UNITED STATES OF AMERICA

 

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           FOOD AND DRUG ADMINISTRATION

        MEDICAL DEVICES ADVISORY COMMITTEE

 

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         OPHTHALMIC DEVICES ADVISORY PANEL

                   106TH MEETING

 

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                      FRIDAY,

                  OCTOBER 3, 2003

 

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

 

PRESENT:

 

JAYNE S. WEISS, MD., Chair

ARTHUR BRADLEY, Ph.D., Member

MICHAEL R. GRIMMETT, M.D., Member

ALICE Y. MATOBA, M.D., Member

TIMOTHY T. McMAHON, O.D., Member

ALLEN C. HO, M.D., Member

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

KAREN BANDEEN-ROCHE, Ph.D, Consultant,

                     deputized to vote

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

                     deputized to vote

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

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

                     deputized to vote

JAMES P. McCULLEY, M.D., Consultant

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

                     deputized to vote

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

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

                     Acting Industry Representative

SPONSOR'S PRESENTERS:

 

HENRY F. EDELHAUSER, Ph.D

HELENE LAMIELLE, M.D.

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

STEVEN G. SLADE, M.D.

JOHN A. VUKICH, M.D.

 

FDA PARTICIPANTS:

 

A. RALPH ROSENTHAL, M..D.

GERRY W. GRAY, Ph.D.

DONNA R. LOCHNER

MALVINA B. EYDELMAN, M.D.

SARA THORNTON

 

OPEN PUBLIC HEARING SPEAKER:

 

CAPT. STEVEN C. SCHALLHORN, M.D.

 


                  C-O-N-T-E-N-T-S

 

Call to order................................... 5

 

Introductory Remarks............................ 5

 

FDA Presentation............................... 13

 

Open Public Hearing............................ 15

 

Open Committee Session......................... 26

 

Division Update................................ 26

 

Branch Updates................................. 31

 

PMA P030016

      Sponsor Presentation

      Helene Lamielle, M.D..................... 32

      Steven Slade, M.D........................ 34

      John Vukich, M.D......................... 44

      Henry Edelhauser, Ph.D................... 55

 

      Panel Questions for Sponsor.............. 69

 

      FDA Presentation

      Donna Lochner........................... 120

      Malvina Eydelman, M.D................... 128

      Gerry Gray, Ph.D........................ 138

 

Panel Questions for FDA....................... 154

 

Additional Comments from the Sponsor.......... 169

 

Committee Deliberations

      Primary Panel Reviewers

      Dr. Marian S. Macsai‑Kaplan............. 174

      Dr. Joel Sugar.......................... 187

      Dr. Michael R. Grimmett................. 192

 

Panel Discussion of PMA P030016............... 219

to Include FDA Questions to the Panel

 

 

                  C-O-N-T-E-N-T-S

 

FDA ‑ Closing Comments........................ 374

 

SPONSOR ‑ Closing Comments.................... 374

 

Voting Options Read........................... 384

 

Panel Recommendation Takes by Vote............ 422

 

Polling of Panel Votes........................ 426

 

Meeting Adjourned............................. 432


               P-R-O-C-E-E-D-I-N-G-S

                                       (8:34 a.m.)

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

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

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

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

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

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

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

            MS. SUCH:  Glenda Such, Consumer Representative.

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

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

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

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

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

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

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

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

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

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

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

            DR. COLEMAN:  Anne Coleman, UCLA.

            DR. ROSENTHAL:  Ralph Rosenthal, FDA.

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

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

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

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

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

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

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

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

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

            DR. ROSENTHAL:  I do thank you very much.

            DR. WEISS:  That's very important.

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

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

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

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

            (Applause)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. WEISS:  Thank you, Dr. Schallhorn.

            (Applause)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. WEISS:  Thank you.  Donna?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            Cells need to be grouped into form in a contiguous area and then after you have dotted all the cells, it's extremely important that the evaluator or the reader check to see that the cells haven't been double-dotted or cells missing because if you miss three cells, you have a significant change in the end of field cell density because what you see from this specular micrograph is multiplied by 106.  Precision of the readings is an important factor in the analysis of any endothelium.  We have estimated that the precision to be two percent in the ideal situation which was published in our study of LASIK patients.  In this particular case we had one single clinical site, photographer and one single reader.  When you undertake multi-center study where you have numerous photographers and then you then send this to a reading center and one single reader, the precision is somewhere between eight to 10 percent.

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

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

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

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

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

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

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

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

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

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

            DR. GRIMMETT:  Thank you.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. WEISS:  Please identify yourself.

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

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

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

            DR. MACSAI:  Thank you.

            DR. WEISS:  Dr. Grimmett?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. EDELHAUSER:  Yes.

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

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

            DR. SUGAR:  I'll limit myself.

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

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

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

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

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

            DR. WEISS:  Yes.

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

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

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

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

            DR. WEISS:  Dr. Bandeen-Roche?

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

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

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

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

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

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

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

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

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

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

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

            DR. BANDEEN-ROCHE:  Thank you.

            DR. WEISS:  Dr. Matoba?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. MATHERS:  Thank you.

            DR. WEISS:  Dr. Schein?

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. SCHEIN:  Correct.

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

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

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

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

            DR. WEISS:  Dr. Grimmett.

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

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

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

            DR. SLADE:  `98.

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

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

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

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

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

            DR. SLADE:  It was not a required examination.

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

            DR. VUKICH:  Yes, it was.

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

            DR. VUKICH:  It was not.

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

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

            DR. GRIMMETT:  Okay.

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

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

            DR. VUKICH:  The same ones you are.

            DR. GRIMMETT:  Oh, okay.

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

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

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

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

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

            DR. GRIMMETT:  Okay, thank you very much.

            DR. WEISS:  Dr. Coleman?

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

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

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

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

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

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

            DR. WEISS:  Dr. Macsai?

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

            DR. EDELHAUSER:  No problem.

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

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

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

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

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

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

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

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

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

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

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

            DR. MACSAI:  But they were replaced.

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

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

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

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

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

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

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

            DR. WEISS:  Dr. Ho.

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

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

            DR. HO:  Is there anything in the literature?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. VUKICH:  Correct.

            DR. WEISS:  Dr. Grimmett?

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

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

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

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

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

            DR. SANDERS:  Yes.

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

            DR. WEISS:  Thank you.  Dr. Mathers?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. EDELHAUSER:  Yeah.

            DR. WEISS:  Okay.

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

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

            (A brief recess was taken.)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            Now, Dr. Eydelman will present the clinical questions.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. GRAY:  Two or more, yes.

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

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

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

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

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

            DR. GRIMMETT:  Okay, thank you. 

            DR. WEISS:  Dr. Bradley?

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

            DR. GRAY:  Yes.

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

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

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

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

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

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

            DR. BANDEEN-ROCHE:  Yes, yes.

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

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

            DR. BANDEEN-ROCHE:  Okay, thank you.

            DR. WEISS:  Dr. McCulley?

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

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

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

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

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

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

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

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

            DR. WEISS:  Dr. Mathers?

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

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

            DR. MATHERS:  Right, okay. 

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

            DR. MATHERS:  Right.

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

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

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

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

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

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

            MS. LOCHNER:  Oh, yes, yes.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. VUKICH:  Pardon me?

            MS. THORNTON:  Are you ready?

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

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

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

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

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

            DR. WEISS:  Thank you for making it brief.

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

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

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

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

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

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

            DR. MACSAI:  I'm done.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. WEISS:  Dr. Macsai.

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

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

            DR. MACSAI:  Well, I did.

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

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

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

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

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

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

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

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

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

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

            DR. WEISS:  Dr. McCulley.

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

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

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

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

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

            DR. WEISS:  Dr. McCulley.

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

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

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

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

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

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

            DR. SCHEIN:  Okay.

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

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

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

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

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

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

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

            (Vote taken.)

            DR. WEISS:  So I think that's ‑‑

            SPEAKER:  Is this a reduction, Jayne?

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

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

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

            DR. SUGAR:  Corrections to treatment.

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

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

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

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

            DR. WEISS:  Dr. Coleman.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            DR. SUGAR:  If they have such information.

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

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

            DR. WEISS:  I know.  Intentionally.

            DR. McCULLEY:  Okay.

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

            DR. McCULLEY:  You pretty much rusted his wrench.

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

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

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

            DR. WEISS:  That's dangerous around here.

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

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

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

            DR. WEISS:  Dr. Grimmett.

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

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

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

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

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

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

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

            DR. WEISS:  Dr. Schein.

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

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

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

            DR. WEISS:  Dr. Sugar.

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

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

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

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

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

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

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

            DR. WEISS:  What did you intend?

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

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

            DR. MACSAI:  I want to suggest ‑‑

            DR. WEISS:  You suggest, okay.

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

            SPEAKER:  For what time?

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

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

            DR. MACSAI:  Annually for five years.

            SPEAKER:  Oh, annually.

            DR. MACSAI:  Is that what you want?

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

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

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

            DR. ROSENTHAL:  Did I make myself clear?

            DR. WEISS:  Malvina.

            SPEAKER:  You put people at medical legal risk.

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

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

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

            DR. WEISS:  Dr. Sugar and then ‑‑

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

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

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

            DR. WEISS:  Dr. Ho.

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

            SPEAKER:  Yes.  Routine.

            SPEAKER:  yeah.

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

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

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  When it was reimbursable ‑‑

            DR. WEISS:  Dr. Macsai.

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

            DR. HO:  Furthermore ‑‑

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

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

            DR. WEISS:  Dr. McCulley.

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

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

            (Vote taken.)

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

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

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

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

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

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

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

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

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

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

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

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

            DR. WEISS:  Dr. Bradley.

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

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

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

            DR. WEISS:  Dr. Grimmett.

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

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

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

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

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

            DR. BANDEEN‑ROCHE:  Sorry.

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

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

            DR. BANDEEN‑ROCHE:  Thank you.

            DR. WEISS:  Dr. McCulley.

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

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

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

            DR. WEISS:  Dr. McCulley.

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

            DR. GRIMMETT:  Anyway, enough.

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

            DR. ROSENTHAL:  Vote.

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

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

            DR. WEISS:  At this point?

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

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

            DR. ROSENTHAL:  Yeah.

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

            DR. EYDELMAN:  It's actually above 3.

            DR. WEISS:  Above 3.

            (Vote taken.)

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

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

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

            (Vote taken.)

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

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

            DR. WEISS:  Fine.

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

            DR. WEISS:  That's fine.

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

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

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

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

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

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

            DR. BRADLEY:  Let Karen answer that.

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

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

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

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

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

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

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

            DR. ROSENTHAL:  With all kinds of devices.

            DR. McCULLEY:  All right.

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

            DR. ROSENTHAL:  Wait.

            DR. WEISS:  Yes.

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

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

            DR. ROSENTHAL:  No.

            DR. McCULLEY:  I think that is opinion ‑‑

            DR. MACSAI:  That's my opinion.

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

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

            (Laughter.)

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

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

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

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

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

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

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

            DR. McCULLEY:  For which purpose?

            DR. WEISS:  For both.

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

            DR. WEISS:  So you would like ‑‑

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

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

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

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

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

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

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

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

            DR. McCULLEY:  Right.

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

            DR. McCULLEY:  Yes.

            DR. WEISS:  Okay.  Dr. Mathers.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

            (Vote taken.)

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

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

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

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

            DR. McCULLEY:  I think five is reasonable.

            DR. WEISS:  An additional five years?

            DR. McCULLEY:  No.

            DR. WEISS:  Total of five years.

            DR. McCULLEY:  Total of five years.

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

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

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

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

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

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

            DR. SUGAR:  With specular microscopy.

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

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

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

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

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

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

            DR. McCULLEY:  Post.

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

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

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

            DR. SUGAR:  Yes.  I mean ‑‑

            DR. WEISS:  Post‑market.

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

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

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

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

            DR. McCULLEY:  I would agree with Joel, but to put it back more broadly for Ralph, I mean, if it's not approved, then we would request that ‑‑ or recommended for approvable, that they be followed annually.  If we do recommend approvable, which I too would ‑ not being a voting ‑ not going to get to vote, but I would.  And I would be comfortable with that, and I would say then, I would prefer this ‑‑ as I said, I'd be comfortable with a recommendation for approvable with a post‑market surveillance annually of that initial cohort.  You had pre‑ops for a total of five years.

            DR. WEISS:  Dr. Mathers.

            DR. MATHERS:  When you say "approval" there, you're talking about three different groups here, and they are very different.  You have myopes for minus 3, myopes for 15 to 20.

            DR. WEISS:  We're going to get to that in a moment.

            DR. MATHERS:  Okay.  But that's ‑‑ I mean ‑‑

            DR. WEISS:  We're just talking about the specular microscopy portion, and then in terms of the different categories, we will be getting to that.  Have no fear.

            DR. MATHERS:  Okay.

            DR. WEISS:  Dr. Macsai.  And I'd sort of like to wrap‑up this.  Dr. Macsai, then Bandeen‑Roche, and then I'd like to wrap‑up this particular issue.  Yes.

            DR. MACSAI:  I agree with Joel about post‑market surveillance.  I would add two comments.  One, if approvable, it's got to be labeled that this stability has not been documented, and it's got to be an education for patients and physicians.  And if data comes out later that shows there's massive problems, the FDA has an obligation to take an action.

            Number two, if perhaps we're all wrong, and we don't have to wait until 2007, and at 2006 the biostatisticians, or 2005, the biostatisticians say hey, this was much ado about nothing, then the labeling be changed at that point, and we accept the statistician's interpretation that it is, in fact, stable.

            DR. WEISS:  With that in mind, if you want to put in labeling that stability of endothelial cell loss has not been documented, would you want to put a warning in there that there could be risk of corneal edema or no?  Dr. McCulley.

            DR. McCULLEY:  I don't remember well enough.  There are different implications to these words, and I don't ‑‑

            DR. WEISS:  Dr. Rosenthal.  Would it be fair, if we're going to be putting in labeling that there is no documentation of a stabilization point as far as endothelial cell loss by specular microscopy, would it be fair to put in labeling there could be the risk, or the risk of corneal edema is undefined.  Or because it's undefined, we shouldn't say it?

            DR. ROSENTHAL:  That's the panel's decision.

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  I don't ‑‑ we don't have corneal edema.  We don't have one patient yet with corneal edema.  What we have is ‑‑

            DR. WEISS:  Well, that's what we're talking about, isn't it?

            DR. MACSAI:  Right.  But no ‑‑

            DR. WEISS:  That's what we're afraid of.

            DR. MACSAI:  No, what we're talking about is long‑term endothelial cell loss.  So what we say is that the data and the outcomes and long‑term effects on the endothelium are unknown.

            DR. WEISS:  But for patient labeling, I think you'd have to put that in terms that it means something to someone, because endothelial cell loss doesn't have any significance to a patient.  And I would maybe defer this one to Glenda Such.

            MS. SUCH:  Yes.  I was just going to say, I don't know if this belongs in the labeling section of our discussion or not, but I was going to say there should be something at least at the bottom of the precautions that says something about the fact that no information is known about this beyond four years.  Whether or not it's regarding this issue or any of the issues.

            DR. WEISS:  So maybe we'll get back to that when we get back to labeling.  When we're talking about ‑‑ so we've talked about, and I think hopefully to your satisfaction, we've talked about a post‑ market study, and following the cohort.  Does anyone want what's suggested, taking another fresh cohort of patients who are having this done after, if it gets approved, after approval, and following these patients.  Does anyone want that?

            DR. SCHEIN:  May I make another comment?

            DR. WEISS:  Dr. Schein.

            DR. SCHEIN:  What is the logic of having a post‑market surveillance study for an extended wear contact lens where not a single ulcer is seen in a pre‑market trial?  The logic is that there's a concern about the particular end‑point, which requires a different kind of study.  And I think the situation is exactly analogous.  We have a new kind of device.  We don't have any historical data to rely on.  The situation is analogous to the way the rigid anterior chamber lenses were when ophthalmologists were putting them in their mothers, which is just after the pre‑market approval.  There was a lot of excitement, so I think to not set up some mechanism that's an early warning is completely irresponsible on our part.  And I do believe it's the industry's responsibility, if they want to introduce these kinds of products.

            The idea is not to stifle innovation.  As you'll see, I'm going to be voting for approval.  But the idea is to set up a mechanism that we can trust to either restrict labeling in the future, pull back the product, or to provide very sound information about its safety.

            DR. WEISS:  Well, in that case I think what we'll do is we'll confine that one to labeling.  If anyone else wants to comment on specifically a labeling issue.  Dr. Matoba.

            DR. MATOBA:  In the case of the contact lens issue, that we had an indication from your study that there was a certain risk for microbial keratitis, and here we don't have any information that there is that type of calamitous outcome that could occur, so here you'd be fishing.

            DR. SCHEIN:  The rate of retinal detachment is higher in this study is higher than ulcerative keratitis was in any of the other studies.  The rate of cataract is higher, so it's not just corneal edema.

            DR. WEISS:  Dr. Bandeen‑Roche, then Dr. McCulley, then Dr. Mathers, then Dr. Sugar.  Not Dr. Sugar.

            DR. BANDEEN‑ROCHE:  If you want to defer this to the safety discussion, that's fine.  But I have to at least raise it now, which is that we saw no hint of stabilization through three years.  I mean, it was just, you know, all of the year‑to‑year changes were pretty even.  So suppose the data come in, and my overly pessimistic tendencies for once, you know, bear out, and we see exactly the same continuing rate of decline, once all of the data are in.  Would you then declare the product safe and go ahead?

            DR. WEISS:  Dr. McCulley.

            DR. McCULLEY:  Yeah.  Could we ask maybe the FDA to respond to that?  And could we also ask the FDA to respond to Oliver's suggestion for ‑‑ I don't ever recall a discussion at a panel, at least that I've been at, where that kind of study post‑market surveillance, or whatever the term would be for that particular one, would come up.  I'd like to hear what the FDA says about both of those issues in terms of authority and practicality.

            DR. ROSENTHAL:  We have a member of the staff from the Office of Science and Biometrics who's ready to address this issue for you.  Dr. Roselie Bright.

            DR. BRIGHT:  One minute.

            DR. ROSENTHAL:  I still ‑‑ while Dr. Bright is getting ready, you still have to decide whether you want this fourth and five year data on the existing cohort before it goes to market, so you have assurance of ‑‑ a reasonable assurance of safety and efficacy.  Or do you have that reasonable assurance of safety and efficacy now, and the follow‑up can occur after it is put on the market.  That is different than this type of approach, which is in addition to the follow‑up of the endothelial cell.

            DR. WEISS:  So I think what Dr. Rosenthal is pointing out is we've put the cart before the horse.

            DR. ROSENTHAL:  A little bit.

            DR. WEISS:  And that if everyone is in agreement that we have no evidence there's stabilization of endothelial cell loss, then is anyone in the panel bothered by the potential of a continued cell loss rate of 2 percent per year in these patients.  And if anyone in the panel is bothered by that fact, how do you justify that, or explain that, or accept that?

            DR. McCULLEY:  Jayne, I've said it before and I'll say it again.  We don't have the solid data.  We need more data.  My sense of this, based on everything including my broad clinical experience and past history with things, is that I would be comfortable enough with this being recommended for approvable.  But to further give us assurance and comfort that we follow it post‑market.

            DR. WEISS:  Then I would ask you, Dr. McCulley, can you explain to the panel why you're comfortable with approval?  What factors about this PMA in the face of no documentation of stabilization of the cell loss make you comfortable with approving this?

            DR. McCULLEY:  Okay.  I don't think there's no documentation.  I think there's suggestion that there is, but I don't think there's proof.  And the suggestion to me is that we have stabilization in the cell size, variability in shape, and that it does appear that with a limited number of patients that the cell loss between years three and four is leveling off.  And I've seen ‑‑ and in the absence of any apparent known reason for continued endothelial cell loss, absence of any known mechanism to support continued endothelial cell loss, those give me the degree of comfort that I think this is reasonable.  But do I think I have data that would let me nail that down if I wanted to switch sides and argue it the other way?  No.  But I think that it would be reasonable to try to gather more data to give more comfort to everyone else, and to myself.  I could be wrong.  I don't think I am, but I have reasonable comfort, but I don't have as solid a data ‑‑ if I did, we wouldn't be having this discussion.

            DR. WEISS:  But the question for the panel really now is whether there should be pre‑market data or post‑market data, if there's ‑‑

            DR. McCULLEY:  And what I'm saying is, I think we have sufficient assurance now to recommend approvable with continued surveillance post‑market.

            DR. WEISS:  Dr. Mathers, and then Dr. Macsai, and then Dr. McMahon.

            DR. MATHERS:  well, finish this discussion.  That goes more to Oliver's question.

            DR. ROSENTHAL:  Finish your discussion about this.

            DR. WEISS:  Finish our discussion, and then go forward.

            DR. ROSENTHAL:  And then we'll move on.

            DR. MATHERS:  It's a philosophic point.  You're saying that we don't know, so let's go ahead.  I would say we don't know, so let's make sure before we go ahead.  And again I'll say that I don't think that what we say about minus 10 to 15, or 15 to 20 applies to what we say about the 3 to 10.  But in the absence of some indication of safety in this regard, I think going ahead is not the correct answer.

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  If you look at my review, I didn't make a slide of this ‑ I'm sorry.  I did make a table of the rate of annual endothelial cell loss, assuming a pre‑operative mean count of 2,657, which was the pre‑operative mean endothelial cell count here.  And if we take the average loss, I'm not going to argue with Mike or Bill Bourne, but if you take the average loss at .6 percent by natural attrition, that would mean you'd lose 15.9 cells per year.

            In that August `02 panel meeting that Dr. Grimmett did his report on, he said 1.5 percent would be okay.  And that's 39.8 cells per year.  This PMA has 1.8 percent, which is 48 cells per year.  And then the ANSI Standard is set at 2 percent, which would be 53.1 cells per year, so this PMA lies right smack dab in the middle between the recommendations of the August `02 panel meeting, and the ANSI ‑ which was 1.5 percent, and the ANSI guidance document referred to, which was 2 percent.  So at 1.8 percent, it ain't bad.  I just don't know if it's going to be bad in the future, so I think looking at these patients to five years is prudent.

            I guess my question to ‑‑ I have another question I just want to ask Dr. Schein, since I can't ask him private, is ‑ what if you look at this cohort for five years, this endothelial cell counted cohort for five years to see about retinal detachments, and cataracts, and I forgot what else you said.  Would that answer your question?  No?

            DR. WEISS:  Dr. Schein.

            DR. SCHEIN:  The reason it wouldn't answer the question is, one, sample size; and two, representativeness, the latter being more important.  So I would want some sample of patients that are actually getting the device post‑market, and some sample of surgeons that are doing it.

            DR. MACSAI:  Oh, to see who performs the same?

            DR. SCHEIN:  Absolutely.  And also a larger number, but not for cell counts.  That's a different story.  That's a longer term issue.

            DR. WEISS:  Dr. McMahon.

            DR. McMAHON:  This is to Ralph, and this is sort of a semantics question, because we're dealing with a situation with regard to endothelial cell loss, where we kind of don't know.  And so the obligation of the panel of voting on safety and efficacy, one can be that we have to have reasonable assurances that the device is safe, versus reasonable assurance that it's not unsafe.

            DR. WEISS:  Well, the way it reads is "reasonable safety and efficacy".

            DR. McMAHON:  Yeah, but I want to know the spirit of that view, because it makes a difference on how I would vote.

            DR. WEISS:  Well, I'll call on our spiritual counselor, Dr. Rosenthal.

            (Laughter.)

            MS. THORNTON:  Ralph, could you speak into the microphone, please.  We want to get this one.

            MR. ROSENTHAL:  The reasonable assurance of safety and efficacy.

            DR. WEISS:  Okay.  So with this in mind, since it seems ‑‑ from what I understood from the vote before, most of the panel members didn't feel the stabilization was ‑‑ the data showed stabilization.  Do most of the panel, even with that fact, would most ‑‑ those panel members who would feel that there is still ‑‑ this is still reasonably safe to have a post‑market study, and go ahead with approval under any means, or we're not talking about what type or whatever, in terms of labeling or other issues.  What number ‑‑ if you could raise your hands.

            DR. ROSENTHAL:  Excuse me, Dr. Weiss.  It's a post‑market follow‑ up of the existing IDE subjects.

            DR. WEISS:  Fine.

            DR. ROSENTHAL:  That's very different than a post‑market study of another group of patients.

            DR. WEISS:  So we're talking post‑market study in order to get further data, and approval with the information we have at the present.  At the present point, and we haven't gone through the other issues, the members of the panel who would ‑‑ yes.

            DR. BRIGHT:  Well, I have a presentation that goes over what's appropriate for pre‑market, what's appropriate after the device is allowed on the market, what you can get in a pre‑market setting versus condition of approval, versus post‑market.  And that might short‑circuit some of the questions.

            DR. WEISS:  Okay.

            DR. McCULLEY:  Jayne, can I say one thing, and I do want to hear what she has to say.

            DR. WEISS:  Yes.

            DR. McCULLEY:  In response to Bill's philosophical question, the issue is do we have reasonable assurance of safety and efficacy.  I think we do.  I don't think we have absolute, and I would like to go ahead and get the absolute.  That's the reason for requesting additional surveillance.  I think we have reasonable, but it's not absolute.

            DR. WEISS:  Would I be able to ‑‑ just in the interest of time, would you be able to show whatever that you have that speaks specifically to the choice of studies the panel might have, as opposed to the background information that you might have, that we could look at concrete stuff as far as what our choice in terms of studies that we might recommend?

            DR. BRIGHT:  Well, I have two concrete choices, but I want to lead up why I got there, if that's okay.

            DR. WEISS:  If you can make a quick lead‑up.

            DR. BRIGHT:  I'm covering many slopes.  Okay.  Well, the disclaimer is that just because I'm presenting about those market studies, doesn't mean that I think it's approvable right now, but it would apply even if there was a later discussion about approvability.

            The reasons for doing post‑market assurance would be that the study population for the pivotal study is small, and not large enough to detect the potentially serious adverse events.  And the study population for the pivotal study is highly selected.  It doesn't include vulnerable sub‑populations.

            The study duration is typically shorter in real‑world exposure, so we've been talking about the 3 and 4 year effects, versus 30 and 40 years.  And it can detect problems due to improper or unskilled use of the device in the real‑world.  And study centers ‑‑ but the study centers that you already have the data from are typically highly skilled and motivated.

            And another general reason is to detect adverse events due to drug‑device, or device‑device interactions that would not be detected in controlled studies.  So questions that might need to be addressed for this particular device are the longer term decline in endothelial cell count, long term development of cataract.  Dr. Schein mentioned some other outcomes.

            Some issues for phakic IOLs is the prior history in the 1980s with an implantable lens that was associated with safety concerns after 10 years of use, so we would want ‑‑ might want an earlier warning system.  And PIOLs could be implanted in a large number of young adults with moderate vision problems.  And, therefore, in the worst case scenario, there's a potential for a large number of middle aged to elderly adults needing corneal transplants.

            So what are the three authorities we have for requiring studies?  We have the pre‑market authority, the study has to be done in order for the device to get to market.  But the disadvantage is a small sample size and short follow‑up time.  The condition of approval study is one where the approval is conditional until the results of that study are satisfactory, but you have to order it before the device even gets the conditional approval.  And the post‑market surveillance study, we can order that study any time, but patient and physician approval is the most difficult during that time because the device is freely available.

            So in considering the type of conditional approval study, it has to be least burdensome.  We can consider any appropriate study design, and it does not need to be simply an extension of the pre‑ market study.  The sponsor could be asked to report progress and results to the panel each year if the panel desires, and the sponsor can use the results to change the labeling and marketing.

            So there are two main types of observational study designs.  There's case control and follow‑up.  The advantage of the case control study is you can be more efficient with a smaller sample size, but in this instance, I think it's impractical because I think the use of this device is likely to be relatively uncommon.  And you also have to decide in advance what outcomes you're going to look for.

            But in the follow‑up study, you can enroll patients as they get the PIOL, so if it's vastly popular, you get your cohort up and running very quickly.  If it takes longer, then it takes longer to accrue, but that's fine because it's affecting a smaller portion of the population anyway.  You get flexible follow‑up time, and you can discover new outcomes that weren't anticipated.  But the disadvantage is are that you need to minimize the drop‑out rate, and you need a large number of patients.

            We worked out two options.  There's nothing required about any of these, but they're basically discussion and talking points.  The first option was called registry, so you could ask patients at less than one year intervals whether they had an ophthalmic visit for a problem.  And we said less than a year because if we use the mail system, which is considered least burdensome of different kinds of ways you could contact patients, they're forwarding interval is one year.  And you could ask a very simple question, did you have to go to the ophthalmologist.  And then if they say yes, ask for the details for getting their records.  And you could follow as many patients as possible for a decade or more, whatever time period the panel is interested in.

            The advantages are, you can readily describe and identify the population of users in the event that some kind of regulatory intervention is needed.  And it's a relatively inexpensive study.  The disadvantage is that there's no early warning of impending problems.  You get the warning when somebody has the problem that's bad enough to go to the ophthalmologist.

            The other option that could be considered is something called a nested cohort, where you could build on the existing clinical trial population, and then sample some new patients, collect cell counts at baseline and regular intervals.  And have all of the specular microscopy results assessed at a central location for the sake of comparability of results.

            You'd want the sample to reflect the diversity of patients and implanting physicians so that you can get at the real‑world aspects, and follow as many sample patients as possible for 30 years, or whatever time is deemed proper.

            And the advantages of doing this would be that the follow‑up would be concentrated at expert centers, and there would be central reading of the counts.  There would be early warning of cell count decline, and it could be used to detect other adverse events, such as cataract or the other outcomes.

            Disadvantages are you need aggressive persuasion of the sample patients to come in for their visits, and it would be more expensive.  Is there any questions?

            DR. WEISS:  Okay.  Thank you.  What I'd like to do is sort of cut to the chase, because I feel we're ‑‑ the reason we're raising this question, and I couldn't delay it as long as I wanted to, to get to other issues, was because I feared we were going to go around in circles, and that's what's begun to happen.  So what I'd like to do is just address ourselves to the issues of safety to sort of hone down on what our concerns are, as bespeaks the endothelial cell count.

            What I'd like is, those who are concerned that any of these patients, even if they didn't have any other surgery, could develop corneal decompensation, corneal edema from this procedure, I'd like a show of hands for those members of the panel who are concerned that from the data they've seen, these patients could develop corneal edema, at any point down the line.  Are you concerned that that could happen?

            (Vote taken.)

            DR. McCULLEY:  That's an open‑ended question.

            DR. WEISS:  That is an open‑ended question.  So that's true, it is an open‑ended question, Jim.  Then the second question I have for those of you who have that concern, do you think a large percentage of patients ‑‑ are you concerned that a large percentage of patients could develop corneal edema from just the implantation of this device?

            (Vote taken.)

            DR. WEISS:  So you have ‑‑ no one has any ideas on ‑‑ so is that what the safety concern is here?  Because if that's what the safety concern is, then I think we're talking about specifically the loss of endothelial cells, and we should address ourselves to doing a study that addresses that particular concern, which is the loss of endothelial cells.  Is that the concern on the panel, is the loss of corneal endothelial cells?

            DR. MATHERS:  That's one concern.

            DR. WEISS:  That's one concern.  Okay.  So let's address ourselves to that concern.  What ‑‑ is there any problem ‑‑ why ‑‑ would not following the cohort of 306 patients for up to a five year period of time to see if there was stabilization with an additional year, address the concern of loss of endothelial cell count, or why would that not address that concern?  Dr. Mathers.

            DR. MATHERS:  It might or might not, depending on how the data came out.  It would certainly help.

            DR. WEISS:  Dr. Bradley.

            DR. BRADLEY:  It seems we've had a discussion of do the data stabilize or do they not stabilize.  And I wonder whether that's the appropriate question we should be challenging the Sponsor and the FDA with, in terms of this post ‑‑ possible post‑approval analysis.  Mike Grimmett a couple of years ago suggested 1.5 percent per year loss was okay.  The current data is 1.8 percent, I believe.  Is that what Marian said?  A simple statistical question is whether or not the data show a significantly greater decline than the decline that is considered safe.  If the decline is concerned safe as 1.5 percent per year, it becomes a statistical question to analyze the data.  And it may take five years to do that, to show whether or not the data are declining not significantly more than this supposedly safe decline rate of 1.5 percent.  So the issue of stabilization versus not, doesn't seem to be the issue here.  It seems to be whether or not the decline is greater than what is considered safe.  And that becomes a very straightforward statistical question, which surely the Sponsor and the FDA could sort out.

            DR. WEISS:  Dr. Bandeen‑Roche.

            DR. BANDEEN‑ROCHE:  More from a public health point of view, you could state it the other way.  Right?  In other words, you might want to demonstrate that it's at least that safe, you know, that it's no greater than 1.5, rather than just that it's not statistically different than 1.5.

            DR. BRADLEY:  I think that surely that's all one is able to do, to say whether it's statistically different or not.

            DR. BANDEEN‑ROCHE:  Right, but you might want to reverse the Type 1 and Type 2 error, and require evidence that the rate is lower than 1.5, rather than just saying it's not statistically greater.

            DR. WEISS:  Dr. Rosenthal, could we have some help, because I could see we're getting nowhere here.  And we're taking a long time to get nowhere.  Do you have any suggestions for the panel?

            DR. ROSENTHAL:  The panel has to decide whether they want follow‑ up of these patients before they give an approvable.  They can give approvable with conditions, and the conditions can be follow‑up of the patients before it goes on the market, or after it goes on the market.  And give not‑approvable because then that ‑‑ with the same ‑‑ of course, in the not‑approvable situation, it would be because they don't have the data before they give the approvable.

            DR. WEISS:  At the present time, as concerns the issue of endothelial cell loss, can the panel members who feel there is not enough information right now to make a decision on safety before this is released into the market, could raise their hands.  Dr. Matoba.

            DR. MATOBA:  What about if we vote on whether panel members would be satisfied if Sponsors were to follow for an additional amount of time, the patients for whom they have pre‑op endothelial or specular microscopy, and then vote on whether it should be four years or five years.

            DR. WEISS:  Well, the first question that we need to answer, and which the FDA is bringing forth to us, is if we don't have that data, I'm getting ‑‑ I'm not getting a sense from the panel whether that data can be given after this is released into market, or it's a condition for ‑‑

            DR. MATOBA:  But I think we can agree on whether we want ‑‑

            DR. McCULLEY:  Vote on it.

            DR. MATOBA:  I think we can agree on whether we want the data or not.  And then we can decide whether we would be willing to approve or not approve.

            DR. WEISS:  Fine.

            DR. McCULLEY:  We want the data.

            DR. MACSAI:  We want the data.

            DR. WEISS:  Everyone ‑‑

            DR. MATOBA:  Okay.  So but then do we agree that if they follow those patients who had pre‑operative specular microscopy that's adequate, or are we going to ask for something ‑‑

            DR. WEISS:  Well, why don't we just break this down into simple points.  Is everyone in agreement that we would want to get at least five year data for the patients who've had pre‑operative specular microscopy?  Those who are in agreement with that, could you raise your hand?

            (Vote taken.)

            DR. WEISS:  Does anyone want longer than five year specular microscopy or would like the FDA to determine the length of the study depending on what the results of five year microscopy?  Depending on the results of the five year microscopy, that would determine the length of that particular study.

            DR. MACSAI:  Jayne, we can request that that be brought back to panel, that five year data for review, or the FDA can review it.

            DR. WEISS: Well, I think FDA will look at it.  I don't think that has to be ‑‑ if we're ‑‑ well, whether or not it got brought back to panel depends on whether this gets approved with conditions or not, so that's ‑‑ am I correct, Ralph, on that?

            DR. ROSENTHAL:  Yes.

            DR. WEISS:  Yeah.  Okay, so we ‑‑ I think ‑‑

            DR. ROSENTHAL:  It's whether you do not approve it.

            DR. WEISS:  Then it would come back for another go around.  So the panel is in agreement that they would like the cohort that's had pre‑operative specular microscopy, have another specular microscopy done at five years time, and then ‑‑

            SPEAKER:  Annually until five.

            DR. WEISS:  Annually until five years, and then have the FDA determine how long after, in terms of those results.  Now on that basis, what I need to find out from panel is, would that be information that is needed before this gets approved?  And how many of you would require that information before you would feel comfortable voting for saying that this is a safe device?

            DR. GRIMMETT:  Jayne, there's two issues there.  How many would feel comfortable just having year four, or needing both, so there's two parts to that.

            DR. WEISS:  No, I don't want to break it down any further.  We're splicing ‑‑ I'm stating the question.  Actually ‑‑ okay.  I don't ‑ ‑ if we keep on deviating, we're going to be here until tomorrow, which I don't ‑‑ I'd just like to hone in on this particular question.  We've talked about up to five years.  We want specular microscopy.  We've talked about perhaps extending that, depending on what that data shows.  What I just want is a show of hands from the panel, is this needed to vote for approval?  Would you need this data before you would feel that this is approvable, with or without conditions?

            DR. GRIMMETT:  All the way to five, inclusive of everything, needing five.

            DR. WEISS:  So, Mike, you would need five ‑‑  you would need an additional year data before you would approve this?

            DR. GRIMMETT:  No.  I would need four year data as a condition of approval, in order to approve it.

            DR. WEISS:  Okay.

            DR. GRIMMETT:  With five year being a post‑market surveillance.

            DR. WEISS:  Fine.

            DR. GRIMMETT:  That's my position.

            DR. WEISS:  Fine.  Does anyone have a position different than what Dr. Grimmett said?  Dr. Sugar.

            DR. SUGAR:  I would suggest conditional approval with continued acquisition of that data up to five years; that is, this would be a marketable device once the agency approves it, while we're still acquiring that data.

            DR. GRIMMETT:  When they see four year data, ‑‑ just as a clarification, Dr. Sugar, when the FDA sees four year data, and feels that it shows a reasonable level of stability, then it can be approved.

            DR. SUGAR:  Well, no.  It would still ‑‑ it would be conditionally approved, so it would be marketed now.

            DR. GRIMMETT:  Oh, so your's are all post‑market.  Year four and year five are post‑market.

            DR. SUGAR:  Unless I misinterpreted Dr. Bright's statement, that we could conditionally approve it, and it could be marketed with the condition that that data continued to be acquired; that is, this is a marketed device ‑‑

            DR. GRIMMETT:  Isn't that post‑market surveillance?

            DR. ROSENTHAL:  You can do it two ways.  You can require the data to be submitted to us before it can go to market, four years, five years, four years only, four and five years, or you can say it can go out right now, but once it's out in the marketplace, we have to get the data at four and five years.

            DR. SUGAR:  The latter is ‑‑

            SPEAKER:  You want post‑market surveillance.   You are in agreement on that.

            DR. SUGAR:  Post‑market acquisition of data through five years, with it being conditionally approved.

            DR. WEISS:  So I'm getting a sense from the panel right now, there are these two different choices.  But from what I'm hearing from the panel, they would feel comfortable with the post‑market surveillance, post‑market ‑‑

            DR. McCULLEY:  Get a vote on the two.

            DR. WEISS:  Dr. Bandeen ‑‑

            DR. GRIMMETT:  Four years before it gets out with continued post‑ market to five.  That's choice one.  Choice two is, let it go now and do post‑market surveillance on four and five when it's already out in the market.  That's choice two.  Vote for one or two.

            DR. WEISS:  Dr.  Bandeen‑Roche.

            DR. BANDEEN‑ROCHE:  Am I correct in presuming that by the time the four year follow‑up is complete, there will be some five year data?

            DR. WEISS:  Yes.

            DR. BANDEEN‑ROCHE:  So that's another ‑‑

            DR. WEISS:  So why don't you state the first choice, and we can have panel ‑‑

            DR. GRIMMETT:  Let's state the second.  How many would vote for approval now with the current existing data, with post‑market surveillance of endothelial data at four years and five years?

            (Vote taken.)

            DR. GRIMMETT:  That was your choice, if I stated correctly.  That's enough.

            DR. ROSENTHAL:  How many were there?

            DR. WEISS:  And how many would vote for ‑‑ restate the first one.

            DR. GRIMMETT:  For gathering the four year data now as a condition of approval, and if satisfactory by review of the FDA, then approve it, and then continue post‑market surveillance out to year five.

            (Vote taken.)

            MS. THORNTON:  It was six to five.

            DR. GRIMMETT:  You want to take it again?

            DR. ROSENTHAL:  Yeah, could we.

            DR. GRIMMETT:  Take it again.

            MS. THORNTON:  It was six to five.

            DR. GRIMMETT:  Which way?

            DR. ROSENTHAL:  Could we have the other first?

            DR. WEISS:  Now I just want to clarify the four year data that we're trying to get, you have a continual number of patients who are getting four year data, so when will you get this four year data?  At what time point would you ‑‑

            DR. ROSENTHAL:  We need you to tell us.

            DR. WEISS:  I know it's ongoing, so if the ‑‑ so you would ‑‑ so the panel ‑‑

            DR. ROSENTHAL:  Ten more eyes, 20 more eyes?

            DR. WEISS:  How many ‑‑

            DR. ROSENTHAL:  All the eyes.  It's up to you.

            DR. WEISS:  Okay.  So then I would ‑‑ I'd like the panel to understand that if they went with, I believe it's the first option, it's undefined when that condition would be met.  Am I correct?

            DR. ROSENTHAL:  Do you want to explain?

            DR. WEISS:  When would that condition that all the four year data for all these patients would be met?  Because we also have to realize that they only have four year data on 57 patients at the present time, so how many more patients would they be able to get four year data on?

            MS. LOCHNER:  At the present time, they obviously have more than that number.  That cut‑off on the database happened a couple of months ago, so as we speak, more and more people are reaching four years.  I think the Sponsor can address, you know, the issue is when was the last patient enrolled.  When will the last patient be out to four years in that cohort, and so they'll know exactly when they'll have the complete group.

            DR. MACSAI:  It's December of 2006.

            DR. WEISS:  What I would like to know from ‑‑

            MS. LOCHNER:  No.

            DR. WEISS:  Yeah.  I'd like to know from Dr. Gray statistically what number would you need, or what number of patients would you need to have four year data before you feel that you could make a ‑ ‑ Dr. Gray, do you have any comment on finding four year data for all the remaining patients helpful?

            DR. GRAY:  Helpful?

            DR. ROSENTHAL:  Oh, no.  He's not to give you any ‑‑

            DR. GRAY:  I can't answer that kind of a question without a lot more information.  I mean, that's a difficult ‑‑

            DR. WEISS:  How many ‑‑

            DR. GRAY:  I can't do it off the top of my head.  I'm sorry.

            DR. WEISS:  From the FDA, how many ‑‑ the last four year data would be coming back when?  When would be the ‑‑ Sponsor, please.

            DR. LAMIELLE:  Helene Lamielle.  December, 2006.

            SPEAKER:  What did she say?

            DR. WEISS:  December, 2006.  Dr. Macsai.

            DR. MACSAI:  Dr. Lamielle, is that ‑‑ because I ‑‑ that's what I thought too, but now I'm rethinking it.  Is that the last person enrolled, or is that the last person with specular microscopy?  I don't get that clear.

            DR. LAMIELLE:  That's the last person on the whole.

            DR. MACSAI:  But when was the enrollment of the 306 specular microscopy patients completed?

            DR. LAMIELLE:  We have to look at the data, when the last microscopic specular patient was enrolled.

            DR. MACSAI:  Okay.

            DR. LAMIELLE:  But the specular microscopy data have been done all along the study, so there is no reason ‑‑ it's earlier than the rest of the cohort.

            DR. WEISS:  So I would just like clarification from the panel members who would require this data that perhaps may go out to approximately two years from now in order to release this into the market.  I would presume that you would want to delay approval of this for two years, or more than two years, because you have concerns about safety because of the specular microscopy data.  Am I correct ‑‑ for those of you who voted for Option 1, am I correct on assuming that's the cause of the vote in that direction?  Dr. Mathers?

            DR. MATHERS:  Concerns about the endothelial issues ‑ I'm sorry.

            DR. WEISS:  Yes, because you would be delaying the vote, or it would have to come back to ‑‑ you'd be delaying this for more than two years, because you have concerns about safety as regards to the issue of the findings on the specular microscopy.

            DR. MATHERS:  That is precisely the problem, and I think that it is a very significant issue, and we should know more before we get approval.  That's why I voted for conditional approval, that we need to know this before we approve it.

            DR. WEISS:  Yeah, Donna.

            MS. LOCHNER:  I was just going to say, it is possible that as the Sponsor theorized that the rate is essentially going, you know, dramatically down at four years, that the data will have sufficient power before the last of the patients are enrolled.  So if what they're theorizing is true, they may not have to wait as long as you're saying to have sufficient power to show that the loss is decreased from the three year point.

            However, in a worst case situation, maybe they'll need all their data, and have to wait that long.  But if their theory is true, one would expect that they would be able to have sufficient power much earlier than that.

            DR. WEISS:  So the panel could say that they would want acquisition of four year data until ‑‑ for the number, until which point the FDA deems that they can determine with certainty that the data shows stability, at which point then that would be the condition that would be met for it to be released into market.

            MS. LOCHNER:  Certainly.  And no matter what the panel or FDA says, the sponsor will push that point in any case, so you don't have to worry ‑‑

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

            DR. MATHERS:  I would like the condition to be achieved, such that at the end of the lifetime of the device, that the patient would still have 1500 cell count.

            MS. LOCHNER:  Right.  And if you just use the data the sponsor has, you can do that calculation and see where they are.

            DR. MATHERS:  That's correct.  It is a lower rate than 1.5 percent per year.

            MS. LOCHNER:  We understand.

            DR. WEISS:  Dr. Bradley.

            DR. BRADLEY:  Again, just to clarify, the stabilization, absolute stabilization is not the gold standard here.  It is the rate which is ‑‑ rate of decline which deemed safe.  And we've got a 1.5 is okay, and a 1.5 is not okay. so there is some debate about what the rate actually is.

            DR. WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  Let me clarify.  That 1.5, the figure came about at last year's meeting due to the fact that in looking at what would be a sample size needed to show a specific rate of cell loss.  And if we set the bar too low, the sample sizes would have to be enormous.  It wasn't that 1.5 was deemed a safe level.  It was that 1.5, if you wanted to screen that they were under that, your sample sizes could be reasonably sized so it wouldn't be onerous.  That's where it came up.

            DR. WEISS:  Dr. Bandeen‑Roche.

            DR. BANDEEN‑ROCHE:  I just wanted to say that I agree with this discussion that's been happening in the last couple of minutes and, you know, just so long as we also keep in mind representation, as well as just power.  You know, that we're not ‑‑ we don't have an overly selective group, both sufficient numbers, and decently representative of the whole cohort.

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  I'd like to speak in favor of my disagreement with the majority of the panel.  We had a presentation by Dr. Edelhauser who's deemed internationally as an expert in the field of endothelial cell data of all sorts, and we've seen that the pleomorphism and polymegathism are pretty darned good here, and they're stabilizing.  And then we looked at that they counted 90 cells, but probably 100 to 150 cells would have been better.  And there's a lot of room for error in the 90 cell count, and now we're arguing about 1.8 versus 1.5, versus 2 percent.  Where, if you looked at the confidence interval of those numbers, and then took a confidence interval of those counts, and then, you know, multiplied it by all those factors out, I think you'd wash this whole thing away.

            You know, I'm concerned as everyone, and I started out my whole review as saying that this ‑‑ we don't want to create ORC ‑ I can't ‑ a situation with a lens ‑ excuse me ‑ take that from the thing ‑ a lens that might cause endothelial cell decompensation, but we have a device that's really effective, probably more effective than what's out there.  And I know safety is really important, and you're talking to Mikey who doesn't like anything here, but I mean, do we really want to wait until 2006?

            We approved these contact lenses when we already had your study saying, you know, they're dangerous.  Okay?

            DR. WEISS:  I think at this point we have the data, and everyone, I think, has their opinions or has quite a few opinions.  And at some point, this may come to a very close vote.  But I think the information is out there, and we all have our perspective on, and we still have a couple of questions.  And I don't want to tell you how many hours behind we are, so we're going to ‑‑ I think we have the information on endothelial cells.  We're going to end up putting it to a vote, and when it gets put to a vote, and what I'd like to do is go on to a non‑controversial topic, like cataracts.   I bet the Sponsor didn't think that was going to be the non‑ controversial portion.

            DR. EYDELMAN:  Question 2(a) ‑ "Do you believe that the three year follow‑up is sufficient to establish a lens pacification profile associated with this device?  If not, what is your recommendation?"

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  It's sufficient.

            DR. WEISS:  I think the panel has gotten beaten into submission.

            DR. SUGAR:  I think we should ask for post‑marketing acquisition of data on cataracts that accrue in this five year period while we're looking at their endothelium.

            DR. WEISS:  Sounds good.  Dr. Schein.

            DR. SCHEIN:  As I said before, I'm more concerned about cataract and retinal detachment, than I am about the cornea.  Because although it is uncertain on endothelium, there has not been progression to any clinical disease, while there has been, in a relatively short time period.  I frankly don't believe most of the cataract rating.  I don't disbelieve it because I think investigators are dishonest, but I know, and it's well‑published, that using clinical grades, whether it's the LOC system or the Wisconsin system, is incredibly unreliable.  You need a photographic standard to really believe it, and that may be why there's such variation between Canada, these investigators, site‑ to‑site, and Dominican Republic, and maybe more than just position skill.  So I think this is a real issue.  People who get cataract surgery, their myopes.  They're going to have the eye entered twice, retinal detachment rate will behave accordingly, so I don't think this is adequate information to establish a lens opacification profile.  You need a larger sample and representative surgeons.

            DR. WEISS:  Well, certainly I would think it would be not difficult if we're going to be getting data at four years, five years, to include cataracts in that.

            DR. SCHEIN:  It's not a large sample, and it's not a representative group of surgeons.

            DR. WEISS:  Dr. Sugar had mentioned considering IOL removal if there's progression of cataract formation.  Did anyone want to put that in the labeling, as well?  And that goes later on, but I have it.

            DR. SUGAR:  I don't think it's ‑‑

            DR. WEISS:  Is that what you said, Joel, or is ‑‑

            DR. SUGAR:  No.  I expressed lack of information ‑‑

            DR. WEISS:  Lack of data.

            DR. SUGAR:  ‑‑ on what the toxicity of the removal event is, in terms of, do cataracts get worse after you take the lens out?  I don't know.

            DR. WEISS:  So you ‑‑

            DR. SUGAR:  And I don't think the Sponsor has sufficient numbers within this cohort to give us an answer that would satisfy me.

            DR. WEISS:  So you're not going to ask the Sponsor for an answer ‑‑ it's a question that remains and will stay unanswered.  Or would you like to ask the Sponsor ‑‑

            DR. SUGAR:  Again, if the Sponsor has data on ‑‑ you know, certainly if they find that removing the IOL is cataractogenic, obviously, they need to let us know that.  And I assume that they're mandated to let us ‑‑ to let the FDA know that as an adverse event.

            DR. WEISS:  As part of the ‑‑ Dr. Rosenthal.

            DR. ROSENTHAL:  Unfortunately, the adverse event issue, if they're informed of it, they are mandated to let us know.  But if they are not informed of it, unless the physician reports it through the MDR system, we will never know about it.

            DR. WEISS:  Well, we can ask them at this point if they have the information to let the FDA know.  Is that correct?

            DR. ROSENTHAL:  Well, at this point you have the information because it was submitted in the PMA.

            DR. SUGAR:  No.  We don't have information on whether removing the lens halts progression or induces progression of whatever opacities were there.

            DR. ROSENTHAL:  No, you don't have that.

            DR. WEISS:  So we can ask them for that information, and that's ‑ ‑ if they have it.

            DR. ROSENTHAL:  When?  When do you want them to give it to us?

            DR. WEISS:  If it was ‑‑ if the panel wanted, that could be a conditional, could it not?

            DR. EYDELMAN:  I just want to make it clear.

            DR. WEISS:  Yes.

            DR. EYDELMAN:  Are you trying ‑‑ there's no data from the PMA cohort that you're discussing obtaining the data from post‑market, or what exactly ‑‑

            DR. WEISS:  I think Dr. Sugar is talking about the patients who've already had this done.  Am I correct?

            DR. SUGAR:  Well, then the number is too low.

            DR. EYDELMAN:  Yes.

            DR. WEISS:  Okay.  So then do you have ‑‑ is there a statement you want to make, or is that just sort of a wish list that's not going to get answered?

            DR. SUGAR:  I guess I don't know how to make the statement about the statement, but yes.

            DR. WEISS:  Dr. Eydelman, do you have a suggestion on how to make a statement about a statement?

            DR. EYDELMAN:  If you want to find out the specific rate, you need to collect data.  If you want to have a general warning, a precaution about lack of data, you can do that in labeling.  Those are the two options.

            DR. SUGAR:  I guess both is what I would like, which is to find out if ‑‑ and I don't know how you find this out.  Assuming, as I think we are, that this is a low frequency event, it's going to be hard to acquire that data in any very short period of time.  It would be nice to know what appropriate recommendations are for dealing with lens opacification in these patients that is not visually significant.  Does removing the implant cause progression or halt progression?

            DR. ROSENTHAL:  Ralph Rosenthal.  I think at this point in time, all we can do is put a warning in saying that you do not know what the effect would be on the cataract that develops following implantation when you explant it.

            DR. SUGAR:  Then I think the labeling should reflect there is a lack of data on the impact of removing and/or replacing the lens on the endothelium and on the lens.

            DR. WEISS:  Fine.  Dr. Matoba.

            DR. MATOBA:  Well, okay.  I hate to ask this question because of labeling conditions, but is someone keeping track of all the labeling questions?

            DR. WEISS:  I am, as well as Dr. Mathers, I hope.  Any other issues about cataract?

            DR. SUGAR:  I guess I raise the other one, the axial length measurement.  Is axial length measurement accurate with the lens in place?  And I don't know how to deal with that in this.

            DR. EYDELMAN:  That is actually something we can ask the Sponsor, and work out the proper ‑‑ that is the easiest of the issues.  We have not heard the answer to Question 2(a).

            DR. WEISS:  So the question ‑‑ Question 2(a) is ‑ "Do you believe a three year follow‑up is sufficient to establish a lens opacification profile associated with this device"?  All of those who feel that it is, and would like to answer yes, please raise your hand.

            (Vote taken.)

            MS. THORNTON:  We have eight.

            DR. WEISS:  So it's a majority, not unanimous, but a majority.  And we'll go with the majority.  B.  Question B is ‑‑

            DR. EYDELMAN:  "In light of the findings, they believe surgeon experience to have be an important factor in ASC development secondary to surgical trauma.  If yes, they believe that future users of this lens should be required to undergo special training."

            DR. WEISS:  So I think that there was a consensus that there should be special training.  Would the FDA need to know from us what type of special training, or you can determine that with the Sponsor?  Dr. Macsai had mentioned ‑‑ Dr. Sugar and Dr. Macsai, I think both had mentioned mandate ‑ perhaps proctor for early cases, but that's something that you all can determine with the Sponsor, so we do not have to get involved in that.

            DR. ROSENTHAL:  I think I should clarify.  We can mandate training.  We generally do not mandate what type of training.

            DR. WEISS:  So would it be acceptable to the panel that training or some sort be mandated?

            (Vote taken.)

            DR. WEISS:  Fine.  Dr. Macsai had brought up tracking and recalling.  If there were multiple surgical problems with a physician, I would assume that would be too burdensome and beyond the usual scope that we advise.  Am I correct on that?

            DR. EYDELMAN:  Yes.

            DR. ROSENTHAL:  I've never heard it recommended before.  If the sense of the panel is that that's what they feel is reasonable, we can ask the agency ‑‑ well, we are the agency.  We can ask higher up in the agency what their feeling is about the recommendation.  We may not take it, and we may take it.

            DR. MACSAI:  Jayne, can I clarify?

            DR. WEISS:  Dr. Macsai, yeah.

            DR. MACSAI:  The recommendation really wasn't to the agency, it was to the Sponsor.  The recommendation was simply to the Sponsor, that if there's a disproportionate number, I assume these are not ‑ ‑ these are going to be consignment lenses, and if somebody, you know, keeps ordering new ones, and keeps sending back ones they implanted wrong, or they tore upon implanting because they can't manage to get them through the shooter, red flag.  Go retrain that person.  Rescind their certification.  As simple as that.

            DR. WEISS:  So the agency can take that under advisement.  Okay.  The Sponsor.  C.

            DR. EYDELMAN:  Has to do with recommendation for replacement of ICL.

            SPEAKER:  I think we dealt with that at one point.

            DR. EYDELMAN:  Yes, we did.

            DR. WEISS:  WE did this one.  Okay.  What was the answer?

            SPEAKER:  We don't know.

            DR. WEISS:  We don't know.  Always nice to have definitive answers for the agency.  Question 5, "Do the safety and efficacy outcomes support approval of the STAAR ICL for the eyes with the following pre‑operative manifest.  (A) is minus 3 to minus 7."  Now one thing I will point out, obviously, the results in these patients were much better.  But then again, you might ‑‑ the panel might determine the risk benefit ratio is also a little bit different because there are effective treatments in these patients.  A minus 3 has a whole choice of treatments, where a minus 15 does not.  But having added that introduction, I'd like a vote.  For those who agree that the safety and efficacy outcomes, safety and efficacy support approval for eyes with minus 3 to minus 7 ‑ if you agree, vote with your hand in the affirmative.

            (Vote taken.)

            MS. THORNTON:  I've got one, two, three, four.

            DR. ROSENTHAL:  No, there are five.

            MS. THORNTON:  Five.  Where's the other one?  Tim, keep your hand up.

            DR. ROSENTHAL:  There's one, two, three, four, five.

            DR. WEISS:  Okay.  Five out of 11.

            DR. ROSENTHAL:  No.  You have to vote.

            DR. WEISS:  Why don't we have ‑‑

            DR. ROSENTHAL:  There has to be another vote.

            DR. WEISS:  Five people are voting in the affirmative.  For those who disagree that safety and/or efficacy do not support approval for minus 3 to minus 7, can you vote?  They disagree.

            DR. ROSENTHAL:  Please vote.  You can abstain.  Please vote either yes, no, or abstain.

            DR. MACSAI:  Minus 3 to minus 7.

            DR. ROSENTHAL:  There's four against.

            DR. WEISS:  This is a no vote.  Dr. Bandeen‑Roche.

            DR. BANDEEN‑ROCHE:  We're taking everything into account, including the discussion on ‑‑

            DR. WEISS:  Every single thing.

            DR. BANDEEN‑ROCHE:  ‑‑ endothelial cell count.  Right?

            DR. WEISS:  Everything.  Safety and efficacy.

            DR. EYDELMAN:  Well, you're voting both ways.

            DR. WEISS:  Okay.  What are we voting now?  Okay.  Let's have a vote again.  Those who agree that safety and efficacy outcome support approval for minus 3 to minus 7 ‑ those who ‑‑

            DR. GRIMMETT:  With or without the prior endothelial concerns.  Are you separating that out?  Are you concluding it, the endothelial safety issue?

            DR. WEISS:  Yes.

            DR. GRIMMETT:  We already went over, or are you separating it out?

            DR. SUGAR:  With the condition, I assume.

            DR. GRIMMETT:  Point of clarification.

            DR. WEISS:  Well, with the conditions of ‑‑ let's ‑‑ if you want to break it out, let's break it out into needing the four year data as a condition of approval.  And then we'll have a vote for not needing the four year data, but as a condition of approval having it ‑‑

            DR. SUGAR:  We just did that.  We voted that way.

            DR. WEISS:  So let me ‑‑ I'm going to defer to FDA.  Since we've done, how do you want this phrased at this point to give you any information?

            DR. EYDELMAN:  Okay.  I will assume that you're not expecting to stratify the four year data by preoperative refractive bins, because then we'll never have enough.  So, therefore, you have to take into consideration then endothelial cell data as you know currently.  And assuming that overall four year data will be looked upon until this device is marketed, do you consider that safety and efficacy ‑‑ do they support approval for minus 3 to minus 7?

            DR. WEISS:  So for those of you who require that four year data before as a condition of approval, four year data on the rest of the cohort as a condition of approval, do you believe it's efficacious for minus 3 to minus 7?

            DR. COLEMAN:  Excuse me, Jayne.  Can I have safe and efficacious.

            DR. WEISS:  Safe and ‑‑ is that ‑‑

            DR. GRIMMETT:  For everything else but the endothelium.

            DR. WEISS:  No.  Once you have your four year data, you're going to have your four year data as a condition of approval.

            MS. LOCHNER:  Can I say something?

            DR. ROSENTHAL:  Can I clarify?

            DR. WEISS:  Yes, please clarify.

            DR. ROSENTHAL:  Are you ‑‑ do you want ‑‑ what ‑‑ do you want to limit the power ‑‑ the refractive error for which this device should be used or do you not?

            MS. LOCHNER:  And to say that another way, I think the panel already voted on the endothelial cell issue.  And the motion seemed to carry that the four year data would be obtained pre‑marketly.

            DR. ROSENTHAL:  That was a straw vote, and ‑‑

            MS. THORNTON:  Would you please use the microphone.

            DR. WEISS:  It would be a straw vote.  I'm sorry.  Maybe it wasn't in the ‑‑

            DR. ROSENTHAL:  It was a straw vote, and you still don't know what the ultimate vote will be, and what the conditions will be.

            MS. LOCHNER:  But I think we want you to set aside the endothelial cell issue at this time, and speak to the refractive ranges.

            DR. WEISS:  So we're speaking now basically of efficacy.  If we're speaking about ‑‑

            MS. LOCHNER:  No, safety and any other ‑‑

            DR. WEISS:  Safety and endothelial cell data, and efficacy.  We're trying to get at whether, setting aside the endothelial cell issue, which we already had a straw vote on, and we assume that that issue wouldn't change based on the refractive ranges.  Setting that aside, are there additional concerns that might make you vote differently by the different refractive ranges?  Dr. Coleman.

            DR. COLEMAN:  Yeah, but one of my issues that hasn't been addressed, because we've been voting on safety based on corneal endothelium, is the safety related to glaucoma, and also the lack of gonioscopic data.  And one of the things that I need in terms of  for my feeling, the safety of this procedure is having post‑ operative gonioscopic evaluations on the cohort in this PMA.  And that information is not available.

            DR. WEISS:  Okay.  I would like to ‑‑ I'm getting disturbed how the proceedings are going.  I would like to emphasize, this is reasonable safety and efficacy.  I mean, there ‑‑ I think it would be nice to have gonioscopy, and I think there were other parts that could have been included in the study.  But with all fairness to the sponsor, at the point that this study was approved, it was approved with the input of the agency, so we can't hold them up to a higher requirement, which would be nice, but it's not fair for information that we've subsequently gathered.

            With the data that we have, and that the agency required from them, and that they performed, do we have reasonable safety and efficacy?  I would be disturbed if at this point this was ‑‑ it was not approved on the basis they didn't have post‑operative gonioscopy because that was not a requirement that the agency made, and there is nothing in particular ‑‑

            SPEAKER:  That was a requirement that the panel ‑‑

            DR. WEISS:  Well, the panel made that, but that was not a binding requirement.  I mean, can the agency comment if I'm out of line here?

            DR. COLEMAN:  It's not in the study, but the thing is that they could ‑‑ this is Dr. Coleman again ‑ excuse me.  I thought that you could when you're doing the four year reviews or the five year reviews of these individuals, same with conditional approval, but they could also have gonioscopy by the surgeons to see how the angles were doing, whether there's pigment deposition ‑‑

            DR. WEISS:  No, I think that ‑‑

            DR. COLEMAN:  So it's definitely doable, even now in this current cohort.  It's just that information hasn't been obtained.  And you have an increased rate of interocular pressures of about ‑‑ in three years in this cohort about 6.8 percent of the cohort has a pressure elevation of more than 5 millimeters of mercury from baseline.  If you believe the ocular hypertensive treatment study, that's associated with a 50 percent increased risk of glaucoma in these young individuals.  And so specular microscopy

            DR. WEISS:  What percent of higher myopes would be expected to get glaucoma?

            DR. COLEMAN:  That issue is debatable.  The investigators went ‑‑ the Sponsors went over it, but one of the issues is, is it's still considered debatable whether or not high myopia is associated with an increased risk of glaucoma.

            DR. WEISS:  Okay.  So you would like to put as ‑‑ if data is gone that four years of specular microscopy, you would like gonioscopy to be done at four years, as well.

            DR. COLEMAN:  To looking at pigment deposition and increased peripheral anterior synechiae, because those references that Dr. Grimmett found did show that in those eyes that had elevated pressures that were having problems, they did have increased pigment deposition, and also peripheral anterior synechiae.  Glaucoma is a long‑term risk for these individuals.  I mean, I think that it's something they're going to be living with for a lifetime if they do have an increased risk of glaucoma, because a 40 year old's prevalence of glaucoma is about .18 percent when you look at the Baltimore Eye Survey in Caucasians.  And if you do some extrapolations, this could be actually increasing and doubling that prevalence in this age group.

            DR. WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  Michael Grimmett.  I'm certainly in favor of warning clinicians in the labeling about our concerns about pigment deposition and need for gonioscopy, so that clinicians go ahead and do the correct thing, but the study was approved without gonioscopy.  And while I think it's regrettable, I am not in favor of mandating the Sponsor to gather further gonioscopy data.  I don't think that would be fair.

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

            DR. MATOBA:  Okay.  I want to ask Dr. Eydelman, when the FDA put this question together, did you want us to just address safety efficacy for each of these refractory subsets, or do you want us to also take into consideration philosophical ideas, such as whether we think that an interocular procedure is justified in a patient who is minus 3?

            DR. EYDELMAN:  As I tried to explain in my presentation, what I was hoping that the panel will do is look at each of the refractive ranges, and look at the risk benefit analysis for this device, and for other alternative devices for each of these refractive ranges, and make a decision upon that.

            DR. WEISS:  So with that in mind, let's talk about minus 7 to minus 10.

            DR. SCHEIN:  So to clarify that, because that is my question.

            DR. WEISS:  Yeah.

            DR. SCHEIN:  So the answer is, compared to what?  And so the comparison here is not spectacles or contact lenses, it's compared to other refractive ‑‑

            DR. WEISS:  Dr. Rosenthal.

            DR. ROSENTHAL:  You're not meant to compare it to anything.

            DR. SCHEIN:  Well, that's not what you said.

            MR. ROSENTHAL:  You're meant to take the risk benefit ratio of this device.

            DR. WEISS:  We have the safety and efficacy minus the endothelial cell data for each of these refractive ranges, irregardless of what else is out there.  That's what we have to look at.  So I'm going to ask ‑‑

            DR. SCHEIN:  That makes no sense whatsoever, does it?

            DR. WEISS:  But is that what the agency is asking?

            DR. SCHEIN:  I mean, what ‑‑ obviously, it's inappropriate to ‑‑

            DR. ROSENTHAL:  We're asking do you feel a patient with a minus 3 diopter myopia have a interocular lens put in their eye to treat their minus 3 diopter myopia.

            DR. MATOBA:  That's not the way the question is worded.  I thought that's what you were getting at, but that's not the way the question is worded.

            DR. ROSENTHAL:  And minus 4, and minus 5, and minus 6.  So I think maybe we should look at it ‑ is there a range at which you would feel comfortable subjecting a patient with myopia to an interocular procedure in which this device is implanted?

            DR. SCHEIN:  Okay.  So in other words, it is in comparison to other data that ‑‑

            SPEAKER:  No.

            MR. ROSENTHAL:  Not comparison.

            DR. SCHEIN:  Not in a quantitative way, but it's ‑‑

            DR. WEISS:  Okay.  Dr. Bradley has suggested the following wording, which I think is good wording.  If the Sponsor can establish that the endothelial cell count is not declining at dangerous levels, depending on how you want to classify that word, does the panel consider this device safe and efficacious for the following ranges.  So let's first talk about minus 7 to minus 10.  If there was no issues with the endothelial cell count data, I'd like a raise ‑‑ a show of hands ‑‑ Dr. Matoba.

            DR. MATOBA:  I think risk benefit is different from what you're saying, because safety is never absolute.  It's all relative.  And so the benefit for a minus 3 is different from a benefit for minus 12 ‑‑

            DR. WEISS:  That's why I'm talking about minus 7 to minus 10 first.

            DR. MATOBA:  You can't take that phrase out of the question, I don't think.

            DR. WEISS:  But that's why I'm speaking about minus 7 to minus 10 first.  I'd like to clear up those, and then obviously, when we get into the minus 3s, it sounds like it's going to get more contentious.  Minus 7 to minus 10, are there any issues that the panel has with safety and efficacy, regardless of ‑‑

            DR. ROSENTHAL:  Excuse me.

            DR. WEISS:  Yes, Dr. Rosenthal.

            DR. ROSENTHAL:  I just want to clarify what I was ‑‑ a risk benefit analysis, Mrs. Lochner has told me, does take into account other options.  But you are not to compare the option.  You are to use a clinical judgment to say whether or not you feel that a certain range would be appropriate for this device.

            DR. WEISS:  Minus 7 to minus 10, can we have a vote for those who would feel that this is safe and efficacious if the endothelial cell data shows such for minus 7 to minus 10.

            (Vote taken.)

            DR. WEISS:  So we have a majority of the panel who feels it would safe and efficacious for minus 7 to minus 10.  Minus 10 to minus 15, can we have a similar vote, with some prompting by Dr. Macsai.  That's all right.  We'll use you for other votes here, Marian.  I'm enlisting you.

            (Vote taken.)

            DR. WEISS:  This is in favor of.  So minus 7 to minus 10, and minus 10 to minus 15, it is safe and efficacious.  How about minus 6?

            SPEAKER:  What?

            DR. WEISS:  I know who I'm dealing with here.

            SPEAKER:  Excuse me.

            DR. WEISS:  Minus 6, how many of you ‑‑ I'm not going to go the minus 3 to minus 7 range, because there's going to be possibly a breakdown, so I avoid breakdowns.

            SPEAKER:  Call a vote.

            DR. MACSAI:  Can I ‑‑

            DR. WEISS:  Yes, Dr. Macsai.

            DR. MACSAI:  If we're looking at efficacy and safety, and we have a guidance document that exists for minus 3 to minus 7 for safety and efficacy, and we look at this group, which is how we've broken out minus 3 to minus 7 or 6.9 ‑ I don't remember ‑ compared to the guidance document, okay.  You can eliminate the endothelial issue.  It meets the criteria, safe and effective.

            DR. WEISS:  So you would ‑‑ you feel for minus 3 to minus 15, it's safe and efficacious.  So we can go to minus 3‑minus 7.  Let's go to minus 3‑ minus 7.  Minus 3‑minus 7, can we have a vote by hands for those who feel that this is safe and efficacious.

            MS. THORNTON:  One, two, three, four, five, six.

            DR. WEISS:  Hey, it's a good day.

            DR. MACSAI:  You may not put it in your eye, but it meets the guidance.

            DR. BANDEEN‑ROCHE:  May I just say something for the record?

            DR. WEISS:  Dr. Bandeen‑Roche.

            DR. BANDEEN‑ROCHE:  I just want to make clear that I was abstaining because I don't feel like I have the clinical expertise to make the complicated risk benefit decision that you seem to be asking for.

            MS. THORNTON:  Yeah.  Then I'd like to have a negative vote, are there any other abstenders?

            DR. WEISS:  We're going to have a vote for minus 3 to minus 7, those who did not feel it had evidence of safety and efficacy.  Dr. Schein, Dr. Matoba, Dr. Mathers and Dr. Coleman.  And then we had one abstention by Dr. Bandeen‑Roche.

            MS. THORNTON:  Okay.  I've got it.  That's minus 3 to minus 15.

            DR. WEISS:  Minus 3 to minus 15 at this point.  Are we finished with that question, Question 5.  So we're going to go to Question 7 ‑ additional labeling recommendations.  What I will do is, interest of time, is mention some of those that have been brought up already, and see if there's consensus or disagreement.  There was one comment about adding in the labeling that the stability of the endothelial cell count has not been documented.  That might be a moot point if a condition for approval is getting the four year data.

            DR. SCHEIN:  It's not moot.

            DR. MACSAI:  It's not moot at all.

            DR. SCHEIN:  There's still going to be labeling of whatever goes out there.  If we approve it with condition of acquiring that data post‑approval, then that would have to be in there.

            DR. WEISS:  Fine.  So we'll include that.  Dr. Grimmett had indicated white‑to‑white is not sufficient to determine the lens size.  I don't know that that would go into labeling.  Dr. Macsai wanted non‑Caucasian eyes from the Dominican Republic included.  Dr. Coleman.

            DR. COLEMAN:  Yeah. I wanted to include that long‑term risk for glaucoma are unknown, and then to also in the table that they have on page 20 of 25, they have glaucoma there too.  And I would change that to elevated interocular pressure, ocular hypertension, whatever definition they use.  And also, for the interocular pressure greater than 25 or greater than 10 ‑‑

            DR. WEISS:  Can you ‑‑

            DR. COLEMAN:  Slow down.

            DR. WEISS:  Slow down a little.

            DR. COLEMAN:  I have one, and I think that that's misleading because they had five patients that had pressures of greater than 25, or greater than 10 millimeter increase during baseline to 36 months.  And so I think it's misleading just to use that last visit, because pressure does vary, and we don't just use one ‑‑

            DR. WEISS:  So tell me what you want.

            DR. COLEMAN:  So I want IOP greater than 25, or greater than 10 increased from pre‑op.  And I want the exact number, which is 5, instead of 1.  And so that would be a percentage of 1.4 percent instead of 0.2 percent.  This is in table ‑‑

            DR. WEISS:  I'm going to actually need you to write this down, because it's going too quick for me.

            DR. COLEMAN:  Okay.

            DR. WEISS:  Dr. Macsai had included data about halos and wanted to include data about patients having complaints of halos and glare.

            DR. MACSAI:  Can I elaborate?

            DR. WEISS:  Okay.  Yes, Dr. Macsai.

            DR. MACSAI:  I also wanted to include limbal pathology as an exclusion criterion.  I mean, the same as a pterygium, you can't measure white‑to‑white.

            DR. WEISS:  I'm just wondering if the Sponsor had any patients with pterygias or things along ‑‑

            DR. EDYLMAN:  I think in general, most of those ociopathology was excluded.

            DR. WEISS:  Okay.  So that's fine.  Dr. Grimmett had suggested having something in labeling about a learning curve, that there's a learning curve of the surgeon with a higher rate of upside down lenses and cataracts, and surgeons with less experience.

            Dr. Macsai had also requested, and I don't know ‑‑ this may not go on labeling, but had requested that the 65 excluded eyes was ‑‑ if you could elaborate on that.

            DR. MACSAI:  Sixty‑five eyes with pre‑existing conditions were included in the study.  It would be nice to know what were the pre‑ existing conditions, what happened to those patients.  It would give the implanting surgeon and patient tremendous information, so let us know what happened.  What were the pre‑existing conditions, and what happened to those patients?

            DR. EYDELMAN:  There was actually a section in the PMA that talked about that.

            DR. MACSAI:  Oh, I missed it.  Sorry.  We'll include it then.

            DR. WEISS:  So we don't have to get involved in that then.

            MS. THORNTON:  You want that included in the labeling?

            DR. MACSAI:  Yeah, in the surgeon's information.

            MS. THORNTON:  Okay.

            DR. WEISS:  Dr. Schein, Dr. Matoba, and then Dr. Bradley.

            DR. SCHEIN:  I would like to see the more severe complication rates reported on a per‑patient basis, rather than on a per‑eye basis.

            DR. MATOBA:  Under patient precautions, pigment dispersion should be listed.

            DR. MACSAI:  Can you talk a little louder?

            DR. MATOBA:  Yes.  Under patient precautions or relative ‑‑ yeah, under patient precautions, I would like pigment dispersion to be listed.  I don't think it is right now.  And on page ‑ let's see ‑ L‑36, which is the beginning of the patient information draft, the third paragraph where they mentioned the term "phakic interocular lens surgery", I don't think that the average patient knows what phakic means.  That term should be explained.  It never comes up again as you go on reading it.  It should be explained, and I think there should be a clearer discussion of the alternative treatments for myopia.

            And then lastly, on page L‑43, "List of Adverse Events and Complications", I think they should ‑‑ even though it was not observed in the study, I think they should mention the possibility of endophthalmitis and loss of the eye, even though it's very rare, but that's risk with interocular surgery.

            DR. WEISS:  Dr. Ho, and then Dr. McMahon.

            DR. HO:  Allen Ho.  I would propose that the  labeling include the increased risk of vision loss from retinal detachment remains unknown.

            DR. WEISS:  Well, the risk, not the increased risk.

            DR. HO:  Yes, I'm sorry.  The risk.

            DR. WEISS:  Dr. Bradley, then Dr. Sugar, then Dr. Bandeen‑Roche.

            DR. MACSAI:  You missed McMahon.

            DR. WEISS:  Dr. McMahon.  Excuse me.

            DR. McMAHON:  I'd like to bring up a completely new issue, and that is, I have a problem with the name of this device.  This device has nothing to do with a contact lens, and I think it is a disservice to the public by using this term.  I think it's a Euthanism probably from the marketing department gone hog wild.  And I would like to see all mention to this in the device and labeling removed.

            DR. MACSAI:  What?

            DR. McMAHON:  The word "contact lens" I want removed from the name and all labeling.

            DR. WEISS:  Doctor ‑‑ Sally.  Sorry.

            MS. THORNTON:  I'm Dr. Sally.

            (Laughter.)

            DR. WEISS:  AT this point, I'll give out free M.D.s just ‑‑

            MS. THORNTON:  It sounded like part with Dr. Phil and Dr. Ruth.

            DR. WEISS:  Your book comes out soon.

            MS. THORNTON:  I also think we need to get some comments on the labeling from the consumer representative.

            MS. SUCH:  Now?

            DR. WEISS:  Now is as good a time as any.

            MS. SUCH:  Okay.

            MS. THORNTON:  Before we leave this subject.

            MS. SUCH:  Good.  Glenda Such.  A couple of things.  One is, I could ask a question first and that is, precautions ‑‑ excuse me.  On the precautions versus the contraindications, there's a mention about ‑‑ we have just brought up also about retinal detachment.  And I wonder if there shouldn't be something in the contraindications about retinal detachment.  How long after retinal detachment should you not have this process?  That actually should be in there.

            Also ‑ I just went blank.

            DR. WEISS:  I believe it was an absolute contraindication for inclusion into the study, so we don't ‑‑ we won't change that.  And that would be up to an individual physician if they intended to use this in ‑‑

            DR. MACSAI:  It's not a contraindication.

            DR. WEISS:  A retinal detachment is not a contraindication?

            DR. MACSAI:  No.

            DR. HO:  Correct.  The definition was stable retinal exam, so that ‑‑ you can have a very stable retinal exam post retinal detachment, and in fact, after a retinal detachment surgery, you may be at less risk for a problem, i.e., retinal detachment if you have it, so I'm comfortable with that.  To answer your question, Glenda, I would say ‑‑ I would leave that to surgeon discretion really.

            MS. SUCH:  And not have it in the patient ‑‑

            DR. HO:  Not have a specific time frame.

            MS. SUCH:  Okay.  I was just concerned about that.  The other is something that's very small housecleaning part.  It's on the same issue as the phakic, and that is talking about in the very beginning of the patient brochure, they talk about that it's 3‑D to 20‑D before they get into what a diopter is.  And let me tell you, most people wouldn't know a diopter from a hole in the wall, so that should be spot up right away.  And even though there's a mention about that there's a glossary, most patients won't look at the glossary unless they really, really a very, very academic minded, so anywhere you can, to write out the actual words, even though I know it's going to add to printing cost to actually write out the words.  That's the majority I have right now, this very moment.

            DR. WEISS:  Just in terms of the patient information, I had ‑‑ looking at the labeling, I think it should be listed in patient information that the higher myopes should not expect the same results as low myopes, because this reduces, does not correct myopia.  I'd like long term effect on the endothelium is not known.  And in mentioning ‑ sort of following up on Dr. McMahon's comment ‑  in the glossary, there's a definition, Collamer ICL is a collagen‑ based contact lens.  I have to say, that's the name of this device, but if I ‑‑ I think the average person, if they see Collagen‑based contact lens, that certainly invokes something different than an interocular lens, which we're discussing.  I'm not sure how to address that issue, but Dr. Bradley will tell me.

            DR. BRADLEY:  Yeah, two points.  One, on the issue of naming, I agree with Dr. McMahon.  I think calling this a contact lens will be grossly misleading to the public.  They already have a sense of what a contact lens is.  It's well‑defined.  This is not a contact lens.  It never will be a contact lens, and to tell the public that it is, I think is misleading.  So perhaps we could take a vote on that, if there's some contention over that.

            Second issue, in spite of what Dr. Schallhorn assured us this morning, the issue of pupil size still concerns me with this product.  I mean, it has a small optical zone.  An optical zone size that would not be considered safe for standard refractive surgery.  And even with the larger optical zones used in current LASIK, we're still concerned that the procedure might not be appropriate for people with very large pupils.  And I wonder if some labeling for this particular device should also warn the physician and the patient that if they happen to have large pupils, this device may cause them problems at night.

            DR. WEISS:  Well, I think what would be more accurate to say is the effect of pupil size is not known, because we have no evidence that it does or doesn't.  Sally has pointed out to me, I could see the National Enquirer headline saying I got endophthalmitis from my contact lens.  Those weren't her exact words, but distancing herself from my comments already, didn't take long.  Dr. Coleman, Dr. Grimmett.

            DR. COLEMAN:  So for patient labeling issues, I also wanted to recommend, concerning putting in that they may need to use medications chronically to control eye pressure, because a lot of the patients had ‑‑ they had like ‑‑ they have so far two patients that have needed to use topical beta blockers chronically for their ocular hypertension.

            DR. WEISS:  Well, wouldn't it be more fair to say glaucoma is a risk, than to tell you what the treatment is going to be?

            DR. COLEMAN:  They haven't shown that you've gotten glaucoma.  They're just describing that you've gotten high eye pressures.  And according to them, they didn't have glaucoma.  They just ‑‑ that's why I wanted to change that labeling, because the risk of glaucoma is unknown.  They weren't really ‑‑ they aren't doing visual fields, and you don't see anything about the optic nerve.  And so you really can't say anything about glaucoma.  They aren't doing angle evaluations.  I mean, they aren't doing a glaucoma evaluation, so they really ‑‑

            DR. WEISS:  Okay.  The agency will describe it.

            DR. COLEMAN:  Yeah.

            DR. WEISS:  Okay.  Any other ‑‑ yes.  Go ahead.

            MR. CROMPTON:  Just a little fair balance from the industry rep on labeling, is FDA really does work closely with the Sponsors on labeling.  And a lot of the comments that I'm hearing, these kind of generic comments that aren't specific to the study here, really can be addressed in precautions, black box warnings, things like that.  And I know that all companies want to represent the product correctly.

            When we get into trade names of products, that is a matter of some concern to companies and the agency.  And I think the agency guides that, rather than the panels.  So trade names get into patent issues, copyright, all that sort of stuff.  As long as claims are not being misrepresented, I think that is a key thing.

            DR. WEISS:  The only problem is that contact lens is ‑‑

            MR. CROMPTON:  I understand the issue.

            DR. WEISS:  I would say that's somewhat deceptive.

            MR. CROMPTON:  I understand the issue, and I think FDA has a lot of practice dealing with companies in terms of how they name their products.

            DR. WEISS:  Ralph, do we need ‑‑ does the panel need to get involved in this issue, or does not?

            DR. ROSENTHAL:  (Nodding head no.)

            DR. WEISS:  Fine.  I had two things on the physician labeling.  Is on page 6, there's a discussion of calculation of lens power.  I'd ask the panel and the agency, should they be specifying the two formulas that they specifically used in this study, or just say calculation of lens power?  Do you think it would be helpful to specify the formulas that they used, or not really?  Anyone.  Dr. Sugar.  No, just leave it as is.

            Page 14, they indicate the post‑op regime should be Ocuflox and Tobradex.  I don't think that it has to be specifically ‑‑ there's no reason why they have to use those particular drugs.  And I think that could read that the post‑op regime used in the PMA were those drugs.  Does anyone disagree with that?  No? Any other labeling?

            DR. GRIMMETT:  I have a question.

            DR. WEISS:  Yes, Dr. Grimmett.

            DR. GRIMMETT:  Is the agency going to obtain stratified data by lens optic size on the symptom data, the halos and stuff?  Yes.  Okay.  Moot point.

            DR. MACSAI:  That's what I asked for.

            DR. GRIMMETT:  I just want to make sure it's stratified.

            DR. WEISS:  Does anyone want to have any warning in there that 20 percent of patients fell out of the usual endothelial cell loss, and had a higher rate of endothelial cell loss?  Dr. Schein.

            DR. SCHEIN:  I think the most direct thing to do is simply to show some data at a level that the people reading this would understand.  Maybe a histogram of cell counts at baseline and at 3 or 4 years.

            DR. WEISS:  Dr. McMahon has pointed out to me that there's a ‑‑ I have one list of questions, and he has another.  And on his other, a very important question that has been not handled by panel at this point, so I'm going to jump around.  It is, do the safety and efficacy data for eyes with pre‑operative myopia of greater than 15 to 20 support approval in this refractive range?  We've gone up to 15.     

            MS. THORNTON:  We voted on that.

            DR. ROSENTHAL:  You just did efficacy.  I would like to hear your discussion on safety issues, other than endothelial cell counts, which you're addressing globally.

            DR. WEISS:  Above 15.  We've gone up to 15, but we omitted above 15 to 20.  Those had a higher rate of loss of best corrected vision.  I think we ‑‑ we did talk ‑‑ what do you specifically want us to address, because I have highlighted that the panel did say it was efficacious for reduction of myopia over minus 15.

            DR. ROSENTHAL:  The other safety issues.

            DR. WEISS:  The other safety ‑‑ is the panel satisfied with the safety profile, aside from endothelial cell counts, in this group of higher myopes?  Dr. McMahon.

            DR. McMAHON:  I have some concerns in that in almost all categories, there's a higher incidence of troubles, if you're looking at the troublesome categories, and the numbers are relatively small.  I think it was 57 eyes, and so I have my concerns about that.  And actually would like to see either more data to expand the range to 15 to 20 that demonstrates an acceptable safety profile, or to exclude it.

            DR. WEISS:  Does anyone else have any concerns?  Dr. Mathers, then Dr. Coleman.

            DR. MATHERS:  But I think in this particular group, this device has a very, very strong appeal, because there is nothing else that can help these people besides a contact lens, so in the risk benefit ratio, I think that this is ‑‑ it's my own opinion that this actually has the best risk benefit ratio of any of the other degrees of myopia, because nothing else is available.

            DR. WEISS:  I apologize.  As I recall, I think 100 percent of people in that group would have it done again, so even though the satisfaction wasn't the highest, they had the highest rate of deciding they made the proper decision, probably particularly for the reason that you mentioned, that if you have a majority of those people ending up 20/40, that's probably a miraculous result for them.

            DR. MATHERS:  The alternative treatment is clear lens extraction, and this is preferable.

            DR. WEISS:  Dr. Coleman, then Dr. Ho, then Dr. Bradley.

            DR. COLEMAN:  Yeah.  I just wanted to point out that in this group, the incidence of pressures greater than 10 millimeters of mercury over from baseline was greater.  It's about 4 percent versus the 1.4 percent.

            DR. WEISS:  So, I mean, that could be ‑‑ and this is separate, and I apologize for digressing, but it probably ‑‑ I mentioned putting in the patient information that the high myopes didn't have the same level of efficacy, and we should also probably indicate they had a higher level of risk at the same time.  Dr. Ho.

            DR. HO:  Yeah.  Dr. Mathers makes a very good point.  The issue here for those 28 eyes that were over 15 diopters is ‑‑ I'm, you know, very concerned about the possibility of retinal detachment with any kind of procedure in those large myopic eyes.  But if you look at those that are willing to do it again, it's very telling.  I think it was, as you mentioned, zero out of 28 were not willing to do it again.  And the point of the other procedure being clear lens extraction, I think potentially could be fraught with more risk.  And that's why I'm supportive for this group.

            DR. SCHEIN:  Jayne.

            DR. WEISS:  Dr. Schein.

            DR. SCHEIN:  This could be dealt with in labeling by simply saying this is the highest risk group.  Notice, one of the people that wanted to have it again had a macular detachment, isn't seeing very well.  Now how do you interpret that?

            DR. WEISS:  Hope springs eternal.  Dr. Bradley.

            DR. BRADLEY:  Just to clarify a point Dr. Mathers made.  I think you perhaps meant to say these people have no other surgical options.  They clearly have other options.

            DR. MATHERS:  Contact lens, and spectacles.

            DR. WEISS:  You get terrible vision though.          DR. BRADLEY:  They don't work very well.

            DR. MATHERS:  But yes, it's something.

            DR. WEISS:  Dr. Bandeen‑Roche.

            DR. BANDEEN‑ROCHE:  Would someone briefly speak to the clinical significance of the trace anterior subcapsular, so in other words, between those and the nuclear cataracts, there were 13.5 percent in this group who had a cataract of some type.  And is that an acceptable trade‑off?

            DR. WEISS:  Dr. Eydelman, can you speak to that?

            DR. EYDELMAN:  The slide is up.

            DR. WEISS:  Okay.  Great.  Well, you know, we are speaking though a very small number of eyes.

            DR. EYDELMAN:  Thirty‑one.

            SPEAKER:  They're at risk for cataract in any case.

            DR. WEISS:  I'm not sure what conclusions can be reached on that small number.

            DR. MACSAI:  They're at a greater risk for nuclear sclerotic cataract.

            DR. WEISS:  Dr. Macsai.

            DR. MACSAI:  Oh, sorry.  Dr. Macsai.  These patients are at greater risk for nuclear sclerotic cataracts at an earlier age, whether or not they have this implant ‑‑ this device implanted.

            DR. WEISS:  So I would suggest that this could be handled in ‑‑ the sentiment I'm getting is that there aren't a lot of good options, that even though the safety and efficacy were not as good as other ranges, this could be addressed in labeling to let the patients know that their expectations should be less.  I see some nodding by the panel, so that will be good enough for me.

            And we already indicated that we wanted this to be listed as reduction of myopia, as opposed to correction.  Dr. Sugar had mentioned a couple of other things.  There is something in patient and physician labeling, indicating that this device improves the quality of vision.  I think you mentioned reduction as opposed to correction, if we're talking about contrast sensitivity or rather than just saying the quality of vision.  Am I correct on that, Joel?

            DR. SUGAR:  Well, I can't speak to why the Sponsor put it in there, but they did, I think, ask the patients about their quality of vision.  I don't think that's sufficient.  I think you could say it may improve the quality of vision, but then they should put the data in.

            DR. WEISS:  And then you wanted a brochure with a picture of the device and the positioning.  Anything else in the labeling?  I think we answered above 15 to 20.  Dr. Grimmett.

            DR. GRIMMETT:  Let's take a vote on it.

            DR. WEISS:  I don't ‑‑ I mean, unless you want to vote, Ralph?  Fine.  Above minus 15 to minus 20, excluding endothelial cell data, who would agree that this shows safety and efficacy?

            (Vote taken.)

            MS. THORNTON:  Six for.

            DR. WEISS:  Six for, and who would ‑‑

            DR. ROSENTHAL:  Four there, three there ‑ that is seven.

            MS. THORNTON:  Well, why don't you count.  I can ‑‑ one, two, three, four, five, six, seven.  You're right.  Seven for.

            DR. WEISS:  And those would disagree with safety and efficacy, please raise your hand.

            MS. THORNTON:  Two against.

            DR. SCHEIN:  There's this problem that I would vote for approval, but I don't think it's particularly safe.

            DR. WEISS:  Well, it's both.  It's a marriage, safe and efficacious.

            DR. SCHEIN:  Yeah, that's the problem.

            DR. WEISS:  So life is full of ‑‑ so would you vote for ‑‑ with those two, safe and efficacious, would you vote for approval or not?

            DR. SCHEIN:  Presuming all the information is in the labeling, I would vote for approval.

            DR. WEISS:  Okay.  Fine.  Eight‑one.  Any other labeling issues?  Okay.  Seeing no other labeling issues, does the FDA have any other questions that they want the panel to address?

            MS. THORNTON:  Last chance.

            DR. WEISS:  Last chance.  Okay.  Seeing no other questions, then we are going to go to our open public hearing.  And seeing no one for the open public hearing, we will now move on from that.  I hear applause, so that might have been the correct decision.  FDA closing comments.  No closing comments.  I think everyone has been beaten into submission.  Sponsor closing comments.  Ah, FDA closing comments.

            DR. CALOGERO:  Yes.  Hi there, Don Calogero.  I'd like to clarify something.  I think there's a little sort of confusion here in terms of these rates.  And we were throwing out rates, Dr. Macsai threw out rates, 1.8 percent, ANSI is 2 percent, the panel gave a rate of 1.5 percent, all in the same ball park.  But the rate that you threw out, 1.8 percent and Gerry calculated 2 percent, those are mean rates.  The rates from ANSI and the rates from that panel discussion are the upper 90 percent confidence intervals.  So in terms of ANSI and that discussion, the upper 90 percent confidence interval needs to be below that point.

            If you look at the upper 90 percent confidence interval of the data out to three years, it's actually about 3‑1/2 percent.  So you're saying 3‑1/2 percent, then is acceptable.  If you look at the Sponsor's data, from year 3 to year 4, at the upper 90 percent confidence interval, they have met that criteria of 1.5.  It's 1.42 or something.

            The only problem that I hear from the discussion about that data is, it may ‑‑ that group may not be representative of the entire population.  You may sort of a sampling bias or something, so I just want to point out that there's sort of a little miscommunication here, or confusion.  The actual rates that the Sponsor has from year ‑‑ three months to three years are very different than the levels that ANSI has, and ISO has, and was recommended previously by the panel, so I just wanted to clear that up.

            DR. GRIMMETT:  Thank you.

            DR. WEISS:  Sponsor closing comments.

            DR. SLADE:  The battery on our laptop is not up to the length of your discussion.

            DR. WEISS:  That comforts me, Dr. Slade.

            MS. THORNTON:  Do you want the projector on?

            DR. SLADE:  Yes.  We would like the projector on.  I really appreciate you all staying to listen to my talk.  Okay.  There.  Okay.  And what I would like to do is give you our closing comments from the Sponsor.  Excuse me just a minute.  This is not actually my computer.  Is the toggle F10?  F8.  Okay.  Super.

            Let's just go right to the chase to our comments.  What do we know, and what do we not know about this PMA and this device?  What are the current standards of requirements for safety of the corneal endothelium for any device?  And what do we know about endothelial safety for this particular device?  What information do we have to support a determination of reasonable assurance with post‑market labeling and follow‑up, a reasonable assurance of safety today, and how do we best add to the evolving knowledge‑base in this area over time, a needed area, a needed area for our patients.

            We've looked at the standards for endothelial cell safety.  The ANSI standards of 1‑1/2 percent.  You add the .6 percent, somewhere around 2 percent, and we don't have any targets for hexagonality, or coefficient of variation, although we've seen that those can be the most sensitive indicators of endothelial stress.  That's what we know is the standard.

            Endothelial safety with the ICL, we have a cumulative total mean loss of 8.4 to 9.7 percent.  We do have suggestion of endothelial cell stabilization, or a leveling of cell loss between 3 to 4 years.  We have it with two different cohorts, the 57 eye cohort, and the 37.  While those aren't our largest numbers, those are our best models.  The 37, for example, are the people who made every single visit, so it's the best models, and we can certainly post‑ marketly follow that particular cohort up.

            And then in addition to that, in addition to that, we have the percent hexagonality and the coefficient of variation data, which easily supports the absence of chronic endothelial stress.  This is that 37 eye cohort I just mentioned.  And if anything, it's trending to a leveling‑out, or certainly no farther down.

            It's important to look at these again.  This is the percent of hexagonal cells.  Anything over 45 percent is a winner, and this is clearly, throughout the entire follow‑up, over that, and it's stable.  It's not dancing around.

            The coefficient of variation is the same thing.  Anything that is not above 45 is, again, a winner.  And this does fit into that to the adequate confidence intervals, and it's stable.  It's stable over time, just like the visual acuity results, just like the refractive stability that I showed you.

            Further, if you're trying to figure out the safety of this lens, I would challenge you to postulate a clear mechanism for chronic endothelial cell loss due to the clinical procedure, which is cataract surgery with a lot of the steps left out, or the ICL, the material itself, which is a proven approved material behind the iris.  We have no evidence of inflammation over time when assessed with the most sensitive methods we have today.  Don Sanders, I think, made that point clear.  And we have no evidence of corneal stress or instability based upon the most sensitive measures of morphology by I think who we ‑‑ the person, Henry Edelhauser, who we all respect, over time.  Again, you've seen the morphology of endothelial cells.  If we look at the cell flare study, at no point in time did we ever get the cohort outside the normal range.  That's significant.

            Further, I think we should stress again what Hank Edelhauser presented to us.  There's a change.  We're learning about our understanding of the corneal endothelium.  There does appear to be a reservoir of endothelial cells in the corneal periphery, based upon his lab, and earlier confirmatory studies.  There's even the good evidence for peripheral corneal endothelial stem cells, even in adult corneal tissue.  And again, Dr. Edelhauser, I think, has well‑documented this, just the simple references, the fact of increasing cells.  And then when we make our incision into the cornea, we're not even approaching where we have most of these safety cells, which is superior.

            Further, our understanding of the corneal endothelium, I think we've all struggled today.  And if anything, it's proven that a linear modeling of endothelial cell loss over time is difficult based upon our current knowledge‑base.  The non‑homogenate  endothelial cell density, the presence of an endothelial cell reserve in the periphery, including the stem cells, and the potential for these cells to migrate from the higher density periphery to the lower density central endothelium further supports reasonable safety for this device.

            From Dr. Edelhauser, the higher endothelial cell density found in the paracentral and peripheral cornea affords an additional reassurance of safety beyond the morphology for the endothelium in patients implanted with the ICL.  The surgical incision for the ICL is corneal, and temporal, and it's at a distance, and it's only a couple of clock hours away from the largest endothelial reserves which reside in the superior corneal.

            So to finish this out, what do we know today?  And we actually know, I think, a fairly good deal.  Well, we realized, and we continue to realize the need for additional options, additional good clinical options in refractive surgery.  And one note about this ‑ the beauty of this is it's a non‑dose dependent procedure.  LASIK, the more LASIK you do, the more trouble you run into.  This is the same procedure, the same lens, whether it's a minus 3 or minus 15, or a minus 20.

            Endothelial morphology represents a highly sensitive measure or indicator of corneal endothelial stability, and I think we've seen the results, seen the studies that back that up.  And in the ICL population, I don't know how the results could be any better.  It clearly indicates a stable endothelium without stress by morphology.

            We believe the stabilization of endothelial cell loss occurs between three to four years.  We have the absence of any cases of corneal decompensation in ten years of history greater than 30,000 implants internationally.  Again, as I mentioned, I don't know if we got all of the data from those patients, but I do believe that the first person that had a corneal decompensation would be quite ‑ ‑ we'd know about that.

            There is a iron‑clad Sponsor commitment to continued specular microscopy data.  I don't have a financial interest in STAAR.  I wasn't an investigator in this study.  I am a paid consultant, but I can assure you of their commitment to continue the collection of specular microscopy data post‑market approval, in all study patients through five years or beyond with the same rigor of analysis, the same lab, the same Dr. Edelhauser looking at the specular microscopy images.

            So a long‑term commitment to surveillance of study patients for all safety findings.  A well‑developed training program.  Now we've had the ‑‑ you know, is this something that only the creme de la creme surgeons can do?  Well, remember when LASIK came along and everybody would say well gee, that's pretty crazy.  You know, only corneal surgeons should be doing that.  And it just didn't pan out that way.

            I would submit to you that that was a procedure where surgeons had to learn new steps.  This, they don't.  It's all cataract steps.  I do believe strongly, having been involved in directing the LASIK courses, that the training program will be excellent and superlative beyond what we've had before.  And finally, the Sponsor is totally committed to labeling to encompass your recommendations, no matter how many volumes, or how the package insert becomes.  And that to the panel and the FDA, to provide further assurance of safe use of the ICL.

            I submit to you that the clinical data presented in the PMA does establish the effectiveness of the myopic ICL for the correction or reduction, as labeling ‑‑ as we are dictated to by you for labeling, between minus 3 and minus 20.  And I submit to you that the clinical outcomes presented in this PMA provide a reasonable assurance of safety of the myopic ICL in this patient population, this study designed for moderate to high myopia.  Thank you very much.

            DR. WEISS:  Thank you very much, Dr. Slade.  I would like to thank the Sponsor for an excellent presentation, the primary reviewers, and the member of the panel, as well as the agency for the usual detailed evaluation of the data, and now we will move to the voting options, which will be read by Sally Thornton.

            MS. THORNTON:  "The Medical Device Amendments to the Federal Food, Drug and Cosmetic Act as amended by the Safe Medical Devices Act of 1990 allows the Food and Drug Administration to obtain a recommendation from an expert advisory panel on designated medical device pre‑market approval applications that are filed with the agency.  The PMA must stand on its own merits, and your recommendation must be supported by safety and effectiveness data in the application, or by applicable publicly available information.

            Safety is defined in the Act as reasonable assurance based on valid scientific evidence that the probable benefits to health under conditions on intended use outweigh any probable risk.  Effectiveness is defined as reasonable assurance that in a significant portion of the population, the use of the device for its intended use is in conditions of approval when labeled will provide clinically significant results.

            Your recommendation options for the vote are as follows.  Number one, approval, if there are no conditions attached.  Number two, approvable with conditions.  The panel may recommend that the PMA be found approvable, subject to specified conditions, such as position or patient education, labeling changes or a further analysis of existing data.  Prior to voting, all of the conditions should be discussed by the panel.  Not‑approvable.  The panel may recommend that the PMA is not approvable if the data do not provide a reasonable assurance that the device is safe, or if a reasonable assurance has not been given, that the device is effective under the conditions of use prescribed, recommended, or suggested in the proposed labeling.

            Following the voting, the Chair will ask each panel member to present a brief statement outlining the reasons for their vote."  Thank you.  Jayne.

            DR. WEISS:  Thank you.  I'd like to have someone make a motion.  Dr. Sugar.

            DR. SUGAR:  I'd like to move approval with conditions with the volumes of conditions that Steve Slade mentioned.

            DR. WEISS:  Well, one of the ‑‑

            MS. THORNTON:  Well, you can't do that.

            DR. SUGAR:  I know, but Jayne has them all listed on her computer, and she can give us the words.

            DR. WEISS:  Okay.  Do we have a second for approval with conditions?  Dr. Mathers and Dr. Macsai second it.  There were two conditions, there was a choice of one condition that I think we do need to have the panel list.  We will, of course, vote on the secondary motions, the conditions, before we vote on the primary motion.  But the secondary motion, as far as data to be included for specular microscopy and when that would be needed ‑ I need someone to phrase that for me, because there was a disagreement among the panel, and I need that to be included here.

            MS. THORNTON:  Are you calling for a condition now?

            DR. SUGAR:  Yes.

            DR. WEISS:  What is your ‑‑

            DR. SUGAR:  With the condition that after approval, data continue to be acquired on endothelial cell density on an annual basis, up to a minimum of five years.

            MS. THORNTON:  Is there a second?

            (Seconded.)

            DR. WEISS:  So there's a second for the ‑‑ and can you repeat that condition, Dr. Sugar, because what ‑‑ if it's all right with agency, before we go on with additional ‑‑

            MS. THORNTON:  We can discuss it after the second.

            DR. WEISS:  Okay.  Can you repeat what that motion is and then we're going to have discussion of that.  And the a vote of that condition.

            DR. SUGAR:  Approvable with conditions.  One of the conditions being that data continue to be acquired on an annual basis on endothelial cell density to at least five years.

            DR. WEISS:  Can you ‑‑

            DR. GRIMMETT:  For clarification, he's recommending approval now, post‑market later.

            DR. ROSENTHAL:  Approval now, and the endothelial cell data will be collected after the approval ‑‑

            DR. SUGAR:  Correct.

            DR. ROSENTHAL:  ‑‑ for four and five years.  And longer, if need be.

            DR. WEISS:  Okay.  So approval now, and I would like the panel to be extremely clear when they vote on this.  This is approval now, and then the endothelial cell count data will be collected afterwards, after approval.  We will have a discussion, and Dr. Bradley will have the first point.  After we have discussion of this secondary motion, we will vote on the secondary motion before we go on to other labeling.  Dr. Bradley.

            DR. BRADLEY:  I thought in our earlier discussions that approval was going to be conditional upon the four year data convincing us that, in fact, endothelial count decline was not at a dangerous level.

            DR. GRIMMETT:  Then vote against this motion.

            DR. WEISS:  This is why I wanted a particular motion put forward for a vote.  If you disagree with this, as Dr. Grimmett so kindly pointed out, then you vote that you disagree.  And if you agree with it, then you vote that you agree.  Is there any discussion, aside from when you disagree you vote no, and when you agree you vote yes.  I assume not, so Dr. Ho.

            DR. HO:  Allen Ho.  I would like to add to that, as part of discussion, that the annualized rates of retinal detachment be included.

            DR. WEISS:  This is separate.  That's a separate condition.  This is not, as Dr. Slade indicated, we will have a volume coming up.  But hopefully, it will be done shortly enough.  This is just this particular point.  Dr. Bradley.

            DR. BRADLEY:  A question ‑‑ the motion is that the data be collected post approval.

            DR. SUGAR:  That's correct.

            DR. BRADLEY:  Do you have any desire that something specific be done with the data once collected, or is that irrelevant to your motion?

            DR. SUGAR:  It's certainly not irrelevant. I don't know how specific we need to be with that, but the data be reviewed by the agency and apropos of our discussion, if the endothelial cell density continues to decline at the same rate, that the issue be represented either to the panel, or that there be some further discussion about whether approval should be continued.

            DR. WEISS:  Just for clarification, Ralph, what would the ‑‑ aside from the statement that Dr. Sugar just made as far as collecting the data, do you need any further clarification at this point from the panel what we mean by collecting the data, what we want you to do with the data, or that would be sufficient for you at this point?

            DR. ROSENTHAL:  I think we understand the mood of the motion.

            DR. WEISS:  Okay.  The mood ‑‑

            DR. ROSENTHAL:  The question is, and I'm not sure I can give you an answer, is if the endothelial cell count continued to drop at 4 and 5 years, I'm not sure what our options would be.  And that is something we would have to take up with higher order people in the agency.**

            DR. SUGAR:  Well, could not rescind approval?