -- whoever it may be, our lab or Bill Bourne's

24   or someone else's -- they are doing the entire study
25   themselves.   They are giving you their best shot.   They
                                                                     65

1    know they're going to do the study, and it always comes out

2    cleaner that way.    So my 9 percent is probably reality and

3    the equipment probably is as good as 1 percent.

4                 DR. BANDEEN-ROCHE:   Thank you, and a very brief

5    final question that goes to guttata.     So the point of not

6    counting that, I take it that induced guttata is not a

7    primary problem in phakic IOLs?

8                 DR. EDELHAUSER:   Provided it doesn't cover the

9    whole surface of the corneal endothelium.     I mean, we've

10   all seen patients that have guttata that go from limbus to

11   limbus, and then occasionally you'll have a person who will

12   sit down and you'll get one guttae in the area.       I mean,

13   you still can use that photograph.      So I think there are

14   various degrees.

15                DR. WEISS:   Thank you.

16                Dr. Burns, did you have some questions?

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

19                First, is it true that if you take, say, three

20   sets of images that the one with the highest count is best?

21    I thought I heard you say that, but I might have

22   misinterpreted it.

23                DR. EDELHAUSER:   No, I think you the best image

24   that I was implying is the one where you have a good
25   distribution of cells over the whole screen that you can
                                                                    66

1    see, and not one where a patient may have moved their eye a

2    little bit and you only get a strip of the endothelial

3    cells.   So the best image that I would suggest would be one

4    that has as many cells uniform across the full screen.

5                 DR. BURNS:   So given that you've got three good

6    images, do you just average them?   Do you recommend

7    averaging those counts for that data point?

8                 DR. EDELHAUSER:   Yes, yes.

9                 DR. BURNS:   The second question is when you

10   were talking about how long you'd follow up, was that sort

11   of in laboratory-type data or were you taking into account

12   the realities of variance from a trial?     So the two and a

13   half years you were suggesting, do you think you'd have to

14   lengthen that given the variability you get from a

15   multisite study?

16                DR. EDELHAUSER:   You might.   The best

17   illustration I'd give you is our LASIK data, and we looked
18   at this very carefully for 100 patients and we followed

19   them up to three years.   Of the 100 patients, we able to

20   get 63 of them back -- again, this is all volunteer at this

21   particular stage -- and we really found no change over a

22   three-year time frame.    But I think with something that has

23   the potential where endothelial cell populations may be

24   decreasing, going out to two or three years might be
25   important.
                                                                    67

1                  DR. WEISS:   Dr. Bullimore?

2                  DR. BULLIMORE:   Mark Bullimore.   I'd like to

3    thank both of you for coming.    It's a fabulous presentation

4    and it's very encouraging for those of us who do clinical

5    research in general to see the level of rigor with the

6    reading center.   I mean, that was very refreshing.

7                  We took some data on the Konan probably under

8    the worst-case scenario, and our precision was probably

9    closer to 10 percent than 2 percent, but we weren't

10   counting the number of cells and we weren't doing all the

11   other sophisticated things that you gentlemen do.

12                 I have hopefully a couple of quick questions.

13   First of all, when you talk about coefficient of variation

14   that's what other people, or maybe yourselves, would also

15   refer to as polymegethism?     Are those two terms equivalent

16   or interchangeable?

17                 The other thing is, and this is a particular
18   concern given the fact that many of the patients having

19   phakic IOLs will be long-term contact lens wearer, you

20   inferred or implied that if you take a patient out of

21   contact lenses, there would ultimately be a very slow or

22   potentially no long-term recovery from that insult.     Did I

23   hear you correct?

24                 DR. McCAREY:   That's strictly from the
25   literature.   It's not from my own laboratory experience,
                                                                    68

1    but Brian Holden has done lots of work in this area, and it

2    repeatedly shows up that that's true.

3                DR. BULLIMORE:    So taking that to the next

4    step, were we at some future date to be looking at these

5    data, you would not worry about that contact lens or prior

6    contact lens wear as a confounding factor in any changes in

7    endothelial count that occurred after the patient had a

8    surgery?

9                DR. McCAREY:    There is literature out there

10   that tells you that large polymegethism values often lead

11   to a patient being more susceptible to the trauma of a

12   given surgery as compared to patients with a lower

13   coefficient of variation.    So they do have the potential to

14   be more susceptible to damage.

15               DR. BULLIMORE:    I see, but that's a short-term

16   effect of the surgery, rather than their sort of five-year

17   history, say.
18               DR. McCAREY:     I don't really know if it would

19   mean that the five- and 10-year periods would still be at a

20   higher rate of loss or not.    I don't know.

21               DR. BULLIMORE:    Did you want to go ahead?

22               DR. EDELHAUSER:    There may actually be a

23   benefit of removing the contact lens because I say from our

24   experience, in our three-year data from the LASIK patients,
25   we actually did see an improvement in the coefficient of
                                                                     69

1    variation, and all these patients were contact lens

2    wearers.

3                  DR. BULLIMORE:    And a final question.   There

4    has been a great deal of emphasis on your slides and in

5    other materials I've looked at on the topic on endothelial

6    cell density.   Do you think that should be the primary

7    outcome measure or should we be looking at coefficient of

8    variation as the primary outcome measure in a long-term

9    study or would you consider both to have equal weight?

10                 DR. EDELHAUSER:    I think cell density would be

11   the number one aspect of it.     The difficulty with the

12   coefficient of variation that we have if you use the robo,

13   to some extent that data is a little soft, and the reason I

14   say that is soft is because you're using the center dot

15   method.    If you were tracing cells and using the corner

16   method, that data is much stronger.

17                 One of the things that I have found over the
18   years of using the robo, if you have a patient or a subject

19   that has a high coefficient of variation -- say, .6, or

20   like many of the diabetic patients -- it shows up, but the

21   difference between .27 and .35 is not really a significant

22   change.

23                 DR. BULLIMORE:    So without wanting to put words

24   in your mouth, the precision of the coefficient of
25   variation method is not particularly -- let me rephrase
                                                                     70

1    that.   The precision of the coefficient of variation

2    measure is not particularly impressive.

3                 DR. McCAREY:   Well, the coefficient of

4    variation, I passed the slide very quickly, but the

5    calculation is that you're dividing the mean cell area into

6    the standard deviation or the spread in that mean cell

7    area.   So I feel that it is a piece of informative

8    information, but you do get a lot of noise, though, in it

9    from the fact that there is a spread in the data.      I'd

10   personally like to see that information carried forth in

11   the study.

12                DR. BULLIMORE:   I lied, Madam Chairman.    I do

13   have another question.

14                I'm very familiar with a paper by Scott McCray

15   on long-term PMMA contact lens wear, where he looked at a

16   cohort of patients who'd worn PMMA lenses for 20 years and

17   reported their outcomes, and one of the things I found
18   compelling about the paper is actually, and it's not

19   emphasized in the paper, but the cell density in the

20   contact lens wearers centrally was actually higher than the

21   controls.

22                Okay?   The take-home message was that there was

23   this subset of patients who fell below a given value of

24   cell density.   I think it was nine out of the 81 contact
25   lens wearers compared to two of the controls, which was
                                                                    71

1    statistically significant.

2                So in his analysis, and using that as, if you

3    like, an analogy to what we're doing here with phakic IOLs,

4    would it not be more appropriate, rather than emphasizing

5    the mean endothelial cell density, to look at sort of, for

6    want of a better phrase, incident cases of significant or

7    substantial reductions in cell density?      Have you explored

8    that parameter yourselves or is it in the literature?

9                DR. EDELHAUSER:     It's not in the literature,

10   but in the database that KeraVision submitted to the FDA, I

11   know it's there because they went back and looked very

12   significantly at patients who may have lost greater than 10

13   percent of their cells, and they were reported.

14               The other interesting thing in that paper

15   you're referring to by Dr. McCray, of that subset of

16   patients, there were a group of contact lens wearers who

17   actually lost cells.
18               DR. BULLIMORE:    Yes.   That was my point, and it

19   was nine out of the 81 were way below what you might

20   consider the normal range, but when you actually averaged

21   the cell density --

22               DR. EDELHAUSER:    It was lost.

23               DR. BULLIMORE:    It was lost.    So I think we

24   should maybe keep that in mind.
25               DR. McCAREY:     When you get polymegethism, you
                                                                  72

1    actually appear to be getting smaller cells, not just

2    losing cells and big ones reappear.     That would be a

3    misconception.   There's actually an appearance of what

4    appear to be smaller cells.    Recently, and I unfortunately

5    don't know the author, there was a description of how this

6    occurs.

7                DR. BULLIMORE:     That was Michael Delaty,

8    probably.

9                DR. McCAREY:     I don't remember, but he has

10   certainly has a lot of articles.

11               You can actually see a triangular-like pattern

12   occurring and that triangle shows a smaller top to the

13   aqueous, what looks like a smaller cell.     The volume of the

14   cell may be the same.    So there is a shift in the

15   dimensions of cells, rather than a loss of cells.

16               DR. BULLIMORE:     Sort of from a cylindrical

17   profile to a trapezial.
18               DR. McCAREY:     Right, and so it appears that

19   they could have a very high cell density when that's really

20   true if you counted the whole number of cells across the

21   surface.

22               DR. BULLIMORE:     Thank you both again.   This has

23   been very, very helpful.

24               DR. WEISS:     Thank you.
25               Dr. Matoba, did you have questions?
                                                                     73

1                 And I will again reiterate, because we're

2    already going to be off time and running over.      So if the

3    members of the panel could make their questions short and

4    sweet and directed to the issue at hand, I'd appreciate it.

5                 DR. MATOBA:    Do you want us to identify

6    ourselves?

7                 DR. WEISS:    Yes.   I mean, we can identify

8    ourselves for the first time around, and then I think the

9    transcriptionist won't have a problem.

10                DR. MATOBA:    Okay.   Alice Matoba.   My question

11   is your presentation indicated that there are significant

12   differences between races in terms of endothelial cell

13   density, and I wonder if you have any sense whether there

14   can also be differences between races in terms of the

15   minimum endothelial cell count you would need before one

16   starts to develop clinical edema?

17                DR. EDELHAUSER:      I don't think that's in the
18   literature at all.   I mean, just as a little bit of a

19   sidelight, if you go back and looked at the original radial

20   keratotomy, it was done by Sado, and the reason he was

21   somewhat successful I think is that the population of

22   individuals he did the study on had more endothelial cells.

23    So no, we don't know the minimum, and the best data would

24   probably come from Japan, Dr. Matsuda's laboratory.
25                DR. WEISS:    Dr. Grimmett?
                                                                     74

1                 DR. GRIMMETT:    Dr. Grimmett.   My question was

2    asked by Dr. Bandeen-Roche and answered, so I'll pass at

3    this time.

4                 DR. WEISS:   I'm just going to ask you a quick

5    follow-up question, then.    I understand that you would want

6    CV as part of specular microscopic studies.      Is there a

7    number that you would assign beyond which this is of

8    concern?   I'm being a very concrete person.

9                 DR. EDELHAUSER:    Are you talking about an upper

10   level?

11                DR. WEISS:   Upper level, yes.

12                DR. EDELHAUSER:    Well, the thing that you see

13   in your upper levels are CVs up around, say, 45 and above.

14    You know, that's a very high number.

15                DR. WEISS:   That's of concern.

16                DR. EDELHAUSER:    Yes.

17                DR. WEISS:   Thank you.
18                Dr. Bradley?

19                DR. BRADLEY:    Dr. Bradley.   A couple of

20   statistical questions, really.     You seem to be suggesting

21   you should be avoiding contact lens wearers in the sense

22   that I got the impression you were treating that as perhaps

23   a confounding source of an independent variability, but if

24   the contact lens wear interacts with the effects of phakic
25   IOLs, are you then more susceptible to this?     And these are
                                                                      75

1    the sorts of patients that might be getting phakic IOLs.

2    Surely, they shouldn't be excluded, but should they be

3    specifically included in such a study?      Could you comment

4    on that?

5                   DR. McCAREY:    I agree completely with what

6    you've said.    I just want to make sure that you're aware of

7    which patients has had a contact lens history.

8                   DR. BRADLEY:    Second question.   Again, I think

9    statistically you did quite a thorough job of demonstrating

10   different sources of variance, and I lost track a little

11   bit of the individual sources of the variance, but it

12   seemed you put that all together in a graph and you

13   suggested that in order to detect a change in cell density

14   in an individual eye, it would have to change by 9 percent.

15                  DR. McCAREY:    With that set of data that I

16   presented to you, yes.

17                  DR. BRADLEY:    So the question, and I wondered
18   if you knew the answer, is what would be the sample size

19   required to detect a clinically significant change in the

20   sample of eyes that might be used, for example, in the

21   study of phakic IOLs?

22                  DR. McCAREY:    I'd have to go back to the

23   computer.   I don't know the answer.     It's a statistical

24   question that I didn't ask.
25                  DR. GRIMMETT:    Michael Grimmett.   I'll present
                                                                   76

1    that during my talk.

2                DR. WEISS:   Dr. Huang?

3                DR. HUANG:   Andrew Huang.   My question is that

4    so far we have emphasized the physical characteristics of

5    the endothelium, but we all know corneal thickness is a

6    function of the corneal endothelial functions.     Do the

7    speakers have any thought about what's the value of corneal

8    thickness in terms of evaluating the cornea's general

9    health?

10               DR. McCAREY:    Well, as part of an answer, and

11   I'm sure Dr. Edelhauser can expand on this, but you can get

12   endothelial cell counts down below 1,000 to 900 and 500 and

13   still have normal corneal endothelial thickness.

14               DR. HUANG:   Exactly, yes.

15               DR. McCAREY:    So it seems to be not as

16   sensitive an indicator as to what trauma may have happened

17   to that tissue.
18               DR. HUANG:     But by the same token, the flipside

19   of the coin is that if you have a decrease of cell density

20   from your graph, from the aging population, from 3,000 or

21   4,000 at birth to 2,000, but the patient did not really

22   have any functional visual disturbance, is that a bad thing

23   to have a decrease in those endothelial cells or is that a

24   good thing to have a healthy corneal thickness?
25               DR. EDELHAUSER:    Well, I think there's a limit
                                                                       77

1    obviously.   I mean, a corneal endothelial cell population

2    between, say, 1,000 and 2,000 will survive very nicely,

3    because we see this in many cases with patients with

4    guttata and we see it with postkeratoplasty with patients

5    and it's fine.

6                 I think that obviously when you set up a study

7    that you want to do this where there's a potential loss of

8    endothelial cells or you want to see it, you don't want to

9    start out with patients that have 1,400 cells, for example.

10    So you'd really want to have -- a "normal" endothelial

11   cell population with some polymegethism would be fine, up

12   around 2,500 cells per se.

13                DR. HUANG:   But by the same token, you may now

14   have started with the patient in, say, the Asian population

15   with an endothelial cell count of 2,500, but with a corneal

16   thickness of thicker than 600 microns.

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

19                DR. HUANG:   But that itself may be indicative

20   of the corneal endothelium is compromising.

21                DR. EDELHAUSER:     I understand.   Sure.   That's

22   true, very much so.

23                DR. HUANG:   Yes.    Seeing the cell number does

24   not necessarily mean the cell is alive.
25                DR. EDELHAUSER:     Right, but I think you bring
                                                                  78

1    up, if corneal thickness is going to be an issue, again,

2    that's another training point, and, one, the corneal

3    thickness measurements off of some of the specular

4    microscopes are not that accurate compared to ultrasound.

5                DR. WEISS:   Dr. Mathers?

6                DR. MATHERS:   Presumably, you would recommend

7    that we do not include patients with Fuch's dystrophy and

8    significant guttata because that would confound this

9    measurement considerably, correct?

10               DR. EDELHAUSER:   Yes.

11               DR. MATHERS:   But you see an occasional

12   guttata, maybe one or something like this, in a fairly

13   large percentage of the population.     Could you hazard a

14   guess as to how many in single field could be there and you

15   would qualify them to be excluded?

16               DR. McCAREY:   Well, as a reader of the images,

17   it isn't so much if they're present.    It's can I get a
18   large enough area remaining that's contiguous for counting

19   of the cells.   So I do not count around the cells, and I

20   don't want to count a narrow sheet between guttata because

21   that will louse up the algorithm.

22               DR. MATHERS:   But to do this study, you want to

23   have as clean a group as possible.    So presumably, we

24   wouldn't want to have patients where we're fighting the
25   guttata.
                                                                    79

1                  DR. McCAREY:   Yes.   This is probably one of the

2    reasons I like to see more than one picture taken because

3    if there is a random guttata, I try to select the picture

4    with the least problem.

5                  DR. MATHERS:   So you're not going to --

6                  DR. McCAREY:   Rather than averaging the three.

7     That's not so important to me because I think that when

8    you consider the surface area, it's .003 percent of the

9    surface for one picture.     What's one more picture out of

10   the whole surface?   Very little.

11                 DR. MATHERS:   Yes, right.

12                 DR. McCAREY:   But you want to get a good

13   picture, and if it means getting a good contiguous field of

14   cells, then that's what a good picture is.

15                 DR. MATHERS:   All right.

16                 DR. WEISS:   I get the impression that Dr.

17   Mathers is trying to quantify it because we're doing a
18   guidance document.

19                 DR. MATHERS:   Yes, right, because if you take

20   enough pictures, you're going to get a spot where you can

21   count 150 cells and in a single field you might still have

22   15 guttata.   We may not want to include this in a study

23   where we're looking at this because those guttata are going

24   to indicate a confounding population.      We need some kind of
25   measure as to say this person has too many guttata to
                                                                     80

1    include in a study like this.

2                 DR. EDELHAUSER:    In a preops study, yes.     I

3    mean, I think that this could be an exclusion criteria.

4                 DR. MATHERS:   Right.

5                 DR. EDELHAUSER:    And that would be put in

6    there.   You know, obviously, there are patients that have

7    few guttata, but there are a lot of patients that have a

8    lot of guttata and they should be excluded.

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

10                And presumably, when you suggested a two-year

11   follow-up, you're speaking of an insult and then a process

12   of evaluating the endothelium after that time, but if you

13   have an ongoing insult, ongoing inflammation, presumably

14   then would you modify your two-year recommendation if

15   you're going to assess that?

16                DR. EDELHAUSER:    Indeed, I would.   You know, if

17   you're going to follow these patients, three years
18   certainly would be reasonable to follow these patients out.

19                DR. McCAREY:   Are you implying a chronic

20   inflammation?

21                DR. MATHERS:   Chronic inflammation.

22                DR. McCAREY:   If it was a chronic inflammation,

23   wouldn't you expect a chronic loss?

24                DR. MATHERS:   Correct.
25                DR. McCAREY:   So you would expect to see
                                                                    81

1    eventually a linear line occurring, and that's when I'm

2    telling you that you've followed them long enough.      You

3    don't have to follow them infinitum.     You need to know

4    what's going on at a steady state.

5                  DR. MATHERS:   Right, but that would presumably

6    be longer than an initial insult period study.       So you were

7    asked to give an estimate and when you said two years,

8    certainly that would be longer if you have a chronic

9    process.    Can you give a time?

10                 DR. McCAREY:   I still kind of flip the response

11   back to you by saying that I'm looking for a linear

12   response.

13                 DR. MATHERS:   Yes.

14                 DR. McCAREY:   And if it's still not linear at

15   the end of two years, I have to keep going.     I have to go

16   for a longer follow-up time.

17                 DR. MATHERS:   Right, but we need --
18                 DR. McCAREY:   And I would not know how long it

19   would be.

20                 DR. MATHERS:   You don't know.

21                 DR. McCAREY:   Yes.

22                 DR. MATHERS:   Okay.   Fine.

23                 DR. EDELHAUSER:   I think, Dr. Mathers, the

24   longest study that we've followed through are the LASIK
25   patients, and that's been three years out.
                                                                     82

1                  DR. MATHERS:    Right.

2                  DR. EDELHAUSER:    So I haven't really

3    participated and I think with the KeraVision, their three-

4    year data is just now coming in and being analyzed.

5                  DR. WEISS:    Dr. Owsley?

6                  DR. OWSLEY:    Cynthia Owsley.   Dr. McCarey, you

7    mentioned that when people stop wearing their contact

8    lenses, the cell density counts, if we look at the

9    literature, suggest that it's pretty stable or there's not

10   this miraculous going back to the norm, whatever that is.

11   From the pragmatics of doing a clinical study on patients,

12   most of whom will be contact lens wearers and who have very

13   severe myopia, do you feel it's too burdensome on patients

14   to have them be without the contacts for six months and is

15   that maybe a little inflated?      I mean, I know they can do

16   the spectacles, but being a myope myself, I know that a lot

17   of contact lens wearers, they like to wear their contacts
18   and not the spectacles.      Just in terms of patient

19   enrollment issues.

20                 DR. McCAREY:    I have a great answer for that.

21   I'm a Ph.D.   I don't have to worry about the clinical part.

22    I really don't know how to answer you because --

23                 (Laughter.)

24                 DR. OWSLEY:    That's a good answer.
25                 DR. WEISS:    Dr. Swanson, did you have any
                                                                  83

1    questions?

2                 DR. SWANSON:   No questions at this time.

3                 DR. WEISS:   Great.

4                 I want to thank you both very much.   Those were

5    excellent presentations and extremely helpful to us, and I

6    thank you for your good humor with putting up with our

7    questions as well.

8                 So you can move back from the table if you

9    would like, and we next have Dr. Liliana Werner from the

10   Storm Eye Institute, who will be speaking to us on lens

11   opacity.

12                Donna, do you have something to say first?

13                MS. LOCHNER:   I'd just like to introduce Dr.

14   Werner a little more formally.     She is an assistant

15   professor of ophthalmology at the Storm Eye Institute at

16   the Medical University of South Carolina in Charleston.

17   She is the senior scientist of the Center for Research on
18   Ocular Therapeutics and Biodevices.

19                She received her doctor of medicine from the

20   faculty of medicine of the Federal University of Minas

21   Gerais in Brazil in 1989, her residency in ophthalmology at

22   the Felicio Rocho Hospital in Brazil, and two postresidency

23   programs at the University of Paris and the Hotel-Dieu

24   Hospital in Paris.   In 1999, she received a Ph.D. from the
25   University of Paris and began her work at the Storm Eye
                                                                 84

1    Institute.

2                 She is editor, together with David J. Apple, of

3    the summer 2001 issue of the International Ophthalmology

4    Clinics and is currently serving as a scientific referee

5    for many ophthalmology journals.   She was recently selected

6    to joint the International Intraocular Implant Club and

7    starting in September of 2002, she will be the director of

8    research of the new David J. Apple Laboratories for

9    Ophthalmic Devices Research at the John Moran Eye Center at

10   the University of Utah in Salt Lake City.

11                Thank you.

12                DR. WERNER:   Good morning.   I would like first

13   of all to thank the FDA members for the opportunity to be

14   here and participate in this meeting, and I will be

15   discussing the issue of cataract formation after

16   implantation of phakic posterior chamber intraocular

17   lenses.   This presentation is based on a review of the
18   literature, but also on some studies we performed in our

19   center and, as mentioned, soon we'll be moving back to Salt

20   Lake City, where the center was in fact founded in the '80s

21   by Dr. Apple and Dr. Olson.

22                So in fact what we did is an update of the

23   report we prepared for the ANSI meeting in Newport Beach

24   last year, and I would like to start with a brief overview
25   of the cell types involved in the problem of crystalline
                                                                 85

1    lens and capsular bag opacification.

2                So if you look at this picture, we can in fact

3    divide the crystalline lens epithelium into two different

4    biological zones, and in this zone we have the A-cells, and

5    these cells are attached to the inner surface of the

6    anterior capsule, and when the cells are disturbed, they

7    have the tendency to remain in place and undergo a process

8    of fibrous metaplasia.   These cells are in continuity with

9    the cells in the equatorial region, or the E-cells, and

10   these cells, on the contrary, when they are disturbed, they

11   have the tendency to migrate and proliferate, forming

12   bloated cells.

13               So both cell types are involved in the

14   different forms of capsular bag opacification.      For

15   example, anterior capsular opacification after implantation

16   of different intraocular lenses.   Also, different forms of

17   secondary anterior to capsular cataracts.   Also,
18   interlenticular opacification between piggyback lenses, and

19   finally posterior capsular opacification after implantation

20   of different intraocular lenses.

21               So here, for example, you have the A-cells

22   being the most important cell type involved in the process

23   of anterior capsular opacification after implantation of

24   different intraocular lenses for cataract surgery, and you
25   can see here a beautiful example of the anterior capsule
                                                                    86

1    being opacified only where it's in contact with the IOL

2    material.

3                So here you have another example, and this is a

4    case of capsule contraction syndrome, and because you have

5    asymmetric fibrotic formation and asymmetric contraction,

6    the lens is also decentered.

7                Whenever you prepare those specimens for

8    histopathological evaluation, that's what you're going to

9    find at the level of the capsule axis edge.     So there are

10   always these fibrocellular tissue attached to the inner

11   surface of the anterior capsule, and this in fact

12   corresponds to the opacification in this border.

13               And of course, the A-cells are also the cell

14   type most involved in the anterior capsular cataract

15   associated with phakic IOL implantation, and here I have a

16   bilateral case provided by Dr. Koch.   So we have here the

17   opacity in the right eye and in the left eye.    I'll be
18   talking a lot today about the ICL because the available

19   literature is related to the ICL and also these are the

20   specimens we have available to us in our center.

21               So what happens in this case is that the

22   surgeon has to explant the lens and then he is going to

23   perform the cataract procedure.   So we are recommending

24   them to save for us the capsule excess fragment so we can
25   perform histopathological analysis of this anterior capsule
                                                                 87

1    fragment, and in fact it's been very interesting to notice

2    that there are many similarities between anterior capsule

3    specimens obtained in different situations.

4                  So for example, here you have the capsule

5    excess edge of a case of anterior capsular opacification

6    after implantation of a silicone lens, here you have the

7    specimen, the capsule excess specimen obtained during the

8    surgery of an anterior subcapsular cataract secondary to

9    uveitis, and finally here is the specimen we received in

10   our center.   It's the capsule excess obtained during the

11   cataract procedure for a case of anterior subcapsular

12   cataract after phakic IOL implantation.   So in fact, if you

13   see these three examples, you will always find this

14   fibrocellular tissue attached to the inner surface of the

15   anterior capsule, corresponding to the opacification.

16                 Finally, the E-cells are the most important

17   cells involved in the process of posterior capsule
18   opacification and mostly in the pearl form of posterior

19   capsule opacification.   Both cells, and mostly the E-cells,

20   are involved in the process of interlenticular

21   opacification between piggyback lenses, and when you

22   analyze such specimens in histopathology, you are going to

23   find residual corneal material and pearls very similarly to

24   what is observed with posterior capsular opacification.
25                 I'd like now just to summarize the evolution of
                                                                  88

1    the designs of the phakic posterior chamber lenses.

2                 So, as you know, these lenses were introduced

3    by Fyodorov in the '80s and the first designs were pupil-

4    fixated lenses.   So this lens, for example, was supposed to

5    stay in the sulcus, but the optic component would protrude

6    through the anterior chamber through the pupil.

7                 The second generation was represented by the

8    Chiron Adatomed silicone lens, and in fact this lens was

9    withdrawn from the market because of cataract formation.

10   This was really a very thick lens.

11                Finally, the third and current generation is

12   represented by the Staar ICL manufactured from the collagen

13   material.   This is a much thinner lens, and in fact there

14   are different models of this design and each model has

15   different vaulting characteristics.

16                The third generation is also represented by the

17   Medennium phakic refractive lens, or PRL, manufactured from
18   silicone, and this is also a very thin lens, and you have

19   here the myopic model and the hyperopic model.

20                So let's talk about some relevant aspects of

21   fixation and sizing.   We had the opportunity to analyze

22   some Chiron Adatomed silicone lenses which were explanted

23   because of the problem of cataract formation.    Then, after

24   analysis of the lenses, we reimplanted the lenses in eyes
25   of different sizes, and in fact we could observe from the
                                                                    89

1    posterior view or a side view that the lens was really too

2    big and too thick.    The lens was really sitting on the

3    zonulas.   We could not fixate the lens in the sulcus, and

4    because it was very thick, it was in large contact with the

5    posterior surface of the iris and anterior surface of the

6    crystalline lens.

7                   With respect to the ICL, consecutive V models

8    of this design had different vaulting characteristics, and

9    this was done in order to reduce the possibility of

10   cataractogenesis.    Apparently, the sizing is important for

11   this design.    So a lens that's too large will be followed

12   by excessive vaulting, but a lens that's too small for the

13   eye will be unstable and eventually become decentered.

14                  Dr. Ferdinand Trinidad from Brazil very nicely

15   summarized different situations with incorrect sizing of

16   the ICL.   So for example, if you have a lens that's

17   oversized, the vaulting will be excessive and there will be
18   a large area of contact between the lens and the posterior

19   surface of the iris.

20                  Here, for example, there is a central vault,

21   but a large mid-peripheral contact, and you have a pool of

22   aqueous humor that's stagnated between the lens and the

23   crystalline lens, and eventually, as we're going to discuss

24   further, there is the possibility of some metabolic
25   disturbances.
                                                                  90

1                   Finally, if the lens is clearly undersized, the

2    lens will be unstable and there will be a large area of

3    contact between the lens and the anterior surface of the

4    crystalline lens.

5                   So the sizing issue is eventually a very

6    important issue for phakic IOL implantation in general, and

7    in general surgeons are using the measurement of the white

8    to white to finally choose the size of the lens that's

9    going to be implanted in the eye of the patient.

10                  For example, for the ICL, if you review the

11   literature, surgeons would measure the white to white and

12   then add 0.5 millimeters for a myopic eye or they subtract

13   0.5 millimeters for a hyperopic eye, but this measurement

14   can be so inaccurate, and sometimes we receive some cadaver

15   eyes in our lab and we don't even know exactly where to

16   measure.

17                  This is a very recently published paper by this
18   group.   They analyzed 43 eyes of 24 patients.   They

19   patients were aged at around 34 years and they were highly

20   myopic or hyperopic.    They performed measurements of the

21   white to white with surgical calipers, and they tried to

22   look for a correlation between the white to white and the

23   sulcus diameter measured with composites of UBM

24   photographs.
25                  They concluded that the traditional estimation
                                                                   91

1    of the sulcus size through the limbal measurement is

2    inadequate.    So the limbus size alone would not be able to

3    predict the sulcus size.

4                  We are also trying to do different studies

5    using cadaver eyes regarding the sizing.    For example, we

6    are actually working on this protocol where we get

7    different cadaver eyes, we measure the anterior/posterior

8    length, then we mark the 12 o'clock position, and we

9    localize the horizontal meridian and the vertical meridian.

10    Also, we perform measurements using a plastic sizer of the

11   anterior chamber diameter, and after that we try to fixate

12   the eye with special techniques which allow us to keep the

13   geometry of the whole anterior segment.    Then we select the

14   meridian to be studied with the form sections, and then we

15   directly measure the angle to angle and the sulcus to

16   sulcus with surgical calipers.

17                 So in fact, we have some eyes where we studied
18   the vertical meridian and other eyes where we studied the

19   horizontal meridian, and this is preliminary data and the

20   study is not finished, but it's already very interesting to

21   notice that, for example, here, for the same measurement of

22   the white to white, which here is 11, we obtained real

23   measurements of the sulcus to sulcus which went from 11 to

24   almost 13.    So then if you would choose an 11.5 ICL to
25   implant in these eyes, what would happen with the eyes
                                                                 92

1    between 12 and 13?

2                So I would like to mention the new technology

3    that's being developed that will help in the issue of the

4    sizing, and I mention this device because this is the

5    device we are having the opportunity to work with right

6    now.

7                So we are working this protocol where again we

8    use cadaver eyes and we measure the anterior/posterior

9    length, then we mark the 12 o'clock position, measure the

10   white to white, and with this prototype of ultrasound we

11   are performing of the anterior chamber diameter and then

12   the sulcus-to-sulcus diameter.   Then we prepare the eye

13   with these special techniques for fixation.   We perform the

14   sections in the region we choose, and finally we perform

15   the direct measurements of angle to angle and sulcus to

16   sulcus.

17               This is also preliminary data, but so far we
18   analyzed nine phakic cadaver eyes, and if you compare the

19   angle-to-angle measure by calipers and ultrasound, the

20   results are very similar and this is valid also for the

21   sulcus to sulcus, and this is also valid for pseudophakic

22   cadaver eyes we analyzed.   So far, we analyzed only six.

23               When you look at the pictures you obtain with

24   the ultrasound, in fact they apparently reflect very nicely
25   the morphology we obtain after the fixation of the
                                                                   93

1    specimen, which allows us to perform the measurement which

2    appeared to be very accurate.   So here you have an example

3    of a phakic cadaver eye, and here the same analysis is

4    performed in the pseudophakic cadaver eye.

5                Of course, this technology is going to be

6    extremely important in the follow-up of patients implanted

7    with different phakic IOLs.    It will be important for the

8    measurement of the distance between the edge of the lens

9    and the mid-periphery of the cornea.    For example, in the

10   phakic anterior chamber intraocular lenses, and also

11   extremely important to the measurements of the posterior

12   surface of the lens and the anterior surface of the

13   crystalline lens in phakic posterior chamber IOLs.

14               So let us review briefly the surgical

15   implantation.   We have to remind you there are lots of

16   opportunities for the surgeon to create the cataract

17   observed in the postoperative period.
18               So the first thing the surgeon has to do is in

19   fact to perform these YAG laser iridotomies.   In general,

20   they use two superior iridotomies placed 90 degrees apart,

21   and this is performed one or two weeks before surgery.

22   There are some studies indicating that these have

23   eventually a cataractogenic effect also and that they

24   contribute to pigment deposition which we always observe on
25   the surface of these lenses.    Also, in an alternative way,
                                                                   94

1    the surgeon can perform one single surgical iridectomy.

2                   After that, the surgeon has to perform the

3    incision.    These are foldable lenses, the incision is very

4    small, and it can be used to correct preexisting

5    astigmatism.    The surgeon has to inject viscoelastics,

6    which is extremely important in the protection of

7    intraocular tissues and also to allow the lens to unfold in

8    very controlled manner.

9                   Both lens types can be inserted with forceps

10   and also injected within the anterior chamber, and then

11   finally the haptics will be placed behind the iris with

12   spatulas or hooks, and this is a very important step

13   because no pressure should be placed on the crystalline

14   lens at that time.    Then the pupil is constricted with

15   miotic agents, the viscoelastic is removed, and the wound

16   is closed.

17                  So of course, the crystalline lens should
18   ideally not be touched at all during the whole surgery, but

19   as you can see, there are many opportunities to have

20   accidental contact with the anterior capsule of the

21   crystalline lens not only during the placement of the

22   haptics behind the iris, but also injection of viscoelastic

23   behind the iris, et cetera.    So anterior capsule trauma, as

24   we review the literature, you will notice that this may
25   lead to crystalline lens opacities months later after the
                                                                   95

1    procedure.

2                 There are some studies indicating that in many

3    ways high myopic patients are going to have cataract and

4    with earlier onset.   For example, I can cite this study

5    indicating that moderate to high myopic patients had an

6    association with age-related cataract.      For lower levels of

7    myopia, this relationship has been disputed.     They also

8    indicated that early onset of myopia is a strong

9    independent risk factor for cataract.

10                But we can not forget that they are talking

11   here about age-related cataract.    They are talking about

12   mostly nuclear cataract, and when you review the different

13   forms of cataract according to the age they appear, you're

14   going to notice that anterior subcapsular cataracts are

15   very rare forms of age-related cataract unless they are

16   caused by inflammation or injury.

17                So I'd like to summarize some of the specimens
18   we are receiving in our center.    We had the opportunity, as

19   I mentioned, to analyze some silicone Chiron Adatomed

20   lenses and we have recently received eight ICLs, all

21   explanted because of cataract formation.     There are some

22   bilateral cases and the lenses were explanted between one

23   year and four years after implantation.

24                Here you have some examples.    This is one of
25   the eyes of the patient, and here the corresponding ICL
                                                                  96

1    explanted from this eye, and this is the contralateral eye

2    and the corresponding ICL explanted from the eye.    So this

3    surgeon not only submitted the ICL he explanted, but also

4    he submitted the fragment of capsular excess while he

5    performed the cataract surgery.

6                 So in general, when you analyze the surfaces of

7    these ICLs, you always find some pigment deposition, as you

8    can observe here, and in these specimens, stained with

9    different techniques, you always can observe the

10   fibrocellular tissue attached to the inner surface of the

11   anterior capsule which is corresponding to the opacity.

12                This pigment deposition can be very discrete,

13   as in the previous case, but it can also be very important,

14   as you can see here in this bilateral case.   These lenses

15   were also explanted because of cataract.

16                What about the mechanisms of this cataract

17   formation?   This study is very interesting because it
18   summarized many of the factors that are eventually

19   important.   So these patients were implanted with the ICL

20   and they observed an anterior chamber reduction in 9 to 12

21   percent of the cases.   Central endothelial cell density

22   decrease, not progressive, but very interesting, they

23   report an increase of the aqueous flare in 50 percent of

24   the cases with stabilization, but always above preoperative
25   values.   They reported progressive decrease of crystalline
                                                                   97

1    lens transmittance with time, contact ICL iris in all eyes,

2    peripheral contact ICL and crystalline lens in 60 percent

3    of the cases, central contact of the ICL and crystalline

4    lens in 15 percent of the cases, and changes in ICL axis in

5    10 percent of the cases with rotation of the lens in the

6    postoperative period.    But they didn't observe any cataract

7    formation after the follow-up.

8                   So of course, we mentioned already surgical

9    trauma can cause these cataracts were are observing after

10   implantation of phakic lenses.    We cannot forget the

11   possible effect of the YAG laser for the iridotomy.      We

12   cannot forget the accidental contact of the anterior

13   capsule is possible during different surgical steps.

14   Intermittent microtraumas can also cause these cataracts.

15   There is an increased crystalline lens curvature during

16   efforts for accommodation.    It was demonstrated that the

17   lens can rotate inside the eye in the postoperative period,
18   and of course, there is always an increase in the overall

19   lens size throughout life, so the distance between the

20   phakic lens and the crystalline lens is not always going to

21   be the same.

22                  So what about constant trauma?   This apparently

23   is extremely important.    So here in cases of clearly

24   undersized lenses, there would be a large area of contact
25   between the lens and the anterior surface of the
                                                                  98

1    crystalline lens.

2                Also, there is the possibility of a continuous

3    disruption of the blood/aqueous barrier with subclinical

4    inflammation, and this is caused by friction between the

5    iris and the phakic lens, and eventually by the ciliary

6    sulcus fixation also.   These have effects not only on the

7    crystalline lens transmittance, but eventually on the

8    corneal endothelium.

9                What about crystalline lens metabolic and

10   nutritional disturbances?   We already commented on this

11   situation, for example.   There is a pool of aqueous humor

12   stagnated between the lens and the anterior surface of the

13   natural crystalline lens.   So this could be caused by the

14   previously mentioned subclinical inflammation, but by any

15   cause of blockage of normal circulation of the aqueous

16   humor.

17               When we reviewed the literature, in fact we
18   performed a review from '96 to 2002, and we could only find

19   studies regarding the early Fyodorov lenses, the Chiron

20   Adatomed silicone lenses, and the ICLs.   We could not find

21   any studies regarding the PRL.   I'd like to comment on some

22   of these studies because they have very interesting points

23   which are eventually very important.

24               So for example, in this study of patients
25   implanted with the Chiron Adatomed silicone lens, there was
                                                                      99

1    no space between the phakic lens and the natural

2    crystalline lens in all cataract cases, which places

3    eventually this factor as one of the most important

4    factors.

5                   In this study by Zaldivar and coworkers and

6    studying patients implanted in the ICL, he reported one eye

7    with a peripheral anterior subcapsular opacity which

8    developed in the region of the peripheral laser iridotomy,

9    showing again that these iridotomies eventually have a

10   cataractogenic effect.

11                  So this group in Brazil studying patients

12   implanted with the Staar ICL reported an anterior

13   subcapsular opacity in the central non-contact area.        So

14   the contact eventually is very important, but maybe there

15   are other factors or maybe the follow-up was just not

16   enough.

17                  This group, also studying patients implanted
18   with the ICL, reported anterior subcapsular opacity which

19   developed 24 hours after surgery.    So we may think that

20   this was really caused during the surgery and not by the

21   lens itself.

22                  So this group reported one case of nuclear

23   cataract in a 53-year-old male.     He had already some degree

24   of nuclear sclerosis, so of course, this is not the kind of
25   cataract we are talking about here.     This is maybe just
                                                                 100

1    age-related cataract and is not related to the procedure

2    and not to the lens also.

3                 This is one of the very few studies which

4    really describes the evolution of the opacities.   So they

5    describe opacities which appeared superiorly and then

6    progressed involving the optical zone, and in all cases

7    there was in fact a satisfactory central ICL vaulting in

8    the cases of cataract, indicating that in these particular

9    cataract cases, the contact was not the most important

10   factor.   I like to cite this study because in general there

11   are many surgeons that would say that some peripheral

12   opacities would never progress.

13                Finally, this is maybe the only study which

14   compares patients implanted with an ICL in one eye and the

15   Chiron Adatomed silicone in the other eye, and they

16   demonstrated that the silicone lens was associated with

17   more cataracts and the cataracts appeared earlier in the
18   postoperative period.    In all cases, no space was observed

19   between phakic lens and natural lens, so again, here we

20   believe that the contact is the most important factor.

21                So when you group all these papers together,

22   it's a big problem to really understand what is the real

23   incidence of cataract.   With regards to the silicone lens,

24   the rates vary from 0 to 52.9 percent and regarding the
25   ICL, they go from 0 to 25 percent.
                                                                   101

1                   So why is that?   First of all, because the

2    definition of cataract and opacity is really not the same,

3    some surgeons will report just the cataracts that are

4    creating visual problems for the patient, and some

5    opacities that are not decreasing the visual acuity would

6    not be reported.

7                   Also, there is such a variation in the age of

8    the patients included, and also such a variation in the

9    follow-up considered, and in some studies they would say

10   that the follow-up is from three months to two years, but

11   in fact maybe just two patients had the follow-up of two

12   years and the great majority were followed up for six

13   months only.    And in some studies -- for example, for the

14   ICL -- during the same study different models of the same

15   design were implanted, and you know with different vaulting

16   characteristics, so the effect for cataract formation would

17   not be the same.
18                  So there is a great need of standardization of

19   these studies evaluating cataract formation.     First of all,

20   the parameters used for the YAG iridotomies should be

21   described, because eventually this is cataractogenic.        All

22   trauma to the anterior capsule during this surgery should

23   be noted for future reference.     A follow-up period should

24   be at least two years because in fact, according to the
25   literature, the majority of cataracts appear between one
                                                                102

1    and two years after the procedure.   And of course, we have

2    to evaluate very nicely the relationship of the phakic lens

3    with anatomic structures because the contact is one of the

4    most important factors.

5                Also, of course, we need a very accurate method

6    to choose the IOL size.   To use just the white to white to

7    choose the overall size of the lens that's going to be

8    implanted is not accurate at all, and that's why we're

9    having so many complications, and this could really be

10   avoided.

11               There is a need of evaluation of subclinical

12   inflammation with laser flare meters because in some cases,

13   there was a very good vaulting lens and a cataract appeared

14   anyway.

15               There is a need of evaluation of explanted

16   phakic lenses with histopathological analysis of adjacent

17   tissues, but if you ask me right now if just with
18   histopathologic studies alone we will be able to

19   differentiate cataracts caused by the surgeon and cataracts

20   caused by the lenses, the answer is that we don't know yet.

21    We have just one specimen and we would like to look for

22   more specimens to have an impression about that.

23               And of course, we need to describe the

24   evolution of the anterior subcapsular opacity.
25               So let's talk about the possibility of a
                                                                  103

1    classification for cataract formation after phakic IOL

2    implantation.    So as I mentioned, some surgeons would say

3    that all the opacities they saw are peripheral and they are

4    non-progressive, but we have this paper indicating that the

5    peripheral superior opacity progressed, involving the

6    optical zone.    So if you have a classification, we should

7    maybe classify the opacity in each visit to have an

8    impression about the progression of the problem.

9                   So as you know, there are systems for the

10   classification of cataracts and they are all based on

11   standard retroillumination photographs and the total area

12   of the opacity.    These are three well-known systems, the

13   LOCS system, Wilmer system, and Oxford system.

14                  Here, we have some pictures showing how to

15   classify nuclear, cortical, and posterior subcapsular

16   cataracts with the LOCS system, all based on these standard

17   photographs.    This could eventually be applied to cataract
18   formation after phakic IOL implantation.    This is how we

19   grade the cortical opacities according to the Wilmer system

20   and this is the way we score anterior subcapsular and

21   posterior subcapsular opacities according to the Oxford

22   system.

23                  Also, there are very sophisticated systems

24   combining high-resolution digital retroillumination imaging
25   with image analysis systems, allowing objective and
                                                                   104

1    quantitative measurement, for example, of posterior

2    capsular opacification, which eventually would be very

3    useful in this clinical situation.

4                  So in a way, if there is a way to do a

5    classification, this classification should indicate the

6    location of the opacity.    For example, peripheral or

7    paracentral or central opacity.    Also, maybe there is a

8    possibility to have an index for the intensity of the

9    opacity, and of course, we would have to score the area of

10   the opacity, and by doing that in each visit, we will have

11   an impression about the evolution and the progression of

12   the opacity and we would really understand better the

13   phenomenon.

14                 Thank you very much for your attention.    Thank

15   you very much again for the opportunity.

16                 DR. WEISS:   Thank you very much for an

17   excellent presentation.    Would you be able to take a seat
18   at the table, and we'll open up to the panel for some

19   directed questions.

20                 Dr. Bandeen-Roche, then Dr. Matoba, and then

21   we'll continue around.     Dr. Bandeen-Roche?

22                 DR. BANDEEN-ROCHE:   Yes, I want to thank you

23   for your presentation -- very clear -- and your careful

24   recommendations about the data to collect involving the
25   surgery I think was great.
                                                                  105

1                Just one brief question.     You talked about the

2    importance of tracking the evolution of the cataract and

3    discussed grading.    What implications do you think there

4    are for the frequency of evaluation and do you think that

5    that should be by passive surveillance or by active

6    surveillance?     Just elaborate a little bit more on how to

7    track the evolution of cataract.

8                DR. WERNER:    I don't have a precise idea about

9    when all these gradings should be done.    Of course,

10   immediately after the postoperative period, within one

11   month to anything that's very fast developed, and maybe six

12   months, one year, two years, because this is what we see in

13   the literature.

14               But this is not only to just have the score.

15   It's also for us to understand the phenomenon because still

16   there are many surgeons who believe that the cataract is

17   really not a problem because they have just opacities in
18   the periphery that never progress, and we need to

19   understand if they are not really progressing or he is just

20   not observing.

21               DR. BANDEEN-ROCHE:     Thank you.

22               DR. WEISS:    Dr. Matoba?

23               DR. MATOBA:    In regard to the development of

24   cataracts in areas of contact between the IOL and the
25   crystalline lens, how much do you think the lens material
                                                                     106

1    or the nature of the lens material contributes or is it

2    mostly, you think, a mechanical effect?

3                   DR. WERNER:    Well, I don't know if I can answer

4    this question because we only have results about the ICL,

5    which we know the material.      There is another lens made of

6    silicone and I'm not aware of their results, so we cannot

7    really compare if there is a material effect.

8                   Also, as I mentioned, there are papers showing

9    that cataract is formed only in the area of contact.         Other

10   papers would say that it was formed in a different area,

11   but maybe the follow-up was not enough.       So there are still

12   many questions about that.

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

14   Dr. Mathers.

15                  DR. BRADLEY:    Just a clarification on the

16   peripheral cataracts you described.      How peripheral are

17   they and, for example, would they become visually
18   significant under nighttime viewing conditions where the

19   pupil would dilate?

20                  DR. WERNER:    Well, when you look at the

21   literature, it is really not described, and sometimes, in

22   very early papers, they would describe some peripheral

23   opacities that would cause some glare in light conditions

24   of evening or something like that.      But talking to
25   surgeons, they would say that the peripheral opacities
                                                                   107

1    which are barely visible in the pupil dilation, they would

2    not cause any problem.

3                 DR. WEISS:    Dr. Huang?

4                 DR. HUANG:    Two questions.   The first question

5    was regarding your earlier presentation, you seem to have

6    implied there were two types of cells that were induced in

7    the two different locations of the cataract.      One is A-

8    cells induced in the anterior capsule, and then E-cells

9    induced in the posterior capsule.       Is there any vital stain

10   that can help you to distinguish what type of cells are

11   responsible for the evolution of this cataract?

12                DR. WERNER:    When you perform histopathological

13   studies, in fact what you see is that both cells are always

14   involved in everything, but there is always a predominate

15   type.   For example, even for PESU, you have a fibrotic form

16   of PESU and you have a firm form of PESU, and when you

17   perform normal stains, you can see even morphologically
18   they are very different because E-cells always have the

19   tendency to be bloated, and the other are elongated

20   fibrotic cells, fibrotic-like cells.

21                DR. HUANG:    In the LOCS III grading system,

22   it's really a numerical system and there is a highly

23   individual variation.     Do you have any suggestion how to

24   standardize if that system were to be chosen for the
25   cataract characterization?    And also, I believe the LOCS
                                                                   108

1    III does not have any geographical information about a

2    cataract, and so do you have any suggestion how to modify

3    the system?

4                  DR. WERNER:    I believe there should be a

5    geographic thing because it's very important for the areas

6    of contact who are outside the contact of the lens.        So in

7    this case, it's very important.

8                  But with regards to your first question, I

9    think we should start by collecting many pictures from

10   surgeons to create standard pictures, as they have in the

11   LOCS system, and we have some, but we need more pictures to

12   have really different grading if we use such a system based

13   on standard photographs.

14                 DR. WEISS:     Dr. Mathers?

15                 DR. MATHERS:    Do you think that the

16   photographs, the retroillumination of the opacification,

17   can the photographs detect smaller anterior subcapsular
18   cataract formation than the slit lamp can detect it?       What

19   do you think is actually the finest, highest resolving

20   method?

21                 DR. WERNER:    We have experience with these

22   systems based on retroillumination photographs for

23   posterior capsular opacification, and this is the best we

24   can have for that.
25                 DR. MATHERS:    Do you think that's higher
                                                                     109

1    resolution than the human eye achieves with the slit lamp?

2                   DR. WERNER:    Eventually, yes.

3                   DR. MATHERS:    Yes.   And have you any experience

4    using confocal microscopy, which could actually focus onto

5    the anterior capsule and have even higher resolution?        Do

6    you think that that's possible?

7                   DR. WERNER:    Well, my own experience with

8    confocal microscopy regards the cornea, and I know that

9    there are some objectives which you could switch in some

10   devices and have an imaging of the anterior surface of the

11   crystalline lens.     I have no experience with that and I

12   don't know if there is any data available published about

13   that.

14                  DR. MATHERS:    Sizing is clearly an important

15   process here.    Do you think that the high-resolution

16   ultrasound will give the best sizing data and can that be

17   used clinically to determine which size to put in?
18                  DR. WERNER:    We are evaluating this right now

19   with these cadaver eyes.      The results have been very

20   interesting.    So I don't know exactly the status of

21   development of the technique, when it's going to be

22   available -- maybe this year -- but apparently it's the

23   best we can get for the moment.

24                  DR. MATHERS:    Do you think that the issue of
25   visual significance could be assessed best with glare
                                                                 110

1    testing or what would you suggest as the most significant,

2    highest-resolving method to test the small amounts of

3    visual impairment you might get from an early cataract?

4                DR. WERNER:     Yes, it is a very good question,

5    because in some cases discussed with the surgeon, the

6    lenses were explanted because of glare, and not really

7    decreasing visual acuity.    So glare is very important.

8                DR. MATHERS:     You think it's better than

9    contrast sensitivity testing as it's normally performed?

10               DR. WERNER:     Maybe both.

11               DR. MATHERS:     Just your opinion.

12               DR. WERNER:     Maybe both should be associated in

13   this case, yes.

14               DR. WEISS:    Mr. McCarley, did you have a

15   question as well?

16               MR. McCARLEY:     One question just quickly.   In

17   your experience, and maybe one of the clinical
18   ophthalmologists can answer this maybe even better, a cell

19   flare meter is used to determine subclinical inflammation.

20    Is that different in a posterior chamber lens than it

21   would be, for instance, in an anterior chamber lens?

22               DR. WERNER:     Well, what we saw in the

23   literature is that there are also increased values of flare

24   cell meter with anterior chamber lenses, and apparently the
25   values are even higher and they also stabilize above the
                                                                111

1    preoperative values, contrary to cataract surgery, where

2    you have higher values, but these have a tendency to come

3    back to preoperative values after one year or so.

4                  DR. WEISS:   If there are no other questions, I

5    want to thank you, Dr. Werner, for your excellent

6    presentation.

7                  We can move on to the open public hearing

8    session.   Is there anyone who wanted to make any

9    statements?

10                 (No response.)

11                 DR. WEISS:   If not, I'm going to put a question

12   to the panel.   If we have perhaps a 15-minute coffee break

13   and skip lunch, we might be able to catch earlier flights,

14   as I know is in the interest of some.     Are any of you

15   interested in doing that, taking a 15-minute break, rather

16   than -- so we have two hands up for Dr. Bullimore and Dr.

17   Matoba, and Dr. Mathers for sure.     I would say that passes
18   without a formal vote.

19                 So we'll take a 15-minute coffee break and

20   we'll see you back here in 15 minutes.

21                 (Recess.)

22                 DR. WEISS:   We will now start the FDA

23   presentation and Donna Lochner will introduce the questions

24   for panel discussion.
25                 MS. LOCHNER:   Yes.   I'm just going to go
                                                                 112

1    through the questions and give a little bit of background

2    to where we were coming from with each question.

3                  We're going to begin today with the endothelial

4    cell density study.    After I've stepped through this

5    question, I'll turn the floor over to Dr. Grimmett, and

6    then the panel will discuss the endothelial cell issue

7    before going on to the next questions.

8                  First, "Please comment upon the inclusion

9    criteria recommendations found in Table 1."    This topic is

10   still being actively discussed, and particularly with the

11   ANSI Standards Committee, and so we believe any comments

12   will be very timely.

13                 Table 1, which is just shown right here,

14   provides the recommended minimum endothelial cell

15   densities, and these values for minimum endothelial cell

16   density are generally being used in current U.S. phakic IOL

17   studies.    These values were determined over the course of
18   several meetings over the years with input from FDA,

19   industry, and ophthalmologists that attend these standards

20   meetings.   Allow me to hopefully clarify how the minimum

21   densities per age category were determined.

22                 This slide is included as Attachment B in the

23   handout.    First, the approximate initial cell density for a

24   21-year-old, as shown in the second column in this table,
25   was taken from the 1997 Moller-Pedersen article and the
                                                                  113

1    citation for this article is provided in the handout, but

2    not on this slide.

3                For the 35- and 46-age categories, the cell

4    density at time of implant was approximated by assuming .6

5    percent yearly cell loss due to normal aging, with the .6

6    percent figure taken from the 1997 Bourne article, as

7    referenced earlier by Drs. Edelhauser and McCarey.    This

8    was done to provide a check of whether the minimum

9    inclusion criteria per age group were reasonable.

10               The third column, the estimated rate of cell

11   loss per year, represents potential rates of loss due to

12   the phakic IOL.   In other words, 1.5 and 2 percent assumed

13   loss from the phakic IOLs were used as examples to then

14   calculate the age when the cell density would be less than

15   1,200 cells per millimeter squared and less than 1,000.

16   These ages, shown in the fourth and fifth columns, assume a

17   surgical loss of 10 percent and compound the 1.5 and 2
18   percent loss annually.

19               Finally, in order to determine the minimum cell

20   density inclusion criteria, we looked at the starting

21   densities that would ensure greater than 1,000 cells at age

22   70 for the 21- to 25-age range, and at 75 for 26 and older.

23               So this table verifies that the minimum

24   inclusion criteria, as shown on Table 1, would be
25   sufficient in a worst case situation to allow for adequate
                                                                114

1    cell density for the health of the cornea for roughly the

2    life of the patient, assuming a 2 percent annual loss from

3    the phakic IOL and that patients would have at least 1,000

4    per millimeter squared at ages 70 to 75.

5                As you can see, there are various assumptions

6    inherent in the inclusion criteria and because of the

7    iterations this has undergone because of the committee

8    process, we are very much interested today in the panel's

9    comments on this inclusion criteria.

10               Our statistical calculations suggest that 200

11   subjects should be sufficient to detect a 2 percent loss

12   using measurements at multiple visits in order to establish

13   linearity of the loss.   The measurements, as currently

14   proposed, would taken at the three- or six-month visit, the

15   12-, 24, and 36-month visits.

16               Further, although the statistics suggest that

17   200 subjects would be sufficient, we recommend that
18   specular microscopy be performed on all subjects enrolled

19   in the study to ensure that 200 analyzable photographs are

20   obtained.

21               Last, we recommend that multiple images be

22   captured at each visit and the mean endothelial density

23   from those multiple images be used in the analysis.

24               We are asking for panel comments on these
25   criteria as well.
                                                                    115

1                   Now, I'd like to turn the floor over to Dr.

2    Grimmett for his review.

3                   DR. GRIMMETT:   Thank you, Donna.

4                   This is Michael Grimmett.   I've prepared some

5    comments in outline form which at least the panel members

6    should have on their table.     It's a 10-page outline, and I

7    promise to go very quickly through it.     There are four

8    tables as well.

9                   Regarding the questions, I think I'll go

10   through my outline first.      I was doing the bulk of this

11   thought process and review prior to having the questions.

12   I was doing the work, I'd gone on vacation out in Santa Fe,

13   and I'm relieved and grateful that in the open public

14   hearing session, my wife did not comment on the timing of

15   that review.

16                  (Laughter.)

17                  DR. GRIMMETT:   Notwithstanding that, I think
18   I'll do this review first, and then we'll come back to the

19   questions if some of the issues are not resolved.

20                  Just in general, and some of this has been

21   alluded to by the previous speakers, the peer-reviewed

22   literature on phakic IOLs has numerous limitations, and

23   it's important to recognize that when reviewing any data

24   that's reported in the literature.     Mostly, the data are
25   retrospective in design, they're non-randomized case
                                                                   116

1    series, they have extremely low numbers of eyes reported,

2    there is poor accountability for the longer follow-up

3    intervals, and in general morphometric endothelial analyses

4    are not generally reported.     So coefficient of variation

5    and percent hexagonality are not there.

6                   Additionally, my review is not exhaustive or

7    comprehensive.

8                   I think it's instructive to look at phakic IOL

9    types because we can separate them into three different

10   animals that have different implications for the corneal

11   endothelium.    I've separated them into anterior chamber

12   type and posterior chamber type.    Of the anterior chamber

13   type, there are two, angle-supported and iris-fixated.

14                  Looking at the literature on the angle-

15   supported lens, I'll just give you a smattering of some

16   articles to go over what are reported endothelial cell

17   losses and what's known about design parameters that would
18   impact our recommendations regarding future phakic IOL

19   studies.

20                  To start with, angle-supported lenses, a first-

21   generation lens, the Baikoff ZB lens, had a distance

22   between the IOL edge and the endothelium of only 1.16

23   millimeters, and that was the key factor.    It was

24   determined that there was a high endothelial cell loss
25   secondary to excessive contact between the IOL optic edge
                                                                   117

1    and the endothelium.    One report by Jimenez-Alfaro reported

2    a 16 to 18.8 percent loss at one year and a 20 to 28

3    percent loss at two years.    Another report reported up to

4    56 percent loss with a shorter follow-up.     Of the second

5    report, 37.5 percent had morphologic or cell density

6    changes.

7                   Quotes in these articles include "We have

8    stopped doing this surgical procedure" and "Further

9    implantation of this IOL is unacceptable."

10                  The second-generation lens, the Baikoff ZB5M

11   lens, was manufactured until 1997.    The major difference

12   here is that they increased the distance between the IOL

13   edge and the endothelium, increasing that to 1.56

14   millimeters.    Endothelial cell loss in one study was

15   reported at 4.5 to 5 percent cell loss at one year, 5.6 to

16   6.8 at two years, and 5.5 to 7.5 loss at three years.

17                  A separate study by Perez -- forgive me for my
18   pronunciation -- Perez-Santonja found an endothelial cell

19   loss of 12.33 percent at one year and remaining relatively

20   stable at two years.

21                  Then the larger study was recently reported in

22   Ophthalmology found that at one year there was a 5.53

23   percent loss, and interestingly, after year 2, while the

24   numbers fell down significantly in terms of total eyes
25   examined, the overall loss approximated normal aging
                                                                  118

1    losses.    That is, preop to year one was at 5.5 percent

2    loss; year 1 to year 2, 1.37 percent loss; year 2 to 3, .72

3    percent loss; year 3 to 4, there was a .28 percent loss;

4    year 4 to 5, there was a .55 percent loss; year 5 to 6, .37

5    percent; and year 6 to 7, .56 percent.

6                  So based on this study, and the reason I find

7    this instructive, is that they give us some information

8    regarding what is a reasonable duration to follow these

9    particular lenses before they come to the panel.    If we

10   take this data, which is one of the largest subsets that I

11   could find in the published literature, in year 3 they

12   still had 157 eyes, albeit they're mixing lens times.

13   They're either started or stabilized, and they found

14   stabilization from the two- to three-year period, and you

15   can tell three years is the appropriate duration of a

16   study.

17                 A fourth-generation lens, ZSAL-4 by Morcher,
18   had a distance from the IOL edge to the peripheral cornea

19   of 1.65 millimeters and they reported an endothelial cell

20   loss of 3.5 percent at one year and 4.2 percent at two

21   years, albeit the numbers are low.    There are only 18 eyes.

22    They commented that there is a fifth-generation lens, but

23   I could not locate it in the published data regarding this

24   product.
25                 Another anterior chamber angle-supported lens
                                                                    119

1    in the literature is the Nuvita lens by Bausch & Lomb, and

2    it's a single-piece PMMA IOL.      In one study of 21 eyes by

3    Allemann in Ophthalmology, they reported a 10 percent cell

4    loss in the first year, another 4.3 percent in the second

5    year, and, given these large numbers, certainly if that

6    were to come to the panel, I would want to see more data.

7                   The next category of anterior chamber lenses

8    are iris-fixation lenses.      A Worst-Fechner lens developed

9    in the late '80s, one particular study just reported two

10   eyes of greater than 50 percent cell loss, but they didn't

11   provide any mean cell density analyses or morphometric

12   analyses.   A separate study in 1996 by Perez-Santonja

13   reported a 13 percent loss at one year, another 4.6 percent

14   at two years, indicating to me that the central endothelial

15   cell loss did not stabilize over a two-year period.       The N

16   was only 30 in this particular study.

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

19   Claw lens --

20                  (Laughter.)

21                  DR. GRIMMETT:   Those are synonymous as far as I

22   understand.    There may be some design changes I'm not aware

23   of, but I believe they're in the same family.

24                  It had reported some distances from the corneal
25   endothelium in various publications.      For example, a -15
                                                                  120

1    diopter lens with a 3.2 millimeter anterior chamber leaves

2    1.97 millimeters from the corneal endothelium.    Because

3    these lens are fixated at the iris itself and not vaulted

4    above the iris, certainly you would expect more distance,

5    and this is what we're seeing.    There's more distance from

6    the endothelium.    So the angle-supported lenses, in my

7    view, given their proximity to the cornea, have a higher

8    risk to the corneal endothelium than, let's say, an Iris-

9    Claw lens, assuming that the anterior chamber (inaudible)

10   is constant, whatever it happens to be.

11                  Looking at some data regarding endothelial cell

12   loss on the Artisan lens, a study by Menezo showed a 6.6

13   percent loss at 12 months for 109 eyes and 9.22 percent at

14   two years, but I think it's instructive just to look at the

15   differences.    It's 6.6 percent preop to year 1; 2.63 year 1

16   to 2; 2.5 percent year 2 to 3; 1.74 year 3 to 4.

17                  They found that the cell loss correlated to
18   increased power of the lens, the thicker lens -- that is,

19   perhaps closer to the endothelium -- and shallower anterior

20   chamber depth, which would also tend to bring the lens

21   closer to the corneal endothelium.

22                  This particular study reported morphometric

23   measurements regarding percent hexagonality and coefficient

24   of variation.
25                  They also find some changes that I found
                                                                   121

1    instructive.    They found that there were statistically

2    significant decreases or changes at six months and then

3    return at approximately two years with gradual resolution

4    back to near preop factors in their four-year study.

5                   Then the final category of lenses would be

6    posterior chamber lenses, which we've heard a great deal

7    about already here today by the speakers.    Dr. Werner's

8    excellent presentation showed us pictures of the Fyodorov

9    posterior chamber lens, which is not in general clinical

10   use, with cell losses of 10 percent at 12 months.

11                  Interestingly, the Chiron Adatomed lens that

12   Dr. Werner indicated was pulled because of cataract

13   formation, at least the two studies I pulled, did not

14   report any endothelial cell data whatsoever, reports by

15   Fechner and Marinho.    I didn't locate any other studies on

16   those lenses.

17                  The Staar Surgical ICL that we heard about
18   today already, one study by Zaldivar of 124 eyes didn't

19   report endothelial cell counts, and in another study by

20   Arne, cell loss was actually remarkably low, 2 percent at

21   12 months and 2 percent at 24 months, and no eye had an

22   endothelial cell loss greater than 3.8 percent at one year

23   in 58 eyes.    Since these lenses are in Phase III trials,

24   I'm certain there's some data targeted and reviewed by the
25   FDA in a confidential fashion regarding larger sample
                                                                  122

1    sizes.

2                  Knowing what the literature has to say about

3    endothelial cell loss and the differences between these

4    three types of lenses would help us give guidance regarding

5    future manufacturers' studies.    It's important, as Dr.

6    Edelhauser alluded to, to look at normative data, so that

7    we know what the natural rate of loss is for corneal

8    endothelium in order to gauge our comments.

9                  Rates of normal endothelial cell loss range

10   between .3 and 1 percent per year, depending on where you

11   look.    I've quoted the various studies.   The Bourne article

12   in 1997 with the .6 percent rate is frequently quoted, but

13   there are slight differences in the literature in that

14   regard.    It's in somewhere in that range.

15                 As far as surgical procedures, we all know that

16   operative procedures can create both a direct surgical

17   instantaneous hit to the endothelium as well as possibly
18   change the annualized cell loss rate.    Cataract surgery as

19   far as Bourne's article in 1994 reported a mean 2.5 percent

20   cell loss per year over a 10-year period.     It's important

21   to realize that these were intracapsular and extracapsular

22   surgeries with iris-sutured lenses, transiridectomy clip

23   lenses, and a few posterior chamber lenses.     There are some

24   other articles that indicate that cataract surgery causes a
25   1.1 percent cell loss rate per year, and a Werblin article
                                                                123

1    in '93 said that one year is an 8.8 percent loss, and

2    you'll note that in the FDA table previously shown by Ms.

3    Lochner and in some of the assumptions I'll later make, we

4    just round that figure to a 10 percent surgical loss at the

5    time of the procedure, which obviously is different from

6    the future cell loss rate that may be increased over

7    normal.

8                As a point of interest, penetrating

9    keratoplasty has a 7.8 cell loss per year.

10               I went ahead and quoted the age-stratified

11   normal endothelial cell density values, both from the Yee

12   article in 1985 as well as a pathologic analysis.   The

13   difference between the studies, one is specular microscopy,

14   the other is pathologic.   I found they were similar in

15   terms of mean values.   The lower age bracket, age 20 to 29,

16   they start at 2,900 cells and by the time you get up to age

17   80-89, there are 2,300 mean cells.   The main difference is
18   in the standard deviations.

19               Dr. Edelhauser earlier indicated that the non-

20   contact robo data agrees with the Yee data, and I quite

21   frankly find the standard deviation values in the path

22   study to be huge, plus or minus 500, plus or minus 690.     In

23   talking with Dr. Edelhauser on the break, he's going to

24   look further into the Moller-Pedersen article regarding the
25   standard deviations, but I tend to gravitate toward the Yee
                                                                124

1    article with the standard deviations.

2                The peripheral cornea, if measured, is known to

3    have increased cell density.   Per some data that Dr.

4    Edelhauser provided, there's a 5.8 percent increase in cell

5    density in the paracentral region and a 9.8 percent

6    increase in the peripheral cornea.

7                The next category that I did, knowing the peer-

8    reviewed literature and now knowing normative data, is I

9    tried to determine what would be some thresholds for

10   unacceptable rates of endothelial cell loss.    There are two

11   different questions, I believe.

12               One, as a panel member, when an application

13   comes to panel, we all be concerned about what is an

14   acceptable cell rate when we get that application with a

15   particular observed cell loss rate.    The reason it's

16   important to get some judgement about acceptable cell loss

17   rates now is it will help us give guidance regarding what
18   or how low should thresholds be that we're actually trying

19   to screen for to make the determination how big the sample

20   sizes must be.   So we have to have a sense for what are the

21   maximum and minimum ranges for thresholds that we're even

22   looking at, so we can give some type of guidance regarding

23   sample sizes.

24               I certainly don't expect anyone right now to
25   define an acceptable cell loss rate.    That will certainly
                                                                     125

1    be a hotly debated topic once an application's received,

2    but I think it's instructive that we go through the

3    exercise to see what our limits are, maximum and minimum

4    unacceptable rates of cell loss.

5                   I've approached this argument by first looking

6    at life expectancy data.       The RP-2000 mortality table is

7    based on a study of the mortality experience of pension

8    plans conducted by the Society of Actuaries and was in

9    response to pension legislation that directed the Secretary

10   of Treasury to promulgate the use of updated mortality

11   tables for various pension calculation purposes.

12                  According to that table, the life expectancy

13   for a 21-year-old male is 58 future years or an age of

14   death of 79.    The life expectancy for a 21-year-old female

15   is 62 future years, so an age of death of 83.      Those are

16   United States data.

17                  Realize that depending on your entry date,
18   you'll have change, obviously, to your age of death.      If

19   you enter at age of 80, you don't have an age of death of

20   79.

21                  (Laughter.)

22                  DR. GRIMMETT:    But I used it as a fixed value

23   for this particular analysis, so as to not get confused

24   with multiple iterations of the tables.      Suffice it to say
25   that when you enter at 20, 30, or 40, it may only differ by
                                                                 126

1    a few years in terms of your age of death.

2                  The minimal acceptable corneal endothelial cell

3    density value is critical, and Ms. Lochner presented a

4    table regarding a 1,200 threshold and a 1,000 threshold

5    near death.   I picked values on either side of the range to

6    show the range of acceptable cell loss for sake of

7    argument.

8                  In one of Dr. McCarey's earlier versions of a

9    slide, he quoted a minimal acceptable rate of 1,500 cells.

10    Whether we call that number 1,500 or 1,400 or 1,300 or

11   whatever it's picked as is not really the crucial value,

12   but I think a larger number has the argument that if these

13   patients get into any kind of trouble with their phakic

14   IOL, number one, it allows you to do a surgical procedure

15   to possibly correct that, whether it be explantation of the

16   IOL or manipulation of the IOL.

17                 Secondarily, we all know as clinicians that as
18   patients enter their early 70s, they have a much higher

19   likelihood of having us see them with cataracts just from

20   age-related phenomena.   Whether or not it's increased with

21   phakic IOLs remains to be determined, but this larger

22   target value near or at the age of death will certainly

23   allow a future intraocular surgical procedure, such as

24   cataract surgery.   If we run all of our calculations and
25   run them right down to the wire and leave them the bare
                                                                 127

1    minimum and leave half of the years to the time of death,

2    you are not giving that patient the opportunity to have any

3    intraocular intervention of any kind.   So that's why I

4    picked the number of 1,500, and Dr. McCarey in an earlier

5    version happened to put that number there, so I went with

6    it.

7                 The next number I used is a potential corneal

8    edema of 800 cells per square millimeter.   Acceptance of

9    this particular target will not allow a future intraocular

10   procedure, in my opinion, and certainly if I had a patient

11   of advanced age with immense nuclear sclerotic cataract

12   requiring higher phaco times, I would not be comfortable

13   performing phacoemulsification with entry cell count of

14   800.   I would certainly advise the patient clinically that

15   they would have a higher chance of having postoperative

16   corneal edema.

17                In the literature, there's been a quote of 500
18   cells for imminent corneal decompensation, but I think it

19   depends on the actual function of the remaining cells.    So

20   the exact, precise figure is not locked down, but in my

21   opinion, clinically it's somewhere in the area of 800.

22                The assumptions I made for my threshold

23   analysis is that the endothelial cell loss, as calculated,

24   was an instantaneous, exponential endothelial cell loss
25   rate, that they lose 10 percent at the time of the surgical
                                                                  128

1    procedure, and then they have a continuous stable

2    annualized exponential cell lose rate after that time.       I

3    used a round down analysis of any remaining fraction.    I

4    used .99 rounded down because partial cells do not survive.

5                I did not alter the life expectancy target

6    values, as I had previously mentioned.

7                Table 1.   I'm not going to go through this,

8    obviously, in detail, but all I did is create an Excel

9    spreadsheet with a formula.   I set the target at the end at

10   1,500, I set the percent drop per year, and I was back-

11   calculating the cells you would need to enter the study.

12   That's all it is.   So I was trying to find out what cell

13   count would you need at age 21 in order to end up with a

14   cell count of 1,500 at the time of death for male or

15   female, and then supplying the percent drop per year.

16               For that particular assumption, 1,500 cells at

17   the time of death, 2 percent cell loss per year, I found,
18   for example, age 21, you need 5,900 cells if you're female

19   and you need 5,400 male.   Not possible.   We looked at the

20   normative data and those numbers exceed the normative data.

21               So the conclusion from that scenario is that if

22   a 1,500 cell target is desired at death, a 2 percent annual

23   cell loss rate is not acceptable.   It's not possible to

24   enter with a high enough cell count for all but the very
25   older age ranges.   So everyone will fall below 1,500
                                                                129

1    because you can't enter with a high enough cell count.

2                I did that same type of analysis trying to

3    bracket what would be inclusive of all ages in order to

4    allow everyone to enter the study.   A 1.5 percent cell lose

5    rate, which is Table 2, they're still entering with some

6    very high cell counts.   At age 21, for example, 4,300 for a

7    woman and 4,100 cells for a male.

8                The conclusion from that scenario with 1,500

9    target and 1.5 percent cell loss is that no one could enter

10   with a high enough cell density, except those older than

11   approximately 50.   So that cell loss rate is unacceptable,

12   the 1.5, if you're targeting for 1,500, that target, of

13   course, having the advantage of allowing someone in the

14   future an intraocular surgical procedure.

15               It turns out a .9 percent cell loss rate per

16   year allows all ages to enter with a reasonable cell count

17   that could be achieved based on the normative data.   The .9
18   percent cell loss per year on Table 3 shows all the entry

19   cell requirements, and they reasonably match or were below

20   the normative data for all ages, telling us that the cell

21   density values will approximate or exceed 1,500 at the time

22   of death for all patients entering the study.

23               So the .9, assuming you'd want 1,500 to be your

24   target, is the maximum allowable rate that's inclusive of
25   all ages, and that rate is approximately 50 percent higher
                                                                130

1    than the normal of .6 percent cell loss rate per year.

2    We'll later hear from our statisticians regarding the

3    feasibility of trying to read for that low level of cell

4    loss rate in the face of the variability and precision

5    issues that Dr. Edelhauser brought up, because it's my

6    opinion, based on review of some initial data, that the

7    sample sizes would have to be unreasonably large.

8                Just as an example from the literature, an

9    angle-supported phakic IOL from Alio, 1999, has a cell loss

10   rate of .72 percent from years 2 to 7 after experiencing a

11   6.83 percent loss from preop to year 2.   So based at least

12   on something in the literature that the numbers are not

13   huge, it's doable.

14               Looking at it a different, looking at the

15   target of 800, so running right up to the edge of corneal

16   edema, I can give you all the tables, but the number that I

17   am giving you is 1.9 percent cell loss rate per year.    That
18   number of 1.9 percent cell loss rate per year would allow

19   all patients to enter based on the normative data.

20               So if you desire an 800-cell target value, a

21   1.9 percent rate of annual endothelial cell loss is the

22   maximum allowable rate of loss that's inclusive of all

23   ages, and that's about three-fold higher than the normal .6

24   percent rate per year, and at least based on the Menezo
25   1998 Artisan lens data, I have an average cell loss rate of
                                                                  131

1    2.28 percent from years 1 to 4.

2                 Based on all these analyses and review of the

3    literature, I went ahead and just prepared a bunch of

4    different issues that I would want to see or issues that I

5    would want considered in phakic IOL studies regarding the

6    endothelium, and then we can back to the specific

7    endothelial questions.   Most of the question issues I

8    believe will be covered.

9                 General issues that I would have for all phakic

10   IOL studies is that certainly endothelial cell density

11   measurements are mandatory.   We saw in some of the

12   published literature it did not report endothelial cell

13   densities whatsoever, which I think is unacceptable for a

14   new product of this design because it's a critical issue

15   for the survival of corneal health.

16                Certainly, a central count is mandatory.    A

17   peripheral count will be important, especially if it's an
18   anterior chamber lens.   You'd want a cell density in the

19   region near the IOL edge or in the area of minimum distance

20   between the IOL and endothelium.   That was learned from

21   early lens design.   So especially with an angle-supported

22   lens, I would be highly interested in reviewing the

23   peripheral cell count.

24                It is my belief that morphometric analyses are
25   mandatory.   We know that analysis of cell shape and size
                                                                132

1    provides a more sensitive indication of endothelial cell

2    damage than cell density alone.    I understand the

3    limitations of the issues, as Dr. McCarey and Dr.

4    Edelhauser have outlined, regarding the coefficient of

5    variation and the reliability, especially with the

6    algorithms of the non-contact robo.     Notwithstanding those

7    limitations, I still feel it's an important variable to

8    consider and may give us some additional information.

9                   Just as a matter of course, corneal pachymetry,

10   corneal functional analysis, most certainly would be

11   suggested.

12                  The duration of the study that I would be

13   interested in prior to that study coming to panel would be

14   three years.    Based on the literature, it seems like there

15   is an initial larger decrease and subsequent next decrease,

16   and then stabilization after a year or perhaps two to

17   three.   Depending on what is seen in panel, it would be my
18   guess that there would be discussion of postmarket

19   surveillance of endothelial cell data for possibly a year

20   or two more.

21                  There are some data that it may take four years

22   to see the morphometric data return to baseline levels and

23   ensure stability, but I do not believe, based on what I've

24   seen in the peer-reviewed literature and based on my
25   concern about the corneal endothelium, especially for
                                                                133

1    anterior chamber lenses, that I would be comfortable

2    approving a lens with only two years of data.   So for me,

3    three years would be the minimum I would favor.

4                I would favor a longer endothelial study

5    duration, perhaps postmarket-mandated, for higher risk

6    factors, such as angle-supported lenses, which have a

7    higher risk to culture the endothelium than iris-fixated

8    lenses, which are closer than posterior chamber lenses.

9                The same issue.   Thicker lenses are closer to

10   the endothelium than thinner lenses.   So we would want

11   longer follow-up for those.

12               A shallower anterior chamber depth, such as

13   hyperopic patients, would have a higher risk than deeper

14   anterior chamber depth, perhaps if the IOL is closer to the

15   endothelium, and certainly chronic anterior chamber

16   inflammation, as previously mentioned, would be a higher

17   risk factor for endothelial loss than a quiet anterior
18   chamber.

19               Interestingly, in one early, approximately 50-

20   page paper by Drews in 1991, he went over study parameters

21   versus the FDA grid regarding what he would expect for

22   phakic IOLs, and he recommended a five-year study duration.

23    I certainly don't disagree with that, given the importance

24   of corneal endothelium.
25               With respect to anterior chamber phakic IOLs,
                                                                  134

1    we know that the optic-endothelium distance plays an

2    important role in potential endothelial damage.    Therefore,

3    high-resolution ultrasound, as mentioned by Dr. Werner, I

4    believe would be mandatory to disclose the optic-

5    endothelial distance and distances between other eye

6    structures and the IOLs, such as the crystalline lens.

7                   The peripheral endothelial cell density and

8    morphometric measurements would be mandatory in my opinion

9    in the region of the IOL optic edge, in addition to the

10   central endothelial analysis, because if the examination is

11   limited to the central cornea, it may fail to detect

12   significant endothelial injuries, and then specular images

13   can show significant morphologic changes over the edge of

14   the IOL in the absence of central cell density changes.

15                  I would caution that a preop history of eye

16   rubbing may be a contraindication for entry into the study,

17   especially when we're talking about such low tolerances
18   between the distance between the IOL edge and the corneal

19   endothelium.

20                  Depending on the IOL design, such as an angle-

21   supported lens, a manufacturer must specify a minimum

22   anterior chamber depth that contraindicates IOL insertion.

23                  Because chronic inflammation is a known factor

24   in endothelial damage and because some studies have
25   disclosed chronic anterior segment inflammation after
                                                                 135

1    phakic IOLs using a laser flare cell meter, I would

2    recommend laser flare fluorophotometry to evaluate chronic

3    anterior chamber inflammation, and just raise the question

4    would iris fluorescein angiography be of any help if a lens

5    were either rubbing the iris or directly affixed to the

6    iris?   So that would be an issue that perhaps in a small

7    subset of patients in early studies may be relevant.

8                  Posterior chamber phakic IOLs certainly would

9    have advantages for corneal endothelium.   They would have a

10   maximum distance between the IOL and the endothelium.    They

11   would avoid optic-endothelial contact, but of course, their

12   location behind the iris would have a higher risk for

13   pigment dispersion and introduction of cataract.   If these

14   lens induce chronic anterior segment inflammation, they

15   certainly may have secondary effects on the endothelium, so

16   I do believe that endothelial studies are also important

17   for posterior chamber lenses, irrespective of the fact that
18   they're the furthest lens away from the endothelium.

19                 As far as that table -- now getting back to the

20   two questions, I added these last two portions right at the

21   end.    Getting back to the table, what would be the

22   recommended minimum endothelial cell density to enter these

23   studies?   And we saw that table put forth by the FDA.

24                 I see two approaches to attack the problem.
25   One is standard deviations.   You could look at accepted
                                                                 136

1    normative data and say you don't want anyone entering the

2    study outside of, let's say, lower than, let's say, two

3    standard deviations.

4                 Let's talk about two standard deviations.

5    Assuming the standard deviations are reasonable and your

6    studies are reproducible, you would want to exclude anyone

7    out in that 2.5 percent tail, and I went ahead and just

8    listed the values as they would range from age 20 at about

9    2,700 going down to 2,400 or so by age 60.   That's sort of

10   one way of looking at it.

11                The other way to look at it would be the way

12   that the FDA has approached it.   Look at do you have enough

13   cells to make it near the age of death?   And that's the

14   other way to look at it.

15                In reviewing the FDA Attachment B, the

16   threshold values selected don't exactly -- they do not

17   likely allow a patient to undergo a secondary ocular
18   procedure such as cataract surgery or further phakic IOL

19   manipulation during the life of the patient.   I would have

20   concerns as a clinician if a patient had a cell count of

21   1,000 with a moderately dense cataract doing a phaco

22   procedure.   I have to be worried that I might tip them over

23   into clinical corneal edema.

24                So I think we have to understand that the chart
25   values selected, and I selected 1,500 and the FDA selected
                                                                    137

1    1,200 and 1,000, are variable depending upon what our

2    expectations are for these patients to have elective

3    procedures down the road, and it's impossible to precisely

4    determine the minimum entry requirements without knowing

5    the exact rate of endothelial cell loss per year at the

6    various sites that run these.    So when we discuss that

7    particular table, I'm certain all those issues will come

8    into play.

9                  The issue that I haven't addressed, and I'll

10   leave it to the statisticians, is regarding sample size

11   analysis.    Drs. Edelhauser and Bernie McCarey talked about

12   that in the best case scenario, the best precision they can

13   get on endothelial cell measurements is 2 percent and real-

14   world data is at 9 percent according to Dr. McCarey.     I

15   wold like to know how that translates into the standard

16   deviation values that our statisticians have calculated

17   regarding sample sizes, if that's known, to see what kind
18   of numbers we would actually need if we wanted to screen

19   for the lower rates of annualized loss.

20                 That would conclude my introductory comments at

21   this time.

22                 DR. WEISS:   Thank you very much for a very

23   thorough, as usual, presentation.

24                 DR. GRIMMETT:   Thank you.
25                 DR. WEISS:   Dr. Matoba has a question.   Then
                                                                   138

1    we'll go around.

2                 DR. MATOBA:    Mike, I might have missed this,

3    but when you did your calculations, did you assume any

4    amount of cell loss from the actual surgery?

5                 DR. GRIMMETT:    Yes.   I assumed a 10 percent

6    instantaneous loss at the time of the surgery based on the

7    (inaudible) of having 8.8 percent with a phaco procedure.

8                 DR. WEISS:    Mr. McCarley, did you have a

9    question?

10                MR. McCARLEY:    I just had a couple of

11   questions.   The 9 percent that you're referring to is what

12   Dr. Edelhauser and Dr. McCarey were talking about?     Weren't

13   those the controlled laboratory percentages and not actual

14   real data?

15                DR. GRIMMETT:    I believe it was real data from

16   a real study, but we could probably have Dr. McCarey answer

17   it, but Dr. Edelhauser's number of 2 percent precision was
18   sort of in the best of hands what is the best precision.

19                MR. McCARLEY:    Right, exactly.

20                DR. GRIMMETT:    And Dr. McCarey's number was in

21   order to -- it might be better to have Dr. McCarey answer,

22   but I believe it was real data.      I'm not sure how many eyes

23   were in the study.

24                DR. WEISS:    You can over there.   As I recall,
25   it was different centers, with the variation 9 percent
                                                                      139

1    between different people reading the same thing.

2                  DR. McCAREY:    Yes, it was real data from a

3    clinical trial that Medennium's working.       It's the control

4    data.    There were 58 patients, seven clinical sites.       I

5    just started to collect the data and asked the question and

6    came up with that answer.

7                  MR. McCARLEY:    Okay.   I wonder is the FDA able

8    to provide the panel, especially the voting members and

9    reviewers, with data that they currently have on phakic

10   intraocular lenses.    In order words, the endothelial cell

11   data that has come already out of the studies?       There must

12   be over 2,000 implants so far over --

13                 MR. WHIPPLE:    You mean the ones that are under

14   IDE?

15                 MR. McCARLEY:    Pardon?

16                 MR. WHIPPLE:    Dave Whipple.    You mean the ones

17   that are already under IDE?
18                 MR. McCARLEY:    Yes, correct.

19                 MR. WHIPPLE:    We can summarize it.

20                 MR. McCARLEY:    In other words, we're reviewing

21   the literature and making decisions based on the

22   literature, and a lot of these have been recognized as

23   being small studies.    We don't know what methodology was

24   used to validate -- the validity of the methodology and so
25   forth.    A lot of reference goes back to original studies
                                                                  140

1    that are even from the 1970s, from Bourne and group, and of

2    course, he did a later study, but he did longitudinal study

3    showing I think 10 years' follow-up.

4                 But I'd be curious, one, is can the FDA provide

5    the panel members with the data that they have now to show

6    them what the standard deviation is right now?

7                 MR. WHIPPLE:    Yes.   They're special government

8    employees.   As long as they kept it amongst themselves,

9    they could use it, yes.

10                MR. McCARLEY:   Right.   I would just say before

11   a recommendation is made on limits and so forth, I would

12   say you have real-time data, real data on real phakic

13   intraocular lenses, that is up to date that you may want to

14   consider before you make a final recommendation.

15                DR. WEISS:   Well, actually, the advantage of

16   this sort of meeting is that everyone's entitled to their

17   opinion, there is no final vote, and there has to be
18   consensus.   So basically, the FDA will use all the

19   information gathered here today, and including any other

20   information we think would be helpful to obtain in the

21   future, to come up with some final recommendations on their

22   own.

23                Dr. Grimmett?

24                DR. GRIMMETT:   Yes.   Michael Grimmett.   I
25   alluded to it in my introductory comments that while it
                                                                  141

1    would be wonderful to have the Phase III endothelial cell

2    loss data versus what is published in the literature, we're

3    not trying to set a threshold rate of what is acceptable to

4    this panel or what is not acceptable.    That's not even the

5    purpose of this.   But I approached the analysis in that

6    fashion to show what the edges of the approach would be, so

7    that we can get some data on how many patients would we

8    need to screen in that range.    That was my goal.

9                Understandably, the literature is not giving us

10   that much guidance regarding actual cell loss rates because

11   most of the lens designs have been just started and we're

12   now on the newer lens designs.    So we actually don't know

13   what the newer loss rates are.

14               DR. WEISS:    Dr. Mathers?

15               DR. MATHERS:    Yes, I want to compliment Dr.

16   Grimmett on his excellent analysis, and it may sound like

17   it is rather strict, but I don't think that using the
18   actuarial tables as you have is in any way offbase.     In

19   fact, it's probably ultraconservative because, as we have

20   seen, as medical advances continue, it isn't impossible to

21   look at ages beyond what you are saying, and we all know a

22   lot of 80-year-olds who do not feel like dying right now.

23               (Laughter.)

24               DR. MATHERS:    And who are probably going to
25   live longer as these issues become more relevant.    So 10
                                                                   142

1    years from now, with one advance in cardiac pathology, this

2    would become not strict enough.

3                I would also like to ask who you think should

4    do the reading and the entrance qualification to get into a

5    study like this, because clearly the endothelium, which is

6    actually quite accessible as the cell to study, can be best

7    read perhaps by a central office, and should the entrance

8    requirements be that a central group does the initial

9    reading to get in?   What would you think of that?

10               DR. GRIMMETT:    Michael Grimmett.   Based on the

11   comments of Dr. Edelhauser, given all the variability that

12   exists if the technician is not trained properly and all

13   the parameters to be analyzed, I obviously am in favor of

14   the highest trained, highest precision measurer because of

15   the critical nature of endothelial cell loss over time as

16   our population ages.

17               DR. MATHERS:     It wouldn't be difficult to do
18   this with digital capture.    You can transfer these images

19   instantaneously and you can then decide whether you have

20   good images, because it would seem that a lot of this

21   depends upon having good images to start, so that you know

22   how to get good data afterwards, and that's certainly

23   possible on an instantaneous basis.

24               DR. WEISS:   The way the document reads at the
25   present time is that "The use of a reading center is
                                                                     143

1    strongly recommended.       If the use of a reading center is

2    not possible, the sponsor should establish a protocol for

3    collection and analysis of images to be used by each

4    participating site."

5                   Would you then change it from strongly

6    recommended to required or you'd leave it as strongly

7    recommended?

8                   DR. GRIMMETT:    This is Michael Grimmett again.

9     I think there are always multiple ways to skin a cat, and

10   if a particular study or a sponsor can demonstrate the

11   reliability that they have internal mechanisms to validate

12   precision and validity and it appears to be equivalent to a

13   standardized reading center, I think there is always

14   flexibility in that regard.

15                  DR. WEISS:    Dr. Huang?

16                  DR. HUANG:    My first comment is that regarding

17   Mr. McCarley's comment earlier, using the FDA existing data
18   is almost like using the soccer player to be the referee.

19   You know, that we are judging the safety of the data and

20   then using the data to be the reference for its own safety.

21    I think it's questionable.

22                  The second comment I would like to make is also

23   that Dr. Grimmett used a very nice life table actuary to

24   analyze this, but I think the endpoint is a little bit
25   strict because we don't do cataract surgery at the time of
                                                                 144

1    the death.   We do that cataract surgery maybe hopefully

2    five or 10 years before the patient's life expectancy in

3    order to improve their quality of life.

4                 So maybe we have two points that we can use.

5    You know, maybe one at one point is 10 years before death

6    and then at the death point, and then to find a reasonable

7    middle ground for the starting point.

8                 DR. GRIMMETT:    This is Michael Grimmett again.

9     Just a quick response.    I first attempted to do the

10   cataract surgical procedure 10 years before the age of

11   death with an increased rate of annual cell loss.     The

12   table became so complicated in the formula that I would

13   have to do to change the rate of cell loss midstream and

14   back-calculate to the entry cell data that I couldn't get

15   the spreadsheet to work in that regard.

16                I took took the give-up approach.     You know, I

17   was on vacation.
18                (Laughter.)

19                DR. WEISS:    Well, maybe in that case, the

20   guidance could be to the FDA to recalculate this with the

21   average age of cataract surgery as the final.

22                Yes, Dr. Huang?

23                DR. HUANG:    I'm just joking.   I say, you know,

24   maybe he can take another vacation to calculate that.
25                (Laughter.)
                                                                   145

1                 DR. WEISS:    Dr. Burns?

2                 DR. BURNS:    Yes, but I think all things being

3    equal, if you move the cataract surgery earlier, you're

4    going to actually end up with stricter numbers because

5    you'll have the loss from the surgery and then you'll have

6    an increased growth and you're going to come lower on the

7    curve.   So I think that will only make things stricter.

8                 DR. HUANG:    Andrew Huang again.   I think this

9    is just a recommendation.     Not all the patients eventually

10   are going to need cataract surgery, but I certainly

11   understand that there will be additional loss, and I don't

12   know which one is greater, 2 percent annual loss versus the

13   10 percent initial loss.     So statistics will tell us.

14                DR. WEISS:    I think it would be up to the FDA

15   to crunch the numbers both ways to see what the differences

16   are and if they're clinically relevant or not.

17                Dr. Grimmett?
18                DR. GRIMMETT:    I would just point out on the

19   tables, you realize that it is a 10 percent initial loss

20   for the phakic IOL surgery.     Please realize there are some

21   data on some of the more current studies that say that that

22   initial loss may at that rate, 5 to 6 percent.     The earlier

23   studies did have a higher rate.

24                So I used a cataract surgery
25   phacoemulsification initial rate that may not exactly be
                                                                      146

1    true for phakic IOLs.       I used the most conservative

2    approach to make sure that we leave people with enough

3    cells at the end.

4                   DR. WEISS:    While we're on the endothelial cell

5    topic, I just want to pose one other question relating to

6    this, and then perhaps Ms. Lochner could come up and then

7    we can go on with our other presenters and other

8    discussions.

9                   The other question that I would pose to the

10   panel, as I already did to our experts, is what would you

11   think would be the reasonable number of months to tell a

12   patient they would have to be out of contact lenses?        If

13   you have an opinion.

14                  Dr. Bullimore?

15                  DR. BULLIMORE:    None.   I mean, I think keeping

16   it --

17                  DR. WEISS:    Not even a week?
18                  DR. BULLIMORE:    Well, let me say less than a

19   month.

20                  DR. WEISS:    Less than a month.

21                  DR. BULLIMORE:    I mean, I think trying to sort

22   of take them out of contact lenses with the expectation

23   that the endothelium's going to change in any meaningful

24   fashion, based on my experience and what I heard from the
25   experts today, is futile.
                                                                  147

1                DR. WEISS:     So you would keep them out long

2    enough to get a proper keratometry or corneal topography?

3                DR. BULLIMORE:     I mean, I'd use the same

4    guidelines that exist for corneal refractive surgery.

5                DR. WEISS:     Gee, I think we just eliminated two

6    questions with that comment.

7                Dr. Mathers?

8                DR. MATHERS:     Yes, I strongly agree with that.

9     Aside from the fact that it would be really difficult to

10   have patients go through that period of time, since the

11   polymegethism afterwards doesn't really evolve very quickly

12   and we don't know exactly the significance of it, I think

13   that it's not terribly relevant to have them out of their

14   lenses a long period of time, except to establish their

15   refractive error issue.

16               DR. WEISS:     Dr. Bullimore?

17               DR. BULLIMORE:     And I think we need to be
18   generalizable, and these products and these procedures are

19   going to be done on people who, to a large extent, are

20   long-term contact lens wearers.    We saw yesterday that

21   something like 80 to 90 percent of the patients enrolled in

22   a study for low myopia or low to moderate myopia were

23   contact lens wearers.    So in the high group, it's going to

24   be probably even higher.
25               DR. WEISS:     Another question, which I warn you
                                                                    148

1    in advance I'm going to limit the discussion on because it

2    will come up again, is with this in mind, would you only

3    want one eye done at a time or one eye done and use the

4    other eye as a control for the endothelial cell study?

5                   Dr. Bullimore?

6                   DR. BULLIMORE:    Again, I think you don't want

7    to burden the patients too much, and enrolling them in,

8    say, a three-year study where they can only have one eye

9    done with a device and the other eye has to wait I think is

10   an unreasonable burden to be placed on the patient.       We

11   have a lot of historical control data.      It seems to me we

12   have some historical data on endothelial cell count as a

13   function of age.    We can use that, and what we're looking

14   for, I guess, are the extreme or the worst cases where

15   people really do loss a lot of endothelial cells within a

16   relatively short amount of time, and I don't think we need

17   a control group to necessarily look at those event rates.
18                  DR. WEISS:   Dr. Grimmett?

19                  DR. GRIMMETT:    Dr. Grimmett.   My concern with a

20   unilateral one-eye study would be for quality of life for

21   the patient.    These patients would be typically those that

22   don't qualify for other refractive procedures, and hence

23   they have a higher range of myopia.      There is significant

24   (inaudible) of emmetropia.      So in a three-year duration
25   study, I think that would be unwieldy and probably not very
                                                                  149

1    reasonable for the patient.   So I'm in agreement with Dr.

2    Bullimore.

3                 DR. WEISS:   Dr. Mathers?

4                 DR. MATHERS:   Yes, I'm also highly in

5    agreement.   I think we'll need to discuss again the time

6    delay between the first and second operation, but three

7    years is too long.

8                 DR. WEISS:   Then I would sort of conclude --

9    Dr. Bandeen-Roche?

10                DR. BANDEEN-ROCHE:    Yes, just very briefly.

11   You know, statistically, we'd obviously like to have a

12   contralateral, but I am absolutely swayed by the quality of

13   life considerations as long as we have good quality control

14   data.   So that would include both a precise estimate of the

15   rate of loss, but also of the variability in rates.

16                DR. WEISS:   Okay.   So then I would conclude

17   that the fact that the contact lens issue in terms of the
18   change and shape of the cells and number of the cells might

19   still be evolving after the implant was placed in will be a

20   confounding variable, but not objectionable by the panel.

21   Fine.

22                Ms. Lochner, perhaps we can go on.

23                MS. LOCHNER:   For analysis of the crystalline

24   lens for lens opacity, we currently recommend that "The
25   natural lens should be evaluated preoperatively and at each
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1    of the postoperative intervals.   The level of evaluation

2    should be commensurate with the risk of cataractogenesis or

3    lens changes identified by the risk analysis performed by

4    the manufacturer.   For phakic IOLs where the design or

5    surgical procedure may lead to lens changes, a grading

6    system or quantitative method should be used to evaluate

7    lens changes over time.   For IOLs for which lens changes

8    are not an identified risk, qualitative observation may be

9    adequate."

10                The analyses should include the number of

11   patients with any change in the appearance of the lens

12   stratified by the type of change and the number of patients

13   with clinically significant lens opacities, and the term

14   "clinically significant" is as yet undefined.

15                We are asking for panel comments on whether you

16   believe evaluation of lens changes should be requested of

17   all sponsors or whether this evaluation should only be
18   performed if the sponsor's risk analysis warrants and

19   whether you have any specific recommendations for defining

20   the term "clinically significant" lens opacities.

21                We're also asking for your recommendations

22   about the use of quantitative methods for measurements of

23   lens changes versus the use of grading systems, and finally

24   we'd like your thoughts on the duration of the study and
25   request that you specifically discuss the length of follow-
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1    up you believe would be adequate for panel review of this

2    cataractogenesis outcome.

3                 Now, Dr. Mathers will provide his review.

4                 DR. MATHERS:   Thank you.

5                 Regarding the first question we are asked to

6    address, the evaluation of the lens changes, it is this

7    reviewer's opinion that all phakic IOLs need to be

8    evaluated for any cataract or changes in the lens.

9    Anything that happens essentially inside the anterior

10   chamber in front of the lens is an issue here, and even

11   something that would not touch the lens or is known to be

12   touching the lens would still be a problem.   Certainly,

13   central touch is not the only issue nor is just peripheral

14   touch.   There's anterior chamber inflammation, and all of

15   this can affect the lens changes over time.   So any

16   perturbation would be of interest and all cataract

17   processes need to be assessed.
18                In this direction, I think it's going to be

19   important not just to look at the lens itself, but to look

20   at the source of the possible problem, such as we have

21   heard regarding flare assessment or anterior chamber

22   inflammation, and I think that it would useful to measure

23   flare in these patients with perhaps the laser flare

24   system, and also, regarding the evaluation of the cataract
25   process, that the sizing and the structure of the anterior
                                                                 152

1    chamber is going to be a key issue.   So the use of high-

2    resolution ultrasound I think is going to be extremely

3    important in evaluating this.

4                 Regarding the clinical significance of the lens

5    opacities, this is a more subjective area and we don't have

6    very good data on this, but this of course refers to vision

7    changes, and in this regard we need I think to be as

8    precise as possible because when one measures vision under

9    various circumstances, you get very, very different

10   results.

11                So if you have a central opacification of the

12   anterior subcapsular area, it will not show up in vision

13   testing in a dim room.   You're going to have to do this

14   with a small pupil under conditions that will induce some

15   glare, and in fact, the more glare, the better.   This is

16   not a non-real-life situation.   I mean, when people are in

17   a high-light environment, which they often are, this comes
18   into play.

19                So I think glare testing is the most relevant,

20   but the only way that this should be assessed.    For this,

21   we need to have careful measurements of the patients as

22   they enter the study and a standardized method of

23   evaluating the glare, and that high-glare settings should

24   be used.
25                Now, everyone will have some decrease in visual
                                                                 153

1    acuity with a high setting of a glare.   So we have to

2    decide whether we think one, two, or more lines of loss

3    compared with the preoperative evaluation would be

4    significant.   My recommendation would be two or more lines

5    compared with what they had in the loss before.

6                I think that all lens changes should be

7    reported, not just the anterior subcapsular fibrosis, but

8    we also have anterior cortical changes which may result

9    from these anterior subcapsular processes.

10               The posterior subcapsular cataract is also an

11   issue because the anterior lens cells are not the only ones

12   going to be involved.   As you build lenses that do not ride

13   or touch the central lens, they may ride in the periphery

14   of the lens, and they are going to get closer to those

15   cells on the outside which can migrate posteriorally, and

16   certainly may do so.    So that becomes an issue, and the

17   possibility of inflammation that occurs with the anterior
18   chamber lens of this design may affect the development of

19   nuclear sclerosis, and this is going to be something that

20   is going to be harder to assess, but I think that we need

21   to at least monitor this.

22               In Part C, we're asked to comment on the use of

23   quantitative measures for the measurement of lens changes

24   versus the more semi-quantitative grading system, and by
25   quantitative here, we mean the assessment or the
                                                                154

1    visualization, the optical visualization, of the changes

2    underneath the anterior capsule.

3                There is no standard way to do this and the

4    examination of this is very light-dependent.   If the

5    lighting system is a little bit off, you get a little

6    different view of this and it becomes harder to see, and

7    Dr. Werner's presentation on this was excellent, but even

8    she could not really tell us exactly how much better, say,

9    a photographic system is from a slit lamp system, which of

10   course is going to be subjective.   But I believe that the

11   backlighting and retroillumination of the lens with high-

12   resolution color photography probably offers us the most

13   objective and reliable way to follow this over time.

14               The development of a scale to do this has

15   already been done.   I don't think this needs to be

16   reinvented, but can be perhaps modified slightly.     The LSCS

17   system can grade these opacifications and can be used for
18   all of this -- the anterior subcapsular, the posterior

19   subcapsular, and the nuclear -- and I think something like

20   that would be appropriate.

21               I would strongly recommend the use of digital

22   photography to perform this process and I also think it is

23   possible, as technology improves, that we will have a

24   better understanding through other means of visualization,
25   perhaps confocal microscopy of these cells now that this
                                                                 155

1    becomes an issue and it becomes relevant to look at this.

2    But there are no standards for this now, and that would not

3    necessarily be used in an early study like this.

4                In Part D, we're asked to comment on phakic

5    IOLs and the length of time that it might be useful to

6    evaluate this for, and here, as we've heard with the

7    endothelium, when we're studying the endothelium, we have a

8    fairly clear endpoint.   We have endothelial cell loss and

9    we can follow this fairly objectively.

10               With lens changes, it's much less objective,

11   and one study, noted recently, showed that there was some

12   change in light transmittance with these lenses, not

13   necessarily based on cataract, but I think that with the

14   long time span that we're talking about and the possibility

15   of chronic inflammation associated with this that is

16   subclinical, that at least three years would be necessary

17   to evaluate it.   I think that the monitoring of this
18   perhaps should go on longer than that, but I think the

19   three years is probably enough to give us an idea of what

20   is happening.

21               The capsular process of cataract formation is

22   tied to a number of different other processes.   Not just

23   lens touch, but, as I said, inflammation, and as the lens

24   is redesigned to minimize the cataract process, the other
25   issues, such as iris touch and development of pigment
                                                                  156

1    dispersion and glaucoma, become more of an issue, and I

2    think that the industry or lens manufacturers will be

3    tempted to avoid the obvious problems of lens touch by then

4    shifting the burden to the back of the iris.    I think that

5    this kind of monitoring is also going to be important.       I

6    know it's not part of this particular issue, but I think

7    it's relevant because there are tradeoffs here.   There is

8    not much space in this area and as you design the lens to

9    perform in one way, you then create other issues of

10   significance.

11               That is my summary.

12               DR. WEISS:   Thank you very much.

13               I just have just two questions on things which

14   you've already mentioned, but I just want to clarify.    What

15   would you call a clinically significant cataract?

16               DR. MATHERS:   Clinically significant cataract

17   refers to a loss of a number of lines, but it's highly
18   dependent upon that is assessed, and I think that needs to

19   be assessed not just with standard -- well, our assessment

20   of vision can be done in the standard way in dimly lit room

21   to optimize vision, but it needs to go beyond that.     We

22   need to have glare testing as well because our standard

23   measures of vision will not be adequate to pick up the kind

24   of changes we're going to see with capsular opacification.
25               DR. WEISS:   So then to just restate that, with
                                                                   157

1    glare testing, it depends on sensitive you want to be to a

2    very early cataract, and that's the question I'm asking, is

3    how sensitive do you want to be?     So if we said let's it

4    bring it to the glare testing realm and say, okay, we're

5    going to determine that by a loss of X number of lines by

6    glare testing, is there an idea you have?

7                DR. MATHERS:     Certainly, it has to be more than

8    one line, so I would say two.

9                DR. WEISS:     So would you prefer, if I was going

10   to make you quantify it, would you then say a loss of two

11   lines by glare testing, rather than just a straight loss of

12   two lines without the glare testing or would you want to

13   say something else or it's totally unknown?

14               DR. MATHERS:     I think without the glare testing

15   loss of one line would be important, would be significant.

16    With glare testing, it's going to be two, because the

17   glare testing is much more sensitive.
18               DR. WEISS:     And would you require contrast

19   sensitivity data or that would be optional?

20               DR. MATHERS:     I think contrast sensitivity data

21   also should be included.

22               DR. WEISS:     Okay.   So you'd like to have both,

23   but at least at this point of the discussion, a loss of two

24   lines at glare testing would be considered significant.
25               Dr. Bradley?
                                                                  158

1                DR. BRADLEY:   Yes, just a comment on the means

2    by which one does glare testing and how that interacts with

3    the underlying spatial distribution of the cataract.    We

4    might think of two scenarios, one that was just mentioned

5    of a central cataract that is anterior or posterior.    The

6    idea of most glare testing is you employ a bright light

7    source and, in so doing, the pupil constricts, and

8    therefore the cataract fills a larger proportion of the

9    pupil, and therefore the scattered light becomes a larger

10   proportion of the retinal image, and that leads to an

11   increased visual effect.

12               Obviously, the converse is true.   If you have a

13   peripheral or marginal cataract, as the pupil is

14   constricted, a smaller and smaller proportion of the pupil

15   is covered by the cataract, and therefore a smaller

16   proportion of the retinal image is scattered light, and

17   thus the visual effects are decreased under those
18   circumstances.

19               So I'm not sure there is a single way one can

20   do a glare test that would sensitize the tester to the

21   visual impact of a cataract, and it may be necessary to

22   employ more than one approach.   Just an off-the-cuff

23   suggestion would be to employ the one suggested, which is

24   the standard approach, perhaps, where the pupil constricts
25   in the presence of the bright light and it's highly
                                                                  159

1    sensitive for picking up the visual impact of a central

2    cataract.   I might also suggest performing the same test

3    under cycloplegic pupil dilation to emphasize the impact of

4    a marginal or peripheral cataract that, of course, would be

5    visual manifest for the patient under, for example, night

6    driving circumstances, which arguably are the most

7    important ones.

8                 DR. WEISS:   The question, Arthur, has anyone

9    done cycloplegic glare testing?    Do we have any data to

10   know what the results are in the normals?

11                DR. BRADLEY:   I don't know.

12                DR. WEISS:   Dr. Mathers?

13                DR. MATHERS:   I would strongly agree with what

14   you have suggested.   I meant that we should do standard

15   testing, contrast sensitivity testing, and glare testing,

16   and I do not have any experience doing glare testing in a

17   dilated pupil, but it is similar to night driving, but we
18   just don't have any data on that, and I don't think that

19   the visual assessment is going to give us all of the

20   answer.   I think we're going to see a lot more with the

21   objective and quantitative than we do simply with the

22   vision changes.

23                DR. WEISS:   Well, perhaps if we don't have that

24   data, we could request a subset.   If panel thought that was
25   helpful and so did the agency, we could request a subset of
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1    patients when they have their initial entry dilated exam to

2    be glare tested while dilated and not dilated, so not to be

3    too onerous to any sponsors.

4                   Dr. Grimmett, then Dr. Bullimore.

5                   DR. GRIMMETT:    Dr. Grimmett.   Just a quick

6    comment.   If my memory serves me correctly, I think I've

7    seen some dilated glare testing data in an ARVO abstract by

8    Arthur Ginsberg out of California, San Ramon.       He does

9    functional driving tests and other activities and has some

10   data on that kind of stuff.      He's a contrast sensitivity

11   guru.   I think I've seen that data before, so I think it

12   could exist.

13                  DR. WEISS:   Dr. Bullimore?

14                  DR. BULLIMORE:    My impression is we're going to

15   come to contrast sensitivity in a minute and glare testing,

16   but since it's on the table, this is a real sticky area,

17   and anybody who a few years ago was involved in the Eye
18   Care Technology Forum knows that agreement was quickly

19   reached on some areas, like measurement of intraocular

20   pressure and visual acuity and visual fields, but contrast

21   sensitivity and glare testing became a thorn in the side of

22   the organizers of that meeting, and Morris Waxler was the

23   point person on that and Arthur was involved in the panel

24   as well.   It was very difficult.
25                  As far as assessment of cataract, I think one
                                                                  161

1    of our speakers put forward a number of mechanisms by which

2    a standardized grading system could be used.      I think the

3    panel should consider whether the FDA should strongly

4    recommend a reading center for cataracts or for lens

5    opacities in the same way they're recommending it for

6    endothelial cell density.

7                   It becomes difficult because in the case of

8    endothelial cell density, you have a standardized

9    instrument that can capture the image.     Photographing lens

10   opacity, since you want to capture the different features

11   of the lens, is a much more difficult and sophisticated

12   procedure.

13                  So I think using standardized grading systems

14   is appropriate, paying attention to the kind of opacities

15   that are likely to occur.     Anterior and posterior capsular

16   opacities I think are appropriate, and cortical opacities

17   maybe, but I'm not in favor of requiring a reading center
18   in the same way that it's currently recommended for the

19   endothelium.

20                  DR. WEISS:   If there are no other comments on

21   this section, Ms. Lochner, if we could proceed to the third

22   and last question.

23                  MS. LOCHNER:   At the most recent ANSI meetings,

24   a consensus appeared to be reached on the general
25   parameters of the contrast sensitivity substudy that's
                                                                 162

1    outlined in Section 8.3, and Dr. Bullimore, you might be

2    interested to know that we had Dr. Ginsberg, who's the

3    contrast sensitivity guru, and we had Dr. Jack Holiday,

4    who's advocated contrast acuity testing, actually agreeing

5    on this point.   So it was a red letter day.

6                (Laughter.)

7                DR. BULLIMORE:    For the record, I never called

8    him a contrast sensitivity guru.   That was Dr. Grimmett.     I

9    want to strictly go on the record on that.

10               (Laughter.)

11               MS. LOCHNER:    And I think that the use of the

12   contrast sensitivity systems, rather than contrast acuity,

13   was recommended because of contrast sensitivity's ability

14   to capture the full range of spatial frequencies and

15   contrasts, and it was felt that the contrast acuity charts

16   would potentially miss significant contrast losses because

17   of the unpredictability of the spatial frequency at which
18   these losses may be seen.    Of course, we will have letter

19   recognition performance under low light conditions assessed

20   by the best-corrected visual acuity testing.

21               The contrast sensitivity testing, as proposed,

22   includes mesopic and mesopic with glare conditions.    Please

23   comment on the clinically significant decrease being set at

24   .3 log units, and also on whether this decrease should be
25   at one or two or more spatial frequencies to be considered
                                                                     163

1    significant.

2                   Next, should charts with the minimum contrast

3    at each spatial frequency be used to minimize the problem

4    of missing data, and perhaps first of all, are these charts

5    commercially available?

6                   Please also comment on the recommended analyses

7    of these data, including how missing data should be

8    handled, and by missing data, we mean when the patient is

9    unable to see the target at a particular spatial frequency

10   at any of the available contrast levels.

11                  Last, please provide any additional comments,

12   particularly any recommendations you may have to improve

13   the quality of the data generated from this testing.

14                  Dr. Bullimore?

15                  DR. BULLIMORE:    Can you go back to the first

16   slide?   I want to take these questions one at a time with

17   panel input, if that's okay, Madam Chairman.
18                  DR. WEISS:    Anything you want.

19                  DR. BULLIMORE:    Wow.   I guess lunch is not on

20   the table.

21                  (Laughter.)

22                  DR. WEISS:    That's true.

23                  DR. BULLIMORE:    Let me paraphrase my comments

24   by saying that I have a long and distinguished record of
25   being a fan of letter charts over grating, so anything I
                                                                 164

1    say should be taken in that context.

2                That notwithstanding, I think first of all, the

3    statement about .3 log units being a clinically significant

4    decrease in contrast sensitivity is reasonable.   Just to

5    put that in context, we've come to accept two lines of

6    visual acuity on a logMAR chart as being a meaningful

7    decrease and representing a complication or an adverse

8    event or, to put it more broadly, an unsatisfactory outcome

9    of a refractive procedure.   Here, we're talking in the

10   contrast domain of an equivalent of three lines, and I

11   think this is reasonable and conservative.

12               I think saying that the drop should be at two

13   or more spatial frequencies, again, we get into the martial

14   end of contrast sensitivity testing pretty quickly.    One of

15   the limitations and reservations that some people have

16   about these tests is that unlike letter testing, for

17   example, where the patient has to name a letter, the
18   patients is asked either whether they can actually see the

19   grating or not or is asked to say is the grating on the top

20   part of the chart or on the bottom part of the chart?     So

21   the opportunity for a bias based on shifts in criteria if

22   you use the first approach or the opportunity to sort of

23   guess correctly when it's just a one in two chance compound

24   the analysis of some of these data.
25               But again, in the interests of the goodwill
                                                                   165

1    exhibited between Dr. Holiday and Dr. Ginsberg, I think

2    this again is a reasonable, practical approach, and with a

3    letter chart, of course, you might not have the problem

4    with then having to say, well, is it one or two spatial

5    frequencies, but really I think the panel at this stage

6    should be presented with the data when it's available and

7    let the panel decide, so to speak.

8                 Does anyone want to comment on that first

9    thing?   I'm sure Arthur would.    I'd appreciate Dr. Owsley's

10   input anytime she wants to say something.

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

12                DR. OWSLEY:    Why don't keep going and then I

13   can probably just make a few comments at the end?

14                DR. BULLIMORE:    Okay.   Arthur, can I keep going

15   for you as well or do you want to interject?

16                DR. BRADLEY:    I really appreciate the

17   opportunity to interject.
18                (Laughter.)

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

20                DR. BRADLEY:    Mark raises an interesting sort

21   of comparative analysis to try and decide, well, is .3 log

22   units, obviously a factor of two changing contrast

23   sensitivity, clinically significant?       And he draws the

24   parallel between what people decide is clinically
25   significant in terms of logMAR for visual acuity change,
                                                                   166

1    and two lines, obviously that's .2 log units on a logMAR

2    chart, and I question, Mark, that that is somehow

3    equivalent to .3 log units in contrast sensitivity.     Was

4    the equivalence based upon some sort of Z score change,

5    Mark, or --

6                   DR. BULLIMORE:   I didn't mean to imply that

7    they were equivalent, but I said it sort of parallels the

8    change.

9                   Now, you could say, well, if we're doing .2 log

10   units of visual acuity, we should use .2 log units for

11   contrast sensitivity.    Unfortunately, most of the

12   commercially available tests for contrast sensitivity go in

13   steps of .15.

14                  Again, we're going to have the data.   We're

15   going to be able to look at the number of patients that

16   have lost .3 or more log units at one or two spatial

17   frequencies.    We'll have mean contrast sensitivity data for
18   each spatial frequency and for each lighting condition.

19   There will be a colossal amount of data that we'll be able

20   to sort of chew over in depth when the opportunity arises.

21                  DR. BRADLEY:   Yes, I think we'll have the data,

22   but we'll still be left with the question about what's

23   going to be significant.

24                  Just as a suggestion, then, I would make that
25   if there is consensus that a .2 log unit change of visual
                                                                167

1    acuity is clinically significant, would you think it

2    reasonable that we convert that into some sort of acuity Z

3    score change -- say, two, three, four standard deviations,

4    whatever it is -- and propose that an equivalent Z score

5    change in contrast sensitivity be considered significant.

6    Does that make any sense at all?

7                DR. BULLIMORE:   It makes sense, but I don't

8    think it's an approach that I would advocate at this stage.

9                DR. WEISS:    Dr. Owsley?

10               DR. OWSLEY:   This is Cynthia Owsley.    I think

11   one of the --

12               (Telephone rings.)

13               DR. OWSLEY:   Could somebody get that?

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

15               DR. WEISS:    It's probably Pizza Hut returning

16   someone's surreptitious call.

17               (Laughter.)
18               DR. OWSLEY:   I mean, I think both Mark's

19   approach and Arthur's approach are reasonable approaches.

20   The problem for me, when I think about this, is when you

21   decide how much decline on a visual function test is bad in

22   some sense, clinically significant in a bad sense, you have

23   to ask yourself what is it you're trying to prevent.

24               Answering these questions in vacuo without
25   looking to see how much of a loss you need in contrast
                                                                    168

1    sensitivity or acuity or glare or whatever the visual field

2    causes a problem in functional performance, without looking

3    at it in that way, I just don't see how you could answer

4    the question.

5                   I'm not suggesting that we propose all kinds of

6    -- whatever they're called -- substudies to answer that,

7    but I think it's an important dilemma, because when it's

8    considered on its own, it's abstract.      For the patient,

9    it's in terms of their everyday life.      What implications

10   will a .2 loss in logMAR acuity mean?      What implications

11   for their everyday will be a .3 loss in contrast

12   sensitivity?

13                  So I haven't proposed any answers to this, but

14   I see it as a very sticky dilemma that we might just have

15   to kind of go with something that feels like it has some

16   face validity sort of on a clinical level.

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

19                  MR. McCARLEY:   Yes, just one question.   Is this

20   the first time contrast sensitivity testing has been

21   required by the panel?      My understanding is that

22   manufacturers of refractive lasers also collected this

23   data.   I mean, the question behind that is is there a

24   standard for contrast sensitivity or are we now making the
25   standard?
                                                                  169

1                DR. WEISS:    Well, we're making a standard for

2    phakic IOLs, so even if it wasn't required for anything

3    else, it really --

4                MR. McCARLEY:    In my understanding, it was.

5    Maybe I'm wrong.

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

7                MR. WHIPPLE:    Yes, I believe we have required

8    contrast sensitivity for LASIK studies.

9                DR. BULLIMORE:    Yes, and the current guidance

10   document says that either you have to measure it or

11   basically to say that you didn't measure it.

12               MR. WHIPPLE:    Right, and I'll defer also if

13   Donna and Malvina --

14               PARTICIPANT:    That sounds definitive.

15               DR. BULLIMORE:    I'm paraphrasing a little bit,

16   but that's the general spirit of it.

17               DR. WEISS:    Donna?
18               MS. LOCHNER:    Well, it's not the first time

19   it's been required.    As you point out, the LASIK example,

20   and of course the panel has reviewed extensive contrast

21   sensitivity data in the multifocal IOL example.

22               I think it's also important to point out this

23   question about the clinical significance because I think

24   what Dr. Bullimore was saying about, you know, you're going
25   to have to look at the data and make some judgements when
                                                                170

1    it's received, but this question is backing up to the

2    sample size calculations.    It's not backing up that if it's

3    .3, the device is approved and if it's .29, it isn't.    It's

4    really more is this a reasonable effect to be looking at

5    the sample size calculations, et cetera.

6                I think also, as Dr. Owsley said, the meaning

7    of this is really not going to be clear to many of the

8    panel members, as well as to the patients, unless this were

9    there were this daily living-type testing required, which

10   we really have not -- we're not suggesting that, but I

11   think it's a point well taken.    So really, if you think of

12   this in the context of the sample size.

13               DR. WEISS:   I think Dr. Bullimore --

14               DR. BULLIMORE:    Yes, I mean, you can look at a

15   .3 loss as being clinically significant two ways, whether

16   it occurs in a subset of individual patients or in one

17   individual patient or whether it occurs in the population
18   as a whole, and in terms of sample size, you're interested

19   in the population as a whole.    In terms of the safety of a

20   device, you might say, well, if a two-line loss of visual

21   acuity sets off alarm bells and appears on some summary

22   statistics for safety, then should there be an equivalent

23   here?

24               I'm not comfortable doing the later.    You know,
25   we heard from a speaker this morning who has a lot more
                                                                      171

1    experience with phakic IOLs than the rest of us, and he was

2    advocating that the IOLs be held to the same standard

3    visually as LASIK, and we have some historical precedent

4    here with these tests being done on everybody and I think

5    we should carry on with that.

6                   In terms of the sample size for the entire

7    cohort, I think it's much more likely to be driven by

8    endothelial cell density considerations than anything

9    visual.

10                  MS. LOCHNER:    So it's your recommendation that

11   this testing be performed on all individuals?

12                  DR. BULLIMORE:    Yes.   That would be my

13   recommendation.

14                  DR. WEISS:   I think we're going to go along

15   this time even if it's out of order I originally said.

16                  DR. BULLIMORE:    I'm not asking that everybody

17   flies to Iowa for a driving simulation.         I mean, this a
18   test that should be reasonably easy to incorporate into a

19   protocol and I would like to see data on as many patients

20   as possible.

21                  MR. CALOGERO:    Don Calogero.    Right now, it's

22   set up as a substudy, and I believe the sample size is

23   somewhere between 60 and 100 patients, and that gives us

24   the ability to detect down to .15 log units.        So you're
25   saying that in spite of perhaps having sufficient precision
                                                                    172

1    to the study, you'd like to see it on the entire

2    population?

3                  DR. BULLIMORE:    Well, I think where Dr. Mathers

4    was going with this is that he would like to see data on

5    contrast sensitivity with and without glare that would give

6    you clues, maybe not definitive decisions, as to whether

7    significant cataractogenesis had occurred in these

8    patients.

9                  MR. CALOGERO:    Okay.   So you're also using it

10   for that purpose, then.

11                 DR. BULLIMORE:    Exactly.   Now, if my memory

12   serves me correctly, I mean, yesterday's presentation for

13   an intraocular --

14                 DR. WEISS:   Wavefront.

15                 DR. BULLIMORE:    Wavefront.   That was it.

16                 DR. WEISS:   How quickly we forget.

17                 DR. BULLIMORE:    A good dinner.
18                 For that, we had data on all the patients.       Am

19   I correct?

20                 MR. CALOGERO:    I believe so, yes.

21                 DR. BULLIMORE:    Yes.   So I would have thought,

22   with a newer technology, which, let's face it, these phakic

23   IOLs are, and I think increased or elevated safety concerns

24   in terms of lens opacities, I'd want to have that data on
25   as many patients as possible.
                                                                  173

1                  Now, I realize we may be into latter phases of

2    some PMA investigations, and that's fine, but I think it's

3    going to inform at this stage whether the patients have

4    indeed developed anything that may cause concern in the

5    lens opacity department.

6                  MR. CALOGERO:   Thanks for clarifying that.

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

8    we'll move our way around, and then come back to Dr.

9    Owsley.

10                 Dr. Mathers?

11                 DR. MATHERS:    Yes, I agree with Dr. Owsley that

12   it's difficult to assess how this impacts the patient, but

13   what we need to do is have reasonably high resolution of

14   the data that we're picking up.     When we're talking about

15   whether this is actually a good thing, you have to contrast

16   that with the struggles the patients have with enormous

17   myopia and their tremendous problem and the alternative of
18   clear lens extraction and other significant issues, but we

19   want to have reasonable resolution and an ample sample size

20   so that we can tell what's going on, and it may be that two

21   or three lines is a reasonable expectation considering the

22   other struggles that they have.     But we would determine

23   that later.   We need to have the data now, and I think the

24   contrast sensitivity not only gives us something about the
25   visual function of the system, but also the
                                                                  174

1    cataractogenesis process.

2                DR. WEISS:    I think that probably most people

3    here are in agreement that we need the data and whether or

4    not someone postulates that they know what the data means

5    upfront versus whether they don't know what the data means

6    upfront really won't affect the FDA.    They can just tell

7    you after the fact whether you were right or not.

8                So if anyone has any comments not related to

9    their opinion on that particular topic, we can proceed with

10   them.

11               Dr. Bradley?

12               DR. BRADLEY:    Yes, I think just because this is

13   a new product doesn't necessarily mean we have to measure

14   contrast sensitivity.    We really need to have sort of

15   underlying theoretical rationale for why contrast

16   sensitivity measurement might or might not be useful in

17   this particular case.
18               I think the primary concern we have here is

19   degradation of optical quality, whether it be in the cornea

20   due to endothelial problems or primarily in the lens due to

21   cataract development.    The likely optical and visual

22   consequences of that are related to scattered light, and

23   they have fairly predictable optical effects.    Indeed, they

24   will have some effect on our ability to see fine detail,
25   which ought to be revealed by some visual resolution task.
                                                                  175

1                In addition to that, they will have impact on

2    the image quality for larger targets, and the primary

3    impact will be on contrast reduction.    One method for

4    assessing this is to examine contrast sensitivity.

5                That said, as Mark alluded earlier, there are

6    devotees of letter contrast sensitivity testing and there

7    are devotees of grating contrast sensitivity testing.     One

8    of the arguments in favor of grating testing is that one

9    can test at many spatial frequencies, which academically

10   might be quite interesting, but unless one can come up with

11   a reasonable theoretical argument for why a measurement at

12   a single low spatial frequency might not provide the same

13   information, I think one is wasting one's time measuring at

14   lots of different spatial frequencies.

15               Therefore, I wonder about most grating tests

16   for that reason, and I think Dr. Owsley might be able to

17   comment on that.
18               DR. OWSLEY:   Yes.   I very much agree with the

19   perspective or the question you're raising.    I would not

20   describe myself as a devotee or a guru of any test.

21               The reason I favor letter tests in situations

22   like this is that I know of no convincing evidence in the

23   peer-reviewed literature that shows that letter tests are

24   worse than grating tests or grating tests are better than
25   letter tests, however you want to say it.
                                                                  176

1                  I think that there are a lot of us who do

2    clinical studies, clinical intervention evaluation studies,

3    including bodies like the National Eye Institute, who go

4    the way of letter tests not only based on the evidence that

5    they're not worse than the grating tests, but because of

6    two things.   One, if you're getting a measure of high-

7    resolution visual acuity, and then you do a contrast

8    sensitivity letter test, say like the Pelly-Robson, which

9    has large letters, you're basically getting information

10   about the entire shape of the function.

11                 Then the second reason is that we're talking

12   about -- I don't know which specific test the sponsor would

13   be using or any sponsor would be using, but if you're doing

14   spatial frequency testing in the kinds of things we're

15   talking about in this kind of study, you're doing those

16   spatial frequencies for topically, mesopically, with glare

17   and without glare, before and after surgery.   This is a
18   long testing time, okay?

19                 And then I think -- what was my last point on

20   this?   Well, I'll just leave it like that, but I know that

21   this issue has been visited by this panel before and I've

22   heard about it.   I've never been to the panel to hear it

23   argued as a panel member, but I think that it's an

24   important point that sponsors should hear, the public
25   should hear, and the FDA should hear that there really are
                                                                      177

1    really sound arguments for not, in every case, doing all

2    the spatial frequencies.      You need to ask yourself, what

3    are you doing with that information?       What's it really

4    providing for you that high-contrast acuity in a single

5    measure on a large letter contrast sensitivity chart would

6    not provide?

7                   DR. WEISS:   Dr. Swanson?

8                   DR. SWANSON:   I agree with both sets of

9    comments and wanted to add one other thing.       I've used

10   letters and spatial frequencies.     It depends on what the

11   task is.

12                  The point that Dr. Bullimore raised becomes

13   important for sample size calculations as well as for the

14   amount of time that goes on, particularly if we're looking

15   at this question of glare, but as Dr. Bradley mentioned, in

16   general, these effects should be in a range of spatial

17   frequencies.
18                  If you are using a grating and you have a two-

19   alternative forced choice, basic researchers who use those

20   things do lots of trials because that's the only way you

21   can reduce test/retest variability.        For letter testing,

22   where there's going to be between 10 and 26 options that

23   the person's guessing amongst, a much smaller number of

24   trials is needed.
25                  So in order to have a significant change, you
                                                                  178

1    need to have a test where the test/retest variability is

2    low.   For a small number of trials, which needed to run all

3    these conditions in all these people, a multiple

4    alternative, 10- or 20-alternative forced choice test, is

5    going to be much better than a two-alternative forced

6    choice, and there aren't any commercially available 10-

7    alternative forced choice grating tests and it's going to

8    be very difficult to create on given the response demands

9    on the patients.    So a letter type of acuity test is going

10   to be much more suitable in terms of gathering a fair

11   amount of useful data in a short period of time.

12                Then the questions that come up, such as, well,

13   do we have to have two spatial frequencies down or three

14   spatial frequencies or one spatial frequencies down, those

15   become quite complicated by the high test/retest

16   variability of a two-alternative forced choice with just a

17   single endpoint.
18                DR. WEISS:   So let me get to a bottom line.

19   What do you want?

20                DR. SWANSON:   I'm just trying to hammer home

21   all the points they made about letter charts being superior

22   for this purpose.   I understand there was agreement before.

23                DR. WEISS:   So you would like a letter chart

24   for this purpose.
25                DR. SWANSON:   For the purpose, a letter chart
                                                                 179

1    is going to allow a much smaller sample size and a much

2    larger --

3                DR. WEISS:   And Dr. Owsley, you agree, and Dr.

4    Bradley?

5                DR. BRADLEY:   Yes, I agree, a letter chart.       I

6    think Donna asked us if such charts were available.     There

7    certainly is a letter contrast sensitivity chart, as I

8    think it's been referred to.    Sometimes it's called a

9    Pelly-Robson chart.

10               One thing I would alert the FDA to is if you

11   are to request use of that chart, it doesn't have to be

12   used at the standard distance at which it was originally

13   designed, and there are reasons to pick your distance,

14   depending upon the scale or size of target for which you

15   wish to study.

16               DR. WEISS:   Dr. Bullimore, your comment?

17               DR. BULLIMORE:     I mean, the spirit in sort of
18   guidance documents before, whether for this issue or

19   others, was that the sponsor or a potential sponsor would

20   be able to speak with the FDA and the FDA, in terms of the

21   guidance document, wouldn't specify a given test, but there

22   would be some scope.   I was just a little surprised that

23   this was so specific, even naming spatial frequencies.     I

24   mean, you come pretty close to naming a test or naming a
25   couple of tests, and I'd just like to see some statement
                                                                    180

1    that other tests could be considered if the sponsor in

2    consultation with the agency would be able to agree that

3    these were acceptable.

4                  DR. WEISS:   Don Calogero?

5                  MR. CALOGERO:    I can provide a little

6    background.   At the last ANSI meeting, we sort of discussed

7    this issue, and there was a presentation and the basic

8    summary of the presentation was that it's really not

9    possible for us to predict where the largest effect is

10   going to be in terms of the spatial frequencies.        We went

11   through the literature containing some information --

12                 DR. BULLIMORE:    But Don, the panel's telling

13   you that that's not an appropriate -- well, not necessarily

14   a widely held view of the world.

15                 MR. CALOGERO:    Well, this was from the

16   literature and this is from sort of the internal data we

17   have.   Some devices, depending on the type, had the largest
18   effect at 1.5 cycles per degree, others 12 cycles per

19   degree, and the committee felt that if we had recommended

20   the letter charts, based on sort of the spatial frequency

21   domain that they evaluate, you're essentially just simply

22   getting the highest spatial frequencies, maybe 12 cycles

23   and above, whereas we could potentially miss large drops at

24   other spatial frequencies, and with our current to predict
25   where the effect is, we felt it would be judicious to
                                                                     181

1    recommend that the entire contrast sensitivity function be

2    defined.

3                  DR. OWSLEY:    Can I make a comment?

4                  DR. WEISS:    Yes.   Make a comment, Cynthia, and

5    then also if we could direct it at, from what I understand

6    from the vision scientists on this panel, they don't agree,

7    and is that the case or is that not the case?

8                  DR. OWSLEY:    The vision scientists on this

9    panel I think do agree the letters would be better.

10                 DR. WEISS:    No, you agree that letters would be

11   better, but are you agreeing with what's been put forward

12   by the FDA?

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

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

15                 DR. OWSLEY:    And that's exactly what my comment

16   is on.   I've been reading this literature for 20, 25 years,

17   like Arthur -- Mark's a little younger -- and Steve.
18                 DR. WEISS:    He's thinking a lot younger.

19                 DR. OWSLEY:    I would be happy as a consultant

20   to the panel to look at those peer-reviewed papers.        Of

21   course, if you have internal data you can or cannot share

22   with me, that's your decision, but I have not seen any

23   convincing evidence that measuring all these different

24   spatial frequencies would matter in any of the decisions
25   that you would be faced with at the FDA regarding these
                                                                  182

1    types of devices.   But I'm openminded.    I just haven't seen

2    those papers.

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

4    Swanson.

5                  Dr. Burns has a comment.

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

7    these --

8                  DR. WEISS:    Dr. Burns has a comment.

9                  (Laughter.)

10                 DR. BULLIMORE:    This --

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

12   comment.

13                 (Laughter.)

14                 DR. BULLIMORE:    Since it's my --

15                 DR. WEISS:    Dr. Burns is deferring to you,

16   Mark, so why don't you give your comment?

17                 DR. BULLIMORE:    I have no problem with gratings
18   being used.   It was just having a sentence in there that

19   other avenues could be pursued if --

20                 DR. WEISS:    So you don't like the rigidity of

21   it, but you don't have a --

22                 DR. BULLIMORE:    It's more the rigidity, and I

23   mean, as I said before, you're almost sort of saying you've

24   got to use this test or this test, and those of us who work
25   in other arenas, and we've already spoken about the
                                                                  183

1    limitations of certain types of tests, we just find that a

2    little offensive, I think.

3                 DR. WEISS:   Dr. Burns, and then Karen Bandeen-

4    Roche and Mr. McCarley.

5                 DR. BURNS:   Yes, I just want to chime in that I

6    also believe that the combination of the high contrast and

7    the low contrast letter chart will give us enough

8    sensitivity both for some of the safety issues, such as

9    contrast degradation from cataracts combined with glare,

10   and remember also, this is a refractive procedure.       So we

11   do want to get general decrement information.     But I do

12   believe that a contrast letter chart combined with a high

13   contrast letter chart will be acceptable.

14                DR. WEISS:   Mr. Whipple?

15                MR. WHIPPLE:    Yes, Dave Whipple.   I just wanted

16   to address Mark's comment about the rigidity of the

17   guidance.   We may recommend certain tests or prefer certain
18   things, but a guidance is exactly that.    It's guidance.    It

19   always carries with it the option of using other tests,

20   other test methods, and making arguments why the

21   recommended tests aren't appropriate for that particular

22   device.   So that's inherently built into the guidance

23   document development.

24                DR. WEISS:   We'll go on to the other two
25   comments if they're not related or they don't change what
                                                                   184

1    my next statement is going to be.    It's from why I

2    understand, the members of the panel prefer a letter chart

3    and Dr. Bullimore would also prefer that the wording

4    doesn't sound so restrictive, even if it actually isn't.

5                Having said that, do you have anything else to

6    add to that, Dr. Bandeen-Roche or Mr. McCarley?

7                DR. BANDEEN-ROCHE:     My comment was a brief one

8    on a different topic, so should we finish this?

9                DR. WEISS:    If it's related to this question --

10               DR. BANDEEN-ROCHE:     It's related to clinical

11   significance in terms of functional performance.

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

13               DR. BANDEEN-ROCHE:     I just wanted to mention

14   that there is detailed data from the Salisbury Eye

15   Evaluation Project on glare, contrast, et cetera, with many

16   measures of functional performance.    So I don't think we're

17   completely in the dark.   I think that there are some data
18   that can inform that question, albeit it is a sample of

19   older adults.

20               DR. WEISS:    Good.   Thank you.

21               Mr. McCarley?

22               MR. McCARLEY:    Yes, just very quickly.   I'd

23   like to understand or get clarified for me the intent.       My

24   understanding, at least from the ANSI side of it when we've
25   been discussing this for the last several years, was that
                                                                     185

1    doing contrast sensitivity was to see if the combination of

2    optical components in the eye degraded, similar to what the

3    intent was when they did LASIK studies.    Now, it seems to

4    be that's what's being used to determine whether or not the

5    patient's undergoing a degradation as a result of cataract,

6    for instance.   So one would be a sample size and one would

7    be all patients, I think.

8                DR. WEISS:     Dr. Bullimore, did you want to

9    address that?

10               DR. BULLIMORE:     No.

11               DR. WEISS:     No one wants to address that.    I

12   guess we have no takers?

13               DR. BURNS:     If you're measuring a visual

14   performance like this, you're tapping the whole system, and

15   the degradation can come about from optical imperfections

16   or from what are actually just very high-order optical

17   imperfections of scattering and tissue turbidity.    So it
18   probes the whole system.

19               DR. WEISS:     I think we've beat this one into

20   the ground and it's no longer even gasping.    So why don't

21   we go on to the next one?

22               DR. BULLIMORE:     The next one I think is very

23   easy to deal with.

24               DR. WEISS:     We'll hold you to that.
25               DR. BULLIMORE:     Again, we're asking people to
                                                                186

1    be very specific about the tests, and I think the FDA have

2    enough savvy and flexibility to deal with this, but if

3    somebody can't read or can't see the highest contrast on

4    the chart, I think their contrast sensitivity has to be

5    scored as zero.   One would hope that preoperatively the

6    test was sufficiently intelligently designed such that they

7    could read well above that bottom level.

8                 Certainly, recalling some of the data we were

9    presented with yesterday, we were dealing with contrast

10   sensitivities of one or above most spatial frequencies.    So

11   as long as we have something down at the 40 percent or 60

12   percent, which of course is .3 or so contrast sensitivity,

13   we should be okay.

14                But if they can't see it, it shouldn't be

15   counted as missing data.    We should assume that their

16   contrast sensitivity is zero or some other intelligent

17   value based on the range of the test.
18                DR. WEISS:    So can the transcript reflect there

19   are about six heads bobbing up and down?

20                Next question.

21                DR. BULLIMORE:   And the next question, please,

22   Donna?

23                I think this is kind of tied in with the last

24   one.   If I can answer, I think tests are available and if a
25   patient can't see a targeted spatial frequency at any
                                                                    187

1    contrast, it should be scored as a contrast sensitivity of

2    zero.

3                   MR. WHIPPLE:    That is information.

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

5                   DR. BRADLEY:    I'm having a bit of trouble with

6    the question.    I mean, we're not anticipating these

7    patients are going to have horrible vision, are we?

8                   DR. WEISS:    Before or after the implant?

9                   (Laughter.)

10                  DR. WEISS:    Sorry.

11                  DR. BRADLEY:    I mean, we're talking about some

12   serious methodology here.      We're trying to ascertain

13   something fairly subtle, and I don't think in any of these

14   cases we're going to have the problem that people can't see

15   the target at all.

16                  MR. CALOGERO:    I think why we're asking the

17   question is under the mesopic test conditions.        Under the
18   mesopic test conditions, we do in fact have cases where at

19   the higher spatial frequencies, the patients are unable to

20   perform anything, and so you might have 20 or 30 percent of

21   the population that you're testing that essentially has a

22   zero, let's say, 12 or 18 cycles per degree.      So we wanted

23   some sort of standardized way of handling all of those zero

24   data points.
25                  DR. BRADLEY:    Well, I think the panel has given
                                                                    188

1    you our suggestion on that, which is that you should not do

2    these grating tests.   Particularly, don't try to find out

3    if people can see fine detail in the dark.     We know they

4    can't.

5                 DR. OWSLEY:     This is Cynthia Owsley.   It's very

6    unusual to find a patient who can't see the first triplet

7    of the Pelly-Robson chart, and I see Karen Bandeen-Roche

8    from the SEE Project nodding.

9                 DR. WEISS:    But in that case, I think we have

10   the answer to this question.     We may not like the question,

11   but I think Dr. Bullimore has already given an answer to

12   it, which I assume you would agree to, but you don't think

13   it's going to even come up.

14                Fine.   Next?

15                DR. BULLIMORE:     Beaten to death.   Beaten to

16   death.

17                I really have nothing to add on this one at the
18   moment.   I'll read it again.    "Please provide any

19   additional comments on the contrast sensitivity substudy"

20   -- now it's a substudy -- "including any other guidance

21   that could be provided to enhance the quality of the data

22   that are generated from this testing."

23                Use a good test would be my recommendation.

24                (Laughter.)
25                DR. WEISS:    That's why we call the experts to
                                                                   189

1    figure this out.

2                 DR. BULLIMORE:    And use it well.

3                 DR. WEISS:    So is that the end of your

4    questions?

5                 DR. BULLIMORE:    I'd like to hear what Dr.

6    Owsley has to say.

7                 DR. WEISS:    Dr. Owsley?

8                 DR. OWSLEY:    I think the test should have the

9    best test/retest reliability as possible and should be

10   brief.

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

12   heart.

13                Yes?

14                DR. BULLIMORE:    This is Dr. Bullimore again,

15   not wanting to shut up.     I think it would be ideal and

16   preferable and maybe mandatory that for any test that's

17   going to be used that normal data are available on a wide
18   range of age ranges and for the measured conditions.

19                DR. WEISS:    Dr. Bradley?

20                DR. BRADLEY:    I think just to reiterate what

21   everybody has said here and maybe to put the comment that

22   Bill Swanson made earlier, what we're arguing for regarding

23   the quality of a contrast sensitivity test can be thought

24   of by thinking of an analogy with a visual acuity test.
25                Imagine you had a visual acuity chart, one
                                                                  190

1    letter per line, and it was either A or B.      Would we

2    consider that an appropriate test?   And clearly not, and

3    all we're saying is let's hold the contrast sensitivity

4    test to a similar standard psychophysically in terms of

5    rigor and test/retest reliability that we are quite

6    comfortable demanding from our visual acuity tests, and it

7    turns out at the moment the only convenient one out there

8    that we know of is a letter chart.

9                DR. WEISS:    Dr. Bradley, we get the idea you

10   like the letter chart.

11               DR. BULLIMORE:    He is so proud that he can

12   read.

13               DR. WEISS:    He likes that letter chart.

14               DR. BULLIMORE:    He is so proud.

15               (Laughter.)

16               DR. WEISS:    If there are no other comments on

17   this, what I'd like to do then is move on to panel
18   discussion on remaining issues, and I have three issues,

19   and then we'll introduce if the agency has any additional

20   issues or if any members of the panel want to introduce any

21   additional issues.

22               One issue, which has been alluded to and

23   discussed, but I would like to see if we can give as many

24   opinions as possible, is duration of study before it's
25   presented to the panel.   Somewhere between two and three
                                                                     191

1    years has been mentioned.     Perhaps any of those of you who

2    would like to give your opinions can raise your hand and

3    just give me a number and tell me why.

4                  Dr. Burns?

5                  DR. BURNS:    From what I see of the endothelial

6    cell measurements and their likelihood of accuracy in this

7    population, I think three years is a minimum.

8                  DR. WEISS:    So Dr. Burns feels three years.

9                  Dr. Bullimore, had you -- three years.       We have

10   a sign.    We're going to signs now.     Okay.    So we have Dr.

11   Matoba at three, Dr. Grimmett at three.          Dr. Bradley likes

12   the number chart.

13                 (Laughter.)

14                 DR. WEISS:    Dr. Huang, three.     Dr. Mathers is

15   three.    Dr. Owsley is three.     Dr. Swanson is three.    So I

16   think we have actually, even though we're not looking for a

17   vote, essentially it's almost unanimous, if not unanimous,
18   for three years.

19                 DR. BANDEEN-ROCHE:     Madam Chair?

20                 DR. WEISS:    Yes?

21                 DR. BANDEEN-ROCHE:     May I make a very brief

22   comment?

23                 DR. WEISS:    Yes.

24                 DR. BANDEEN-ROCHE:     And that is that I believe
25   it's important, based on Dr. Grimmett's comments, that at
                                                                      192

1    least one, preferably two, evaluations be scheduled between

2    two and three years because he suggested that linearity was

3    not beginning to be achieved until then.

4                   DR. WEISS:   Okay.    So one to two endothelial

5    cell counts should be performed between the two- and three-

6    year mark.

7                   Dr. Grimmett?

8                   DR. GRIMMETT:    Dr. Grimmett.   I couldn't agree

9    more with Dr. Bandeen-Roche that the data that is present

10   in the peer-reviewed literature do not show a linear

11   approach.    We don't have enough data long enough.       So that

12   is correct.    In an intermediate point.

13                  DR. WEISS:   Dr. Mathers?

14                  DR. MATHERS:    I would not end the data

15   collection necessarily with three years because I think

16   that ongoing data could be important.

17                  DR. WEISS:   That's an important question in
18   terms of a postmarket study.        It could be brought to panel

19   at three years, at least from the recommendations from this

20   panel today.    After that, a postmarket study of what

21   duration of time would you like to see, Dr. Mathers?

22                  DR. MATHERS:    Another two years.

23                  DR. WEISS:   Another two years.

24                  Dr. Grimmett?
25                  DR. GRIMMETT:    Dr. Grimmett.   I would agree
                                                                  193

1    with Dr. Mathers' sentiments, but that decision would be

2    made more accurately with the data in hand with the PMA at

3    three years obviously, but I would feel certainly

4    comfortable with probably a postmarket study.

5                  DR. MATHERS:   Yes.

6                  DR. WEISS:   Dr. Bullimore?

7                  DR. BULLIMORE:   This is endothelium only?

8                  DR. WEISS:   It can be whatever you want.

9                  DR. MATHERS:   Cataract.

10                 DR. WEISS:   And you don't have to define it

11   now.   Basically, what the agency would like is your

12   opinions.

13                 DR. BULLIMORE:   My opinions will be more well-

14   informed once I have some data, but I have considerable

15   concerns about the long-term safety of these intraocular

16   devices.    As the lens continues to grow, as it gets to

17   cohabit with the phakic IOL for a long period of time, I
18   don't think any of us can predict with any accuracy or

19   precision what that's going to do to the crystalline lens

20   on a long-term basis.

21                 You know, these devices we can expect to be

22   better than some of the first-generation phakic intraocular

23   lenses, but they haven't been around long enough for us to

24   tell, so I could foresee a substantial -- i.e., five-year
25   -- postmarket study to track these patients and see, for
                                                                   194

1    example, how many people develop significant lens opacity,

2    whatever that may be, how many people have to have a

3    cataract extraction and conventional IOL implantation, how

4    many of those patients have complications from that

5    procedure, and it can be nothing more than fairly

6    straightforward head counting, but I think tracking these

7    patients long-term, given what we know happened with, for

8    example, extended wear contact lenses in the '80s and

9    anterior chamber intraocular lenses, I think it would be

10   prudent.

11               DR. WEISS:     So the impression I get -- and if

12   there's something you would like to add, then we'll add it

13   -- is that the panel members would like to see postmarket

14   studies from two years on up, maybe even to five years, but

15   pending what the data shows.

16               DR. BULLIMORE:     Once we have a PMA before us,

17   we can make a more informed decision, but certainly, given
18   the fact that this is an intraocular device that's

19   cohabiting with a lens that's continuing to grow and

20   function, I would --

21               DR. WEISS:   You want to see a postmarket study.

22               DR. BULLIMORE:     Well, I would anticipate the

23   possibility of this requirement.

24               DR. WEISS:   Dr. Mathers?
25               DR. MATHERS:    We have not focused on pigment
                                                                   195

1    dispersion, but in the literature there are a number of

2    papers that do.    Not so much that they've had a lot of

3    glaucoma yet, but they often have pigment dispersion in the

4    range of 30 percent, and therefore gonioscopy and pressure

5    measurement.

6                   DR. WEISS:   Actually, that's an excellent

7    point.    I don't recall if that's in the document,

8    gonioscopy, and then how often --

9                   DR. MATHERS:   It is.

10                  DR. WEISS:   And how often should postop.

11                  DR. MATHERS:   It's in there now and it hasn't

12   been focused on, but it's in the literature, and I think

13   it's an important issue.

14                  DR. WEISS:   So we haven't defined here, but

15   there is concern in terms of follow-up as far as not only

16   the cataract and the endothelium, but also gonioscopy and

17   how frequently that would be done and what the postmarket
18   would be would be defined in terms of when some of the data

19   comes in.

20                  Another question is what is an independent

21   entity?    Is the subject an independent entity or is the eye

22   an independent entity?

23                  For example, classically, for intraocular

24   lenses, each patient has been an independent entity.        Each
25   subject has been an independent entity.      So if the FDA
                                                                196

1    statistically said that 300 data points were required, then

2    each patient would be considered separately an entity

3    whether or not they had one or both eyes treated.

4                On the other hand, for LASIK, each eye has been

5    considered an independent entity in the same patient, so

6    that if 300 data points were required, then you might only

7    need 150 patients.

8                So this is a very important point for sponsors

9    to know whether they need 300 patients, and we're going to

10   be getting to sample size as well, but if the sample size

11   is determined to be necessary to be 300, should that be 300

12   patients or can it be 150 patients with both eyes treated?

13               Dr. Bandeen-Roche?

14               DR. BANDEEN-ROCHE:    Yes, I mean, statistically

15   speaking, from a strict point of view, sites are the

16   independent entities.    Now, obviously, we're not going to

17   base sample size on that, but methods are available to
18   account for correlation of eyes within individuals, and in

19   turn, of individuals within sites if necessary in computing

20   power.

21               So one doesn't necessarily need to go to the

22   extreme of saying, for instance, we're going to count

23   people as entity.    One can still account for the

24   information provided by two eyes within an individual, yet
25   accounting for the correlation in that information that two
                                                                   197

1    eyes shouldn't count as much as two separate people, and

2    indeed that perhaps two people within a site shouldn't

3    count as much as two people in different sites.

4                I actually have a figure that I brought on

5    this, but if you prefer to save it, we can.

6                DR. WEISS:    No, sure.

7                DR. BANDEEN-ROCHE:    I need the overhead.   So

8    can I just quickly set that up?

9                DR. BANDEEN-ROCHE:    Sure.   Maybe while you're

10   setting that up, we can go on to a comment by Dr. Burns,

11   and then to Dr. Matoba.

12               DR. BURNS:    Yes, I just want to support that

13   strongly because we're talking here a lot about biological

14   reactions to a foreign body.   So there will be a

15   significant amount of correlation, I assume, between eyes,

16   and so the studies should explain how they're going to

17   handle it statistically in the design, and not in post-hoc
18   analyses.

19               DR. WEISS:    So I want to understand.   Would you

20   feel that an eye should be an independent entity or a

21   subject?

22               DR. BURNS:    I think Karen is going to explain

23   the statistical way to handle it, but it's important that

24   it be handled that way from the outset, that you're
25   accounting for the correlation between eyes.
                                                                 198

1                 DR. WEISS:    Now, we're going to go along with

2    other comments, but we also need to look at this not only

3    statistically, but from a safety standpoint because this is

4    a new device.

5                 Dr. Matoba?

6                 DR. MATOBA:    Yes, in regard to the safety

7    standpoint, since we've already decided that because of the

8    issues of quality of life we're going to allow patients to

9    have both their eyes done instead of limiting it to one eye

10   over a three-year period of time, we might as well get data

11   from both eyes, and so fewer people would have to be

12   involved in the initial study.

13                DR. WEISS:    Dr. Mathers?

14                DR. MATHERS:    Yes, I strongly agree with that

15   comment.   I think we should have both eyes, but we should

16   account for the correlation, and that allows us to get over

17   this quality of life issue, which is going to be very, very
18   important to the patient because only doing one eye is not

19   going to work.

20                DR. WEISS:     Well, we're not talking about only

21   doing one eye.   We're talking about whether you need 300

22   subjects who can both have both eyes done or 150 subjects

23   who can still both have both eyes done.

24                DR. MATHERS:    I think we shouldn't throw away
25   the data on the second eye, but we should use it with an
                                                                   199

1    appropriate correlation.

2                DR. WEISS:     So you basically want to count it

3    and not require another 150 patients.

4                DR. MATHERS:     We're about to hear how we can

5    account for the correlation.

6                DR. WEISS:     Okay.

7                DR. MATHERS:     In estimate.

8                DR. BANDEEN-ROCHE:       Yes, and so certainly one

9    can just state what is the expected design, including eyes

10   within patients, patients within sites, et cetera, and then

11   do power and all other statistical analyses accounting for

12   that correlation.   So what I had diagrammed here was

13   thinking of people within sites, but it could equally well

14   apply to eyes within people.       There might be several

15   levels.

16               So here, M is referring to the larger level.

17   So let me just stick to people within sites because that's
18   the way that I did it.   So M is the number of sites and N

19   is the number of individuals within sites.

20               So for instance, if it were people and eyes, it

21   would be M people, and for two eyes, N would be two eyes

22   per person, and so what I'm showing you here is the

23   standard deviation of the mean -- say, a rate, say, a

24   safety rate -- or I guess to simplify things, this was
25   meant to be a continuous measure.       So it would be something
                                                                200

1    more like an acuity measure that's measured on a continuous

2    scale.

3                So you can see that the standard deviation

4    depends both on the overall number of units, either people

5    times eyes or sites times people, and the symbol rho, which

6    I'll point to here, that's the correlation between outcomes

7    within a person -- so two eyes within a people -- or

8    between visual acuities within a site, and then sigma is

9    just the standard deviation of the measurement that's being

10   taken in the population.

11               So one thing to point out is that if N equals

12   1, then this top term goes away, and you just get the usual

13   standard deviation of the mean.

14               So what I'm showing you here is how the

15   standard deviation varies for the -- I assumed the FDA

16   sample size of 300, but what's varying here is the number

17   of clusters, and so here's where this is really more
18   relevant to sites and people within sites, because the FDA

19   guidance for the number of sites says something like at

20   least 20 per site and no more than a quarter being

21   accounted for by any one site, and so if we had four sites,

22   then that would just be meeting no more than a quarter by

23   any one site.   Then here, up at 300, you only have one

24   patient per site, so that's the outer limit.
25               So the bottom line here, the straight line, is
                                                                  201

1    what you get if there's no correlation.    That's just the

2    standard deviation of the mean.     If there's no correlation,

3    then it doesn't matter how you distribute people by sites.

4                 The other three curves, just to save time, the

5    bottom one here assumes a correlation of .05.     That's

6    small.   That's assuming that 5 percent of the total

7    variation in outcomes is accounted for by variation between

8    sites.

9                 So even with that minimal amount of

10   correlation, notice how much bigger the standard deviation

11   is.   I apologize that the scale on this isn't better, but

12   that's twice as high.     It's approximately twice as high as

13   your analysis ignoring correlation says that it should be.

14                Incidentally, we were about here yesterday.     We

15   had five sites yesterday, and I think two of them accounted

16   for more than 50 percent of the data.

17                The one point is that I would encourage going
18   to more sites than no more than allowing any one to be up

19   to a quarter of the data, but the second point is that if

20   we were just talking about eyes within people, it would be

21   straightforward to do this calculation and just account for

22   it in calculating power and doing the analyses and what

23   have you.

24                DR. WEISS:    Thank you very much.
25                I'm going to ask Donna Lochner to speak with us
                                                                 202

1    a little bit more about this issue.

2                MS. LOCHNER:   Well, I think this is helpful,

3    but the kind of recommendation we need clinically is what

4    factors do we base the correlation on and what is the

5    correlation that would be plugged prospectively, as you're

6    stating, into this equation?

7                DR. WEISS:   And I should also add with

8    information from you already is the precedence to date, is

9    that LASIK is a little unusual because each eye has been

10   considered a separate entity, but the history has basically

11   been for intraocular lenses one patient, whether or not

12   they had both eyes done or one done, was a separate entity.

13    Viscoelastics, whether they had one eye or both eyes done,

14   was a separate entity.   So there's been a little bit of a

15   history of using patients as separate entities, as opposed

16   to eyes.

17               MS. LOCHNER:   Right, and I mean, we want to get
18   a feel for clinically how you would assign this correlation

19   factor for all the various variables that you're looking at

20   outcomes.

21               Now, we, of course, in our guidances, have not

22   addressed this method of potentially using the second eye,

23   and so all of our calculations and sample sizes and whatnot

24   are based on independent people, but if we were to allow
25   this approach, we would have to have some sense of what
                                                                    203

1    would the panel consider acceptable for how correlated are

2    the two eyes for the various safety outcome variables and

3    effectiveness outcome variables.

4                   DR. WEISS:   Dr. Bandeen-Roche?

5                   DR. BANDEEN-ROCHE:      Yes, so certainly the

6    approach of calculating it for people is conservative.

7                   MS. LOCHNER:   Right.

8                   DR. BANDEEN-ROCHE:      That would essentially be

9    it, and so I have a hard time arguing with that, although I

10   know that others would raise we can't afford to waste any

11   data or money or what have you.

12                  So in terms of getting a sense of the

13   correlation, I would think that if you have decent pilot

14   data, that the correlations I'm talking about could be

15   estimated in a straightforward fashion.

16                  DR. WEISS:   Could you perhaps have a subset of

17   the first 20 patients, 50 patients, to draw whatever those
18   correlations are to see whether you could then use separate

19   eyes as separate subjects or the same patient with two eyes

20   as separate?

21                  MS. LOCHNER:   I mean, my general impression is

22   that for most sponsors, developing this pilot study and

23   determining this correlation -- I mean, I've seen nobody

24   suggest that to us, first of all, and secondly, how would
25   they do it if at the end of the study they want to use both
                                                                204

1    eyes?

2                But I've never seen it presented.    I've never

3    even seen a suggestion for what this pilot study would be,

4    and in fact probably what we've recommended in terms of the

5    slow phase in to not put eyes at risk for unproven phakic

6    IOLs -- I mean, if they have foreign experience, we do

7    allow them to phase in quicker, but I kind of suspect that

8    given the slow phase in, doing the pilot study, it's going

9    to be complicated.   I mean, it's going to take a while for

10   them to gather that information.    I'm not sure how many you

11   typically see in a pilot study to establish these

12   correlations.

13               DR. BANDEEN-ROCHE:     And so, you know, certainly

14   I would be perfectly happy with the conservative approach,

15   but my question to the panel, and I have no idea what the

16   answer to this would be, would one expect the data to be so

17   different in these particular studies that a good sense of
18   reasonable correlation could not be obtained from either --

19   I mean, LASIK data, that's probably ridiculous, but aphakic

20   IOL trials or is there historical data that are similar

21   enough in nature that a reasonable estimate of the

22   correlation of outcomes in a subject could be done?

23               DR. WEISS:   I mean, I always wonder, if this is

24   new technology, I wonder in terms of we heard about if the
25   IOL is too small, it can induce cataract by sitting on the
                                                                   205

1    lens.   How often is that phenomena happening and is it

2    correlated between the quality of the measurement, a vagary

3    of that individual and their eye, and is it the quality of

4    the surgery?    So I think some of these may be unknown

5    factors.

6                   Dr. Burns?

7                   DR. BURNS:   I mean, I'd be happy with the

8    conservative approach, too.     I wouldn't be happy with

9    getting the final analysis coming back suddenly treating

10   the eyes as 600 eyes at the end.

11                  MS. LOCHNER:   Oh, no.   No.   That maybe needs to

12   be clarified.    In the sample size calculations that we've

13   done, we've recommended 300 individuals, their first eye,

14   and we require that they collect data on the second eye.

15   The second eye data is not combined in with the first.

16   It's just a separate analysis that's provided to the panel

17   that's really more of a confirmation check that the
18   outcomes are holding up in the second eye and giving you a

19   little bit more numbers.      But no, we don't combine them

20   into a 600 sample size and improve the precision.

21                  DR. WEISS:   Dr. Mathers?

22                  DR. MATHERS:   I was just concerned that there

23   was some thought of holding up doing the second eye for the

24   three-year period.
25                  MS. LOCHNER:   Oh, no.   No.
                                                                    206

1                   DR. MATHERS:   But if that's not the issue, then

2    you can afford to be conservative in your statistical

3    approach if that's what you want.

4                   MS. LOCHNER:   And I think that basically,

5    without the detail and the sort of clear way you've just

6    presented it today, Dr. Bandeen-Roche, we've basically

7    given this advice to sponsors that, should they want to use

8    the second eye, they need to determine the correlation

9    between the two eyes and relook at their sample sizes.

10                  So I think just getting this out on the table

11   is important, and I think the point that Dr. Weiss made is

12   probably where most of us sit in the FDA of there's some

13   unknown information and how do you determine the

14   correlation?    Perhaps a pilot study, but there's just so

15   much unknown, and it's helpful for us to hear you reiterate

16   what we've basically told sponsors is determined on how the

17   two eyes interact.
18                  DR. BANDEEN-ROCHE:      And the only thing I would

19   add to that is that at the end of the study, the data

20   itself provides an estimate of the correlation, and that

21   should be accounted for in any analyses of two eyes.

22                  MS. LOCHNER:   Right.

23                  DR. WEISS:   Dr. Mathers?

24                  DR. MATHERS:   We are saying, though, that the
25   data on the second eye will be collected.        Is that correct?
                                                                   207

1                  MS. LOCHNER:    Oh, yes, and will be reported to

2    the panel.

3                  DR. MATHERS:    Fine.

4                  MS. LOCHNER:    But it will not be combined with

5    the first eye to get a bigger sample size.       It will be

6    reported separately.

7                  DR. MATHERS:    Yes, that's key.

8                  DR. WEISS:   Mr. McCarley?

9                  MR. McCARLEY:    Yes, just quickly.   What are the

10   ISO standards?   What are the requirements in ISO right now?

11                 MS. LOCHNER:    Well, again, all the sample sizes

12   were based on a straightforward calculation not taking the

13   second eye into account, so I believe that the ISO is

14   basically asking for 300 individuals as well.

15                 You know, it's a little different with a

16   standard in terms of -- I mean, you still can go to the

17   notified bodies and present whatever you want, but
18   certainly with the FDA, we would allow companies to propose

19   alternate proposals, but taking into account what's been

20   discussed.

21                 DR. WEISS:   Thank you very much.

22                 The other question that I wanted to answer, and

23   we would probably need your input on this as well, is the

24   question of sample size.      The 300 is what was put forward
25   by the FDA.   Of course, it depends very much on the issues
                                                                208

1    that have been discussed by the three panel reviewers, but

2    does anyone have any comments on that 300 number?

3                 Dr. Bandeen-Roche?

4                 DR. BANDEEN-ROCHE:    Dr. Grimmett was kind

5    enough to hand me a set of analyses yesterday, and I

6    believe they were done at FDA.    Are they going to be

7    presented?

8                 MS. LOCHNER:    Well, I don't know if now's the

9    right time to bring it up, but we did have a bit of a

10   question about the endothelial cell density discussion that

11   went on earlier, and that is based on some of Dr.

12   Grimmett's questions, we prepared that table, which is a

13   table of different potential rates of cell loss due a

14   phakic IOL in sample size, and also different standard

15   deviations in the measurement.

16                DR. WEISS:   Why don't show it now, because that

17   is probably --
18                DR. GRIMMETT:   Why doesn't Don Calogero just go

19   over some of the salient points?

20                MS. LOCHNER:    And let me just, before he does

21   that, say that from the earlier discussion, we heard the

22   1,500 cells and we heard that using the actuarial data, and

23   even perhaps backing the age of cataract and calculating

24   different point on.   We heard all that, but what we didn't
25   get from the earlier discussion was what rate do you want
                                                                   209

1    to be able to detect?      And that essentially is what Don

2    will present.   I mean, just before giving you a clinical

3    impression, of course, you have to see what the sample size

4    is.   We're talking about what really kind of seems

5    reasonable.   It's a combination of your clinical judgement

6    along with the sample size is that translates into you

7    arrive at a rate that seems reasonable.

8                  So Don's passing that out, and I'll let him

9    explain that to you, because we really didn't walk away

10   understanding whether you felt the 2 percent rate that

11   we've set up is reasonable.

12                 DR. HUANG:   Can I make a comment?   Donna, I

13   think the sample size itself is not just for statistical

14   analysis.   It also has to be considered for practical

15   matters.    You know, as we mentioned earlier, in some of the

16   aniridia patients, you may not be able to get all those

17   patients, and so you cannot mandate that 300 eyes.
18                 DR. WEISS:   This is very relevant to the slide

19   you're about to see.

20                 MS. LOCHNER:   And let me also say that the 300

21   sample size actually didn't originate from the endothelial

22   cell density study.    I mean, way back when we started some

23   of studies, it originated from the IOL work and being able

24   to detect low rate of complications, and then, as we
25   developed the statistical analysis for the endothelial cell
                                                                     210

1    density, et cetera, it was a reality check to that sample

2    size and it coincided very nicely, but originally we

3    carried over a lot of the assumptions from aphakic studies

4    in what we wanted to be able to detect in the complication

5    arena.

6                DR. HUANG:    But also the current discussion is

7    really limited to the phakic population, and then we are

8    probably targeting towards a higher myopia patient, and

9    those are patients more difficult to come by as indicated

10   from yesterday.   For the wavefront technology, they could

11   only recruit 130 eyes with a -7.

12               MS. LOCHNER:      That's true.   However, I think

13   most of the studies that are ongoing in the U.S. go down as

14   low as a diopter.    They aren't necessarily limiting --

15   beyond the initial stages, when some of the preliminary

16   safety data is being gathered, in later stages of the

17   study, they are going down to 1, 2, 3 diopters.
18               DR. HUANG:    But if this were to be limited to

19   the higher myopic patients --

20               MS. LOCHNER:      You wouldn't have the problem

21   you're discussing.   Right.

22               DR. HUANG:     Yes.

23               MR. CALOGERO:      Okay.   As Donna said, we need

24   some additional guidance in terms of the sample size.      The
25   sample size that we have in the document now of
                                                                 211

1    approximately 300 subjects is probably powered to detect

2    endothelial cell loss rates of maybe 2 percent and maybe as

3    low as 1.5 percent, but it's not going to get down to the

4    .9 percent, which was the lower extreme that Dr. Grimmett

5    brought up.

6                  In terms of this document that I passed around,

7    what it looks at is it looks at sort of a true yearly loss.

8     The left column is the yearly loss from .9 percent up to 2

9    percent, and then the next three columns on the right are

10   the sample size that you need with an observed, allowable

11   rate per year, which is the fourth column, to give you 90

12   percent confidence that the true rate is up to the yearly

13   loss rate in the lefthand column.

14                 Like in the first one, if you want the true

15   yearly loss rate to .9 percent, if you in your data you

16   have a standard deviation of 10 percent, you would need a

17   sample of 296 subjects, and your allowable observed rate
18   could be as high or as low as .63 to meet that level.

19                 So it becomes important to first get a sense of

20   what the true standard deviation is in this data, and then

21   secondly, to have a sense of what the panel members would

22   like to see in terms of defining a true rate associated

23   with endothelial cell loss for these devices.

24                 I simply generated the numbers, and we'd like
25   some feedback.
                                                                 212

1                DR. WEISS:    I think Dr. Grimmett has a

2    question.

3                DR. GRIMMETT:    Drs. McCarey and Edelhauser put

4    forth precision numbers for those, 2 percent and 9 percent,

5    and I want to know how those correlate over the standard

6    deviation numbers.

7                PARTICIPANT:    Put up the slide.   Are they the

8    same?

9                DR. BANDEEN-ROCHE:    No, they're not quite.

10   They're not quite, and so as I understand it, the numbers

11   that were presented this morning were essentially the

12   absolute difference in two measurements over the maximum of

13   those two measurements.    I read that off of the handout

14   from this morning.

15               So what that means is the numerator is the

16   difference in two measurements, and so essentially what you

17   need to do with that, each one of them has a variance.
18   Each one of them contributes one of those standard

19   deviations from your table, except it has to be done in

20   terms of variance.

21               So to make a long story short, the conversion

22   is that the FDA percent standard deviation is the percent

23   variation that was reported this morning divided by the

24   square root of 2, and that division being that in the
25   numerator of the statistic this morning, there were two
                                                                  213

1    measurements being subtracted.    So if you approximate no

2    correlation between them, they each contribute a variance,

3    and then take the square root of that because it's a

4    standard deviation, rather than a variance.

5                 So that's where that square root of 2 comes

6    from, and so if you do that, then I just sketched out on a

7    thumbnail sketch what the 5 percent, 10 percent, and 15

8    percent on the table in front of you corresponds to in

9    terms of what we hearing this morning.   So respectively,

10   that would be 7 percent, 14 percent, and 21 percent.

11   That's just multiply by 1.4, the approximation of square

12   root of 2.

13                One more number would be that if you went down

14   to 3.5 percent on the FDA table, that would correspond to 5

15   percent in terms of the figures that we were hearing this

16   morning.

17                DR. GRIMMETT:   This is Dr. Grimmett.   If I
18   interpret that correctly, that's actually good news,

19   because that means the numbers that were quoted this

20   morning may be achievable because they actually translate

21   into lower standard deviations.

22                DR. BANDEEN-ROCHE:   I interpret it the same

23   way.   Yes, and it seems important to me that -- I mean,

24   measurement, good quality of measurement, is where we stand
25   to gain precision and power, and however that can be
                                                                     214

1    absolutely pushed for people to up their standards, it's

2    important.

3                 DR. GRIMMETT:   Dr. Grimmett again.    So in Dr.

4    Edelhauser's best case scenario, though, the 2 percent

5    precision factor could be achieved.      Assuming that could be

6    done, then we're talking a standard deviation of just

7    slightly higher than that.    For example, 3 percent or

8    something like that, whatever the number is.

9                 DR. BANDEEN-ROCHE:      Well, even lower, right?

10   Yes.

11                DR. BURNS:   Excuse me.    Just a clarification.

12   That's the precision of the measurement, but not the

13   standard deviation of the population, is it?

14                DR. BANDEEN-ROCHE:      Right, but that's what I

15   understood this to be.    We were talking about the precision

16   of the measurement, right?    Yes.    So that is what appears

17   in the FDA Table 2.    Those standard deviations refer to
18   standard deviation of measurement in a single person.

19                DR. WEISS:   So with this information before us

20   and your extra analysis, I'd like some opinions as far as

21   what numbers of subjects we're looking at and what yearly

22   loss.

23                MR. CALOGERO:   Don Calogero.    Can I just

24   mention one thing?    I believe that data was on the
25   KeraVision rings, and those were sort of low myopia
                                                                       215

1    patients.   I believe they went up to 3 or 4 diopters.         The

2    population that we're looking for with these devices is

3    going to be higher.

4                   I've actually had my endothelial cell counts

5    taken and I'm 4 diopters without my glasses.        It's correct

6    what they're saying.    It's very difficult to focus on that

7    green light.    I can imagine if you're 8 diopters or 12

8    diopters.   So I suspect in the populations we're actually

9    looking at, that's a very conservative estimate.

10                  DR. BANDEEN-ROCHE:      There was a number being

11   cited of 9 percent this morning.        I mean, again, just

12   purely interpolating that would put us at about 7.5.          I

13   mean, it's in-between the 5 and 10 percent on this table.

14                  MR. CALOGERO:   Okay.    That's the KeraVision

15   number.

16                  MS. LOCHNER:    So I think what Don is saying is

17   that 9 percent figure came from the KeraVision, which puts
18   you in-between the 5 percent standard deviation and the 10

19   percent.    Maybe it would be prudent to go up at least to

20   the 10 percent standard deviation because the population

21   these will be used in will be a much more difficult

22   population than the KeraVision.

23                  DR. BANDEEN-ROCHE:      If I could ask one more

24   question, these calculations, were they based on just a
25   three-year minus three-month difference?        That's what was
                                                                     216

1    being analyzed?

2                  MR. CALOGERO:    Yes, yes.

3                  DR. BANDEEN-ROCHE:       Because --

4                  MS. LOCHNER:    No, they were repeated measures.

5                  DR. BANDEEN-ROCHE:       All four measurements?

6                  MS. LOCHNER:    Yes, repeated measures, not --

7                  MR. CALOGERO:    Okay.    As Ashley said, we

8    established linearity with the four measurements, but in

9    terms of this particular calculation --

10                 MS. THORNTON:    Don, please speak into the

11   microphone.

12                 MR. CALOGERO:    In terms of this particular

13   calculation, it's I believe the three-month value, the 36-

14   month minus the three-month, and then you simply divide by

15   2.75.   The actual method and equation is right in the

16   information that we provided to you.        I simply used the

17   equation that's in that document.
18                 DR. BANDEEN-ROCHE:       Right, and so certainly I

19   would expect that some precision could be gained by using

20   all four measurements, rather than just the difference

21   between the last and the first, and so that would impact

22   this table.

23                 Go ahead.   Interject, interject.

24                 DR. BRADLEY:    This is Dr. Bradley.    Could
25   somebody clear up for me, the 9 percent that we're talking
                                                                    217

1    about from this morning, if I recall the presentation, was

2    the difference that would have to occur in a single eye to

3    confirm with 100 percent certainty that in fact a change

4    had occurred.   Therefore, that was an estimate of the

5    overall range, not the standard deviation in that

6    distribution.   Perhaps the speaker from this morning can

7    clarify that.

8                  PARTICIPANT:   I agree with what you just said.

9                  DR. BRADLEY:   But I think it's being treated

10   here as a standard deviation.

11                 DR. BANDEEN-ROCHE:   Well, let me just clarify.

12    So the overall range -- now, let me see if I read the

13   wrong thing off of your handout, but the way that I

14   understood it was two measurements, maximum minus minimum

15   over maximum?

16                 DR. McCAREY:   If you're referring to the

17   graph --
18                 DR. WEISS:   Can you identify yourself first for

19   the transcript?

20                 DR. McCAREY:   My name is McCarey.   If you're

21   referring to the 9 percent one, that was simply a

22   subtraction of baseline and three months for each

23   individual.

24                 DR. BANDEEN-ROCHE:   Right, but that's an
25   absolute difference.
                                                                 218

1                DR. McCAREY:    Yes.

2                DR. BANDEEN-ROCHE:      Yes, and so you can

3    approximate an absolute difference by the square root of

4    the squared difference, and so in turn -- I admit there are

5    multiple approximations here, but it's not a bad

6    approximation.    The square root of the square, then

7    expectation of the square is a variance, and that's how

8    that enters in.

9                Yes, but I agree.      It's worth doing this more

10   carefully than on my thumbnail.

11               DR. WEISS:    So I think we could actually -- I

12   think you've given us the data to look at and try to

13   balance what we're willing to detect as a yearly loss

14   versus what we're willing to balance against as a maximal

15   amount of endothelial cell loss, and then we can choose the

16   numbers we want.

17               I would ask Dr. Grimmett if this is basically
18   and opinion-type thing at this point, but that's basically

19   all you want right now.    So do you have an opinion as far

20   as what you would wish for a yearly loss and an allowable

21   rate?

22               DR. GRIMMETT:    Sure, but I'm taking into

23   account that some of these numbers have largely varied.

24   For example, in the .9 category of the study of 669
25   patients, to have good accountability over three years is
                                                                  219

1    pretty incredible, and which I don't think is really

2    achievable or reasonable.

3                  Keeping that in mind, the higher numbers I

4    guess at this point are 1.9, 2 percent loss.    I would be

5    extremely disappointed and worried if a phakic IOL actually

6    achieved that rate.    I think it would indicate that

7    patients would actually develop corneal edema during their

8    lifetime, especially if they need cataract surgery.     I

9    would hope that they'd have a lower rate of cell loss.

10                 What would I like to detect versus what is

11   reasonable?    Based on the data here, I suppose if we could

12   be at the worst, assure it's not higher than 1.5.    I'd

13   still hope it's a little lower than that.    I think a 2

14   percent threshold is too high based on the actuarial tables

15   that I ran.

16                 Even for some of these lower numbers, even the

17   1 percent, if they have a 250 sample size -- 244 in this
18   example with a 10 percent standard deviation -- you know,

19   they would be allowed to see a rate of .7 to be sure with

20   90 percent confidence is not higher than 1.    You could

21   still determine other factors, just not with this much

22   precision.    It's going to be much harder at the lower

23   rates, and then we admit the normal endothelial cell loss

24   rate is .6 percent per year or so.    So we have to account
25   for that factor, and then there will be zero differential
                                                                  220

1    between what he phakic IOL is actually doing versus normal

2    cell loss rate.   The 1.5 is what I'm looking at.

3                 DR. WEISS:   So I think perhaps you could say

4    the 1.5 percent and allowable rate being --

5                 DR. GRIMMETT:   Yes, just straight off the

6    table.   I mean, once we set the sample size, it's going to

7    lock this in to what their allowable rate is to be sure of

8    a 90 percent confidence is not higher than our threshold.

9                 Given the difference -- for example, let's look

10   at the 1.5 percent category.   Given the difference between

11   the smallest number, the 243 sample size, and the unwieldy

12   542 independent patients over three years, that's a huge

13   number and it would cost probably a fortune to even try to

14   do it.

15                So I'm still, I think based on statistics and

16   -- I see I was looking at the 15 percent standard

17   deviation.   But looking at the statistics and stuff, I
18   think that the sample size that we're actually asking for

19   is somewhere in the neighborhood of 250 or so.   That's what

20   it looks like on this table.   Whatever the number happens

21   to be, but I think asking for higher precision than that is

22   not reasonable.

23                DR. WEISS:   So I think from what I understand

24   you're saying, yearly loss would somewhat be dependent on
25   the fact that most -- I would also agree.    You don't want
                                                                     221

1    to ask for than 250 to 300 patients.      So that already locks

2    us into what we want our yearly loss to be.

3                  DR. GRIMMETT:   My hope is that with the

4    precision and the careful techniques that Dr. Edelhauser

5    described, if they can actually be implemented with care,

6    is that by lowering the true standard deviation, we'll have

7    much better precision than we would want, and that's got to

8    be hopeful.   Controlling technicians is so important to

9    lower that standard deviation to give the power of the

10   study better precision.

11                 DR. WEISS:   Dr. Mathers?

12                 DR. MATHERS:    And our precision is going to

13   improve with time because as we monitor afterwards,

14   presuming that is the case, then monitoring for a longer

15   period of time improves our data on the loss rate.       It's

16   not part of this table, but this doesn't get worse over

17   time.   It gets better if you continue to monitor.
18                 DR. WEISS:   Dr. Bandeen-Roche?

19                 DR. BANDEEN-ROCHE:    Yes, I would just like to

20   bring up a little something about the safety and

21   effectiveness precision given a sample size of 300.      This

22   was Attachment A, Section A.1, and by my calculation -- you

23   know, of course, zero events is the least that you can have

24   -- with a sample size of 300, that gave a 95 percent upper
25   confidence bound of .01.
                                                                   222

1                  Now, so that's a 1 percent, say, adverse event

2    rate, and I would just submit that for the panel's

3    consideration.    I don't think that that can be argued as

4    meeting the .001 standard that was cited in the attachment

5    in the way that I feel is honest and candid.

6                  DR. WEISS:   What sample size would allow you

7    that rate?

8                  DR. BANDEEN-ROCHE:    Well, unfortunately, it's

9    very large.

10                 DR. WEISS:   Well, what is very large?

11                 DR. BANDEEN-ROCHE:    Three-thousand.

12                 DR. WEISS:   So in other words, we have to

13   change the rate.   We might want that rate, but none of us

14   believe that a study with 3,000 patients can be done.

15                 DR. BANDEEN-ROCHE:    That's right, but maybe it

16   just supports the importance of postmarketing data.

17                 DR. WEISS:   Okay.   So it supports our concern
18   for stringency.

19                 Dr. Bullimore?

20                 DR. BULLIMORE:   And one of the continuing

21   limitations of the data we consider is we're presented,

22   bombarded, with event rates and, give complication rates or

23   adverse event rates, we choose to ignore the confidence

24   intervals or we're not presented with the confidence
25   intervals that you give you an indication of the precision
                                                                 223

1    of those estimates, and if you really truly want to ensure

2    that the event rate is, say, less than 1 percent, you would

3    have to do as Dr. Bandeen-Roche suggested, enroll

4    considerably more patients, as was done, say, in recent

5    continuous wear contact lens studies.

6                We choose to ignore information, we sort of try

7    and meet targets, and we keep in the back of our minds

8    often what the precision of the estimate might be, but it's

9    not something we consider on a regular basis, and maybe we

10   should, but I'm not sure that we'd like the answer that

11   we'd get if we were presented with those on a regular

12   basis.

13               DR. WEISS:   Dr. Bandeen-Roche?

14               DR. BANDEEN-ROCHE:   Well, just stating it

15   another way, I mean, is the panel willing to live with 5

16   percent of studies claiming an event rate of .001 or less

17   when in fact it's higher than 1 percent?   I mean, that's
18   the ramification.

19               DR. WEISS:   I think the difficulty is in the

20   real world, if we required the number of patients we would

21   like to get the answer, it would take so many years by that

22   point the technology would be archaic.

23               Mr. McCarley?

24               MR. McCARLEY:   Just one comment.   There is
25   always an ongoing postmarket surveillance on products.
                                                                     224

1    Every year we have an annual report in all products, and

2    especially implants, where we essentially divide the number

3    of adverse events we've had by the number of implants that

4    have taken place.    So if we saw any increase in it, the FDA

5    would immediately take action or we'd have to justify why

6    that would be.

7                   So I agree for the purpose of making an initial

8    decision for a PMA, you might not have all the information,

9    but you certainly have the mechanism in place to continue

10   to monitor any higher rates.

11                  DR. WEISS:    Dr. Grimmett?

12                  DR. GRIMMETT:    Dr. Grimmett.   I would counter

13   that by saying that postapproval, there is probably

14   significant underreporting of adverse events.

15                  DR. MATOBA:    We're going to collect data on

16   both eyes, right?    So for events, specific events, that

17   would become available to the FDA, wouldn't it?       On twice
18   as many eyes potentially as 300?

19                  MS. LOCHNER:    Right, but the statistical

20   assumptions that, for example, would be inherent in this

21   table would then have to be adjusted.

22                  DR. MATOBA:    From a practical point of view,

23   but in terms of missing something terrible, it's not as bad

24   as she says.
25                  MS. LOCHNER:    I think from a practical
                                                                  225

1    standpoint, I hear you.    I mean, you will have more eyes

2    from a practical standpoint.

3                But I think the issue with phakic IOLs isn't

4    missing something catastrophic early on, but missing a slow

5    bleed that's occurring over time and approving it without

6    understanding that the rates could be higher.

7                DR. WEISS:    Dr. Bullimore?

8                DR. BULLIMORE:     Reasonable assurance of safety.

9     That's what we're asked for.

10               DR. WEISS:    I guess that's the difference

11   between the 300 and the 3,000.

12               DR. BULLIMORE:     Exactly.

13               I have one other issue on the endothelial cell

14   count which I've hinted at before and I'll come back to.

15   When these data are presented, I think it will be

16   appropriate not only to have the mean rate of loss, whether

17   you give that annually, but I think over a three-period,
18   knowing the proportion of eyes that have lost 10 percent,

19   20 percent, and 30 percent of endothelial cells -- I mean,

20   I'm sure a reviewer's going to ask for that information,

21   but prospectively it should be at the forefront of the

22   analyses.

23               DR. WEISS:     I wanted to find out if the agency

24   had any other questions for the panel at this point.
25               MS. LOCHNER:    No, just if there are any other
                                                                     226

1    comments on any other sections of the guidance.

2                   One of the things that I think I took away from

3    the earlier discussion on contrast sensitivity is that we

4    may need to provide to vision scientists some of the data

5    upon which we came to this conclusion about contrast

6    sensitivity, and so we may follow up with a homework

7    assignment to look at that because it's possible, first of

8    all, that we're misinterpreting what we're looking at, and

9    so we took those contrast acuity comments especially to

10   heart if we are in fact doing that.

11                  DR. WEISS:    Dr. Matoba had a comment.

12                  DR. MATOBA:    I had a question about the

13   guidance.   Number 5, study population.         This is phakic IOLs

14   for myopes, specified minimum uncorrected visual acuity

15   20/40 or worse, meaning you could have myopia uncorrected

16   visual acuity of 20/40 and then be eligible to get into the

17   myopic phakic IOL study?       Twenty/forty doesn't seem
18   compatible with high myopia.

19                  DR. EYDELMAN:    Dr. Eydelman.    This is for all

20   phakic IOLs.    As Donna has mentioned previously, current

21   studies are not limited to high myopia.         So we have phakic

22   IOLs for -2 and -3.

23                  DR. WEISS:    So would any members -- and I'm

24   going to regret asking this question.
25                  (Laughter.)
                                                                        227

1                  DR. WEISS:    Briefly, would any members of the

2    panel -- or actually, even more importantly, does the FDA

3    care whether the panel wants it to be 20/40 or not or it's

4    irrelevant?

5                  MS. LOCHNER:     We care.

6                  DR. WEISS:    You care.     That's too bad.

7                  (Laughter.)

8                  DR. WEISS:    So do any members of the panel have

9    any disagreement with doing a phakic IOL for someone who's

10   20/40?

11                 DR. BULLIMORE:    I'm having a senior moment.

12   You were talking about excluding patients with entering

13   visual acuity of worse than 20/40?

14                 DR. WEISS:    Twenty/forty uncorrected.       It's

15   uncorrected visual acuity of 20/40.        I want my 20/40 --

16                 DR. MATOBA:    Would make you eligible to get in

17   the study.
18                 DR. WEISS:    Would make you eligible to have a

19   phakic IOL at this point.

20                 DR. GRIMMETT:    This is Dr. Grimmett.     You're

21   using the 20/40 as a marker for your refractive error.

22                 DR. WEISS:    It's about a -1, isn't it?

23                 DR. GRIMMETT:    Yes.   You're really asking the

24   question should patients with low myopic or low refractive
25   errors be entered into trials that have significant risks
                                                                     228

1    that we've discussed today of cataracts, endothelial cell

2    loss, pigment dispersion, glaucoma, et cetera?

3                DR. WEISS:     And at the present time, they are

4    being entered into this.

5                Dr. Mathers?

6                DR. MATHERS:     I think they should not be

7    entered into this study.    We should have a cutoff that is

8    much higher than that for patients to enter the study.

9                DR. WEISS:     Okay.    So what would your cutoff

10   be?

11               DR. MATHERS:     Minus 8.

12               DR. WEISS:     That's pretty high.

13               DR. MATHERS:     Maybe -6.    I mean, -6 is very

14   treatable with most LASIK procedures.

15               DR. WEISS:     So you would come down to a -6.

16               DR. MATHERS:     Yes.

17               DR. WEISS:     Dr. Swanson, do you have an opinion
18   on this?

19               DR. SWANSON:     Well, I have an opinion on most

20   things, but I agree that we're talking about something that

21   has -- we want to determine what the risks are, so it makes

22   sense to look at the population that's supposedly to be

23   served by this risky procedure.

24               DR. BULLIMORE:     I have a question related to
25   the question.   I think if we start prefacing entry criteria
                                                                 229

1    and say, well, this population can be adequately served by

2    other technology, we're actually entering a very dangerous

3    bias zone.

4                 A question for the folks who do this kind of

5    thing.   In terms of the safety of the device, are there any

6    a priori reasons why endothelial cell count, contrast

7    sensitivity loss, and lens opacifications would expect to

8    be greater in a low myope compared to a high myope or vice

9    versa?

10                DR. WEISS:   I don't think they would be, but I

11   think the concern is why make the cutoff at 20/40?    Why not

12   do it at 20/25?

13                DR. BULLIMORE:   Yes.   Well, I agree that -1 is

14   perhaps a little too conservative, but I don't think we

15   should say, well, we approved LASIK up to -6.     That should

16   be our cutoff.

17                DR. WEISS:   You know what?   I think what you're
18   hearing, and obviously this discussion could go on for a

19   while, but I think some members of the panel have a concern

20   that the low myopes, the risk/benefit ratio might not be

21   the same as in the high myopes, and where you would draw

22   that line would be up to discussion.    Perhaps it would it

23   be appropriate for these IDEs to first do a higher group of

24   myopes, and when there is proven to be some sort of
25   clinical safety and efficacy, then expand the trial to the
                                                                 230

1    lower myopes.

2                 Dr. Eydelman?

3                 DR. EYDELMAN:    Malvina Eydelman.   That is

4    exactly what I was trying to make a point of, that we

5    usually allow brand new phakic IOLs only in the higher

6    degrees of myopia, and once the sponsor obtains enough

7    safety information on the high myopes and submits it to

8    FDA, then internally we review it and decide that is

9    sufficient, and we allow lower ranges.    Again, depending on

10   safe we assess it to be, that's the degree of myopia that

11   we allow it to go down to.

12                DR. WEISS:   Mr. McCarley?

13                MR. McCARLEY:    Just very quickly, I agree with

14   it.   I think that it's prudent to study higher myopes,

15   develop a level of confidence and safety, and then move

16   down, but I would ask I guess a question about LASIK,

17   another refractive technology that apparently is now safe
18   and effective, though from what we heard yesterday morning

19   or at the beginning of this session, it may not be

20   completely true when you have large numbers of patients.

21                Aren't there lasers approved right now for -15,

22   for instance?   I think so.

23                DR. WEISS:   There are, but I don't think

24   they're being used for it.
25                MR. McCARLEY:    They're approved for it.   That's
                                                                   231

1    what I'm saying.   So it's sort of a double standard and I

2    agree we all think of phakic intraocular lenses as treating

3    high myopia, and in fact, if you look at the means of the

4    data that's presented at the American Academy of

5    Ophthalmology and ASCRS, you'll see that that's up around

6    the 12, 13.

7                  But in fact, this may be a replacement

8    technology.   There may be benefits we don't know over

9    LASIK.

10                 DR. WEISS:   Dr. Swanson?

11                 DR. SWANSON:   Good.   Thanks.   I've been

12   promoted.

13                 Well, I think the one question to consider

14   there is, in terms of effectiveness, one of the

15   effectiveness criteria is percentage of eyes that achieve

16   uncorrected visual acuity of 20/40 or better.      So if there

17   are a lot of people enrolled that are just worse than --
18   that are 20/50, that effectiveness is not going to mean as

19   much.    So that's something in terms of study design.      The

20   safety may not be different across eyes, but the

21   effectiveness should be considered.

22                 DR. WEISS:   Does the agency have any other

23   questions?

24                 (No response.)
25                 DR. WEISS:   I want to thank the panel and the
                                                                  232

1    presenters and the agency for all their work and excellent

2    preparation, and Sally will have some closing comments

3    before we end the meeting.

4                  MS. THORNTON:   I, too, would like to add my

5    thanks to the panel, and to Drs. Werner, Edelhauser, and

6    McCarey for being with us today.    It's been quite a

7    contribution you've given to our proceedings, and I thank

8    the panel for all their hard work for yesterday as well.

9                  I will be letting you know about mid-September

10   what the story is for the November 14-15 tentative panel

11   meeting schedule.   So stay in touch with your website.

12                 DR. WEISS:   The meeting is closed.

13                 (Whereupon, at 2:03 p.m., the meeting was

14   adjourned.)

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