The LASIK industry & the FDA have conspired since LASIK's inception to purposely withhold information vital to the public in making a truly informed LASIK decision. With Lasikdecision.com, The hope is to show you what the industry and FDA would not and did not even think of doing until LASIK casualties started speaking out, and yet, they still did NOTHING.
What's OK by the FDA... PDF Print E-mail
Thursday, 15 December 2005 19:00
This was found in a hearing for CK approval, but it gives you an idea of what's OK by the FDA...

A surgeon can give patients 2 diopters of induced astigmatism as long as it's less than 5% of eyes. That's a LOT of blurry vision folks, and for the record... induced astigmatism was not in my informed consent materials. Was it in yours?

"As shown in this slide, the absolute change in refractive cylinder remained well below the FDA limit of less than 5 percent of eyes with greater than 2 diopters of induced cylinder at all follow-up examinations." P36 lines 6-9.

The below was found at: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3806t1.rtf

UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

     CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

   + + + + +

OPHTHALMIC DEVICES PANEL MEETING

102ND MEETING

+ + + + +

FRIDAY        NOVEMBER 30, 2001

 The panel met at 9:45 a.m. in the Whetstone Room of the Gaithersburg Holiday Inn, Two Montgomery Village Avenue, Gaithersburg, Maryland, Dr. Joel Sugar, Interim Chair, presiding.

                     Present:

JOEL SUGAR, M.D., Interim Chair

ARTHUR BRADLEY, Ph.D., Voting Member

MICHAEL R. GRIMMETT, M.D., Voting Member

ALLEN C. HO, M.D., Consultant

ANDREW J. HUANG, M.D., Consultant

JANICE M. JURKUS, O.D., Consultant

WILLIAM D. MATHERS, M.D., Consultant

ALICE Y. MATOBA, M.D., Voting Member

RONALD E. McCARLEY, Industry Representative

TIMOTHY T. McMAHON, O.D., Consultant

JOSE S. PULIDO, M.D., Consultant

JAYNE S. WEISS, M.D., Voting Member

SARA M. THORNTON, Executive Secretary

                       I-N-D-E-X

Call to Order, Joel Sugar, M.D., Interim Chair  4

Introductory Remarks, Sara M. Thornton, Executive Secretary      4

Open Public Hearing     11

                  Open Committee Session:

FDA Presentation         13

Division Update, A. Ralph Rosenthal, M.D.      18

                        Branch Updates

Everette T. Beers, Ph.D.           18

James F. Saviola, O.D. 19

PMA P010018            24

Sponsor Presentation    25

Panel Questions            57

FDA Presentation         91

Joel P. Glover   91

Sheryl L. Berman, M.D.           92

Panel Questions for FDA          99

Additional Comments from the Sponsor           101

Committee Deliberations           109

                     Primary Panel Reviewers: 

Arthur Bradley, Ph.D.   109

Michael R. Grimmett, M.D.      125

Jayne S. Weiss, M.D.   139

Open Public Hearing Session    195

FDA - Closing Comments        196

Sponsor - Closing Comments   196

                     I-N-D-E-X

Voting Options Read    196

Panel Recommendation Taken by Vote 205

Polling of Panel Votes   217

Final Panel Comments  220

Adjourn            221

            P-R-O-C-E-E-D-I-N-G-S

            (9:49 a.m.)

                        DR. SUGAR:  I'd like to call this meeting of the Ophthalmic Devices Panel to order.  And have introductory remarks from Sara Thornton.

                        MS. THORNTON:  Is everybody here?  All present and accounted for?

                        Good morning and welcome to the 102nd meeting of the Ophthalmic Devices Panel.  Before we proceed with today's agenda, I've a few short announcements to make. 

                        I would like to remind everyone, that's Panel, public, FDA, to sign in on the attendance sheets in the registration area just outside the meeting room. 

                        All of the public handouts for today's meeting are available at the registration table. 

                        If there are messages for Panel Members and FDA participants, information or special needs, they should be directed through Ms. Ann-Marie Williams, Ms. Shirley Meeks or Mr. Hashim Khalif, who are available in the registration area.

                        The phone number for calls to the meeting area here is 301/948-8900 and instruct your people if you contact them in advance for something that they need to just ask for the FDA registration desk.

                        In consideration for the Panel and the sponsor, the Agency, we ask that those of you with cell phones and pagers either turn them off or put them on vibrator mode while you are in this room. 

                        We ask that all meeting participants please speak into the microphone and give your names clearly, so that the transcribers will have an accurate recording of your comments.

                        The next Ophthalmic Devices Panel meeting will be on Thursday and Friday, January 17th and 18th, 2002.  All available information for that meeting will be on the Advisory Committee website in approximately one week.

                        Now at this time I'd like to extend a special welcome and introduce to the public the Panel and the FDA staff, three Panel Consultants who are with us for the first time today and our new Industry Rep.  One of our new consultants, beginning with Dr. Allen Ho comes to us from Philadelphia where he is an Associate Professor of Ophthalmology at the Thomas Jefferson University School of Medicine and an Associate Surgeon with the Retinal Service at the Wills Eye Hospital.  Dr. Ho, we welcome you.

                        Dr. Andrew Huang is from Minneapolis, Minnesota where he is an Associate Professor and the Director of the Cornea and External Disease Service of the Department of Ophthalmology at the University of Minnesota.  We welcome you also, Dr. Huang.

                        And our third new Panel Consultant, Dr. William Mathers is from Portland, Oregon where is Professor of Ophthalmology at the Oregon Health Sciences University, Casey Eye Institute and is a specialist in cornea and external disease.  Welcome, Dr. Mathers.

 

                        And Mr. Ronald "Rick" McCarley, the Industry Representative to the Panel who is President, CEO and Founder of Ophtec USA, Inc.  Welcome, Rick.

                        We very much appreciate your commitment to serve and we welcome you, all of us welcome you to the Panel table today. 

                        To continue, will the remaining Panel Members please introduce themselves beginning with Dr. Pulido.

                        DR. PULIDO:  Jose Pulido, Professor and Head of the Department of Ophthalmology, University of Illinois, Chicago.

                        DR. McMAHON:  I'm Tim McMahon, Professor, University of Illinois, Chicago.

                        MS. THORNTON:  I can't hear Dr. McMahon very clearly.  You want to check that one out.

                        DR. McMAHON:  Tim McMahon, Professor, University of Illinois, Chicago.

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

                        DR. WEISS:  Jayne Weiss, Professor of Ophthalmology and Pathology, Kresge Eye Institute, Wayne State University, Detroit.

                        DR. SUGAR:  Joel Sugar, Professor of Ophthalmology, also University of Illinois, Chicago.

                        DR. GRIMMETT:  Michael Grimmett, Assistant Professor, University of Miami, Bascom Palmer Eye Institute.

                        DR. MATOBA:  Alice Matoba, Associate Professor, Department of Ophthalmology, Baylor College of Medicine.

                        DR. JURKUS:  Jan Jurkus, Professor of Optometry, Illinois College of Optometry in Chicago, Illinois.

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

                        MS. THORNTON:  Thank you, Panel.  I'd like to note for the record and with regret, that Ms. Glenda Such, our new Panel Consumer Representative cannot be with us today.  Earlier this week she had to undergo surgery so we wish her a speedy recovery and we look forward to having with us at our January meeting.

                        DR. SUGAR:  Thank you, Sally.  We now have time for an open public hearing.

                        MS. THORNTON:  Wait, I've got two more things.

                        DR. SUGAR:  I missed something.  We still have time for that.

                        MS. THORNTON:  Two more things.  Okay, here we go.  I'd like to read the conflict of interest statement for this meeting.  The following announcement addresses conflict of interest issues associated with this meeting and is made part of the record to preclude even the appearance of an impropriety.  To determine if any conflict existed, the Agency reviewed the submitted agenda for this meeting and all financial interests reported by the Committee participants.  The conflict of interest statutes prohibit special government employees from participating in matters that could affect their or their employer's financial interests.  However, the agency has determined that participation of certain members and consultants, the need for whose services outweighs the potential conflict of interest involved is in the best interest of the government.  Therefore, a waiver has been granted for Dr. Michael Grimmett, for his imputed interest in a firm at issue that could potentially be affected by the Panel's recommendations.  The waiver allows this individual to participate fully in today's deliberations.  Copies of this waiver may be obtained from the Agency's Freedom of Information Office, Room 12A-15 of the Parklawn Building.

                        We would also like to note for the record that the Agency took into consideration certain matters regarding Drs. Arthur Bradley, Timothy McMahon and Allen Ho.  These Panelists reported past and/or current financial interests in firms at issue, but in matters not related to today's agenda.  The Agency has determined, therefore, that they may participate fully in today's deliberations.    

                        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.

                        I'd like to now read the appointment to temporary voting status.  Pursuant to the authority granted under the Medical Devices Advisory Committee Charter dated October 27, 1990 and as amended, August 18, 1999, I appoint the following individuals as voting members of the Ophthalmic Devices Panel for this meeting on November 30, 2001:  Drs. Janice Jurkus, Allen Ho, Andrew Huang, Timothy McMahon, William Mathers, Jose Pulido, Joel Sugar.  In addition, I appoint Dr. Joel Sugar to serve as Interim Panel Chair for the duration of this meeting.

                        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 material to be considered at this meeting.  This is signed David W. Feigal, Jr., M.D., M.P.H., Director of the Center for Devices and Radiological Health, dated November 16, 2001.

                        Thank you, Joel.

                        DR. SUGAR:  Thank you again.  We now have time for open public hearing.  If anyone has public statements to make, they need to identify themselves and state any financial conflicts or potential conflicts. 

                        There is a submission by mail that Sally will read.

                        MS. THORNTON:  This is a letter submitted to be read at this meeting by Dr. I. Howard Fine, President of the American Society of Cataract and Refractive Surgery, Clinical Associate Professor of Ophthalmology, Casey Eye Institute, Oregon Health and Sciences University.

                        "Dear FDA Panel Members, unfortunately, I was not able to attend today's Panel meeting scheduled to review the conductive keratoplasty procedure.  However, in my absence, I would like to request that this letter be read aloud on my behalf.  As part of full disclosure, I would like to inform the Panel that I am a member of Refractec's Medical Device Advisory Board.  However, I hold this position gratis.  I am not paid for my time to participate on the Board, nor do I have an equity position in the company.  As a Medical Advisor, I feel that the outcomes from the clinical trial are as safe and effective as those presented by other refractive technologies.  I make this statement with confidence as I am current President of the American Society of Cataract and Refractive Surgery and in this role have the opportunity to see and review many scientific presentations on refractive procedures.  One very promising aspect of conductive keratoplasty is the potential for the technique to not induce dry eye post-operatively.  As we all know, Lasik transects the cornea nerves, therefore inducing dry eyes in most patients.  The investigators participating in the conductive keratoplasty trial have all reported little or no dry eyes post-operatively with this technology.  I feel that the addition of another refractive technology will only strengthen our ability to practice medicine and allow us to provide our patients with the most appropriate procedure for them and their condition.  For these reasons, I respectfully ask the Panel Members to approve conductive keratoplasty, allowing the Members of the ASCRS and ophthalmologists throughout the U.S. to utilize this technology.  Sincerely, Dr. Howard Fine."

                        Thank you, Dr. Sugar.

                        DR. SUGAR:  Thank you.  This now closes the open public hearing session and we'll move on to the open committee session and we'll begin with a presentation by Dr. Statland from the FDA.

                        DR. STATLAND:  Good morning.  It's nice to be here for a number of reasons.  One, it's always good to get out of the shop occasionally and see the real world events in front of us and this Panel Meeting is an example of a very important real world event.  And second, in a very general way, to acknowledge all of you on the Panel who diligently look at the material given to you, make a scientific, clinical and pragmatic assessment of the information and give us your best recommendations.

                        I also for the third reason I'm here, is to give some plaques and some awards for individuals who served the FDA and there are four individuals that I'm going to acknowledge today and if you'll just bear with me.  I have a short paragraph about each of you, so when I mention your name, don't be too concerned and I'll give you information.

                        First of all, one individual who actually received her placque earlier is Marcia, where is she?  Marcia Yaross, Dr. Yaross is the Director of

World-wide Regulatory Affairs and Medical Compliance for Allergen of Irvine, California.  She graduated Reed College in Portland, Oregon with a degree in Biology and completed her doctorate in Cell and Developmental Biology at the University of California in Irvine.  After a career in Biological Research, she entered the field of regulatory affairs as a Regulatory Affairs Coordinator for a major manufacturer of ophthalmic devices and has responsibility for many of the types of devices reviewed by the Ophthalmic Devices Advisory Panel.  And as you know, she was the Industry Representative.  Thank you for time and effort.

                        Now for the three individuals here on the Panel, okay, the first is for Joel Sugar.  Dr. Sugar, as you probably all know, is a Professor of Ophthalmology, the Director of Cornea Service and Vice Chair of the Department of Ophthalmology at the University of Illinois, Eye and Ear Infirmary in Chicago.  He graduated from the University of Michigan Medical School and completed a residency in Ophthalmology at Washington University in St. Louis and a post-graduate fellowship in Cornea and External Disease at the University of Florida Medical School in Gainesville.  Dr. Sugar is currently on the Board of Directors of the Eye Bank Association of America and also is on the Accreditation Committee and the Medical Advisory Board where he served as Chairman from 1991 to 1996.  He has published extensively and is internationally recognized for his research and publications on many specific aspects of corneal surgery, in addition to addressing numerous issues on corneal diseases, contact lens, intraocular lenses.  Dr. Sugar and the two other individuals will be basically acting as special government employees at this particular meeting, so I will hand to him and to all the others both a letter from Linda Suydam, expressing in the same words of appreciation as well as this placque for recognition of distinguished service.

                        DR. SUGAR:  Thank you very much.

                        DR. STATLAND:  My pleasure.  The next individual to be recognized is Dr. Janice Jurkus who is a Professor of Optometry at the Illinois College of Optometry in Chicago.  She received her Optometry degree from the Illinois College of Optometry and a Master's in Business Administration from Loyola University, also from Chicago.  In addition to her professional involvement as a contact lens clinician, educator and coordinator of practice management, she is chairperson of the Faculty Council Executive Committee.  Dr. Jurkus is a Fellow of the International Association of Contact Lenses Educators, a Fellow of the American Academy of Optometry and serves on the editorial board of Optometric Management.  She has lectured and published extensively on contact lens materials and design, clinical complications, patient education and informed consent and is internationally recognized for her expertise.

                        DR. JURKUS:  Thank you very much.

                        DR. STATLAND:  My pleasure.  The last individual to receive the award is Dr. Jose Pulido.  Dr. Pulido is Professor and newly appointed Chairperson of the Department of Ophthalmology, University of Illinois Eye and Ear Infirmary in Chicago.  He received his Bachelor's and Master's degrees from the University of Chicago in four years and consequently his M.D. from Tulane University School of Medicine in New Orleans. Following his Ophthalmology residency at the University of Illinois, he completed a fellowship in vitreoretinal surgery at the Bascom Palmer Eye Institute, University of Miami School of Medicine in Miami.  He also has an M.B.A. from the University of Iowa.  He is presently the National Director for Diabetes 2000 and serves as an editor for EyeNet.  In addition, he's reviewer for numerous publications that include the Archives of Ophthalmology, American Journal of Ophthalmology, and Investigative Ophthalmology and Visual Sciences.  Dr. Pulido is a Member of the Retina Society, the Macula Society, the American Uveitis Society and the American Ophthalmology Society.  Congratulations.

                        DR. PULIDO:  Thank you very much.

                        DR. STATLAND:  As I listen to myself speak and realize all the attributes that all of you have and all the other Panelists as well, as I said before, I think we're so fortunate.  We benefit so much from the excellent input that you give to us.  We listen well, we are interested in what you have to say and just to state one more time that those individuals who have completed their term are acting today as special government employees and we appreciate that as well.  So thank you for giving me this opportunity of being here and making these presentations.  Have a great meeting.

                        (Applause.)

                        DR. SUGAR:  Thank you very much. Dr. Statland.

                        DR. PULIDO:  Mr. Chairman, I would like to say some words, this being my last meeting here and that is over the last few months, we've heard a lot about public safety and public safety officers and I can assure you that over these last four years I have had the opportunity to work with some wonderful public safety officers.  These people in the FDA walk a very, very fine line between the needs of our private enterprises here in the United States and the need for public safety and I know that they are extremely pushed to try to do the best they can to serve both their constituencies and it's been an honor and a privilege to have worked with them.  Thank you.

                        DR. SUGAR:  I'd like to now move on to the Division Update.  Dr. Rosenthal?

                        DR. ROSENTHAL:  The only thing I have, Mr. Chairman, is that the -- which is not related to Ophthalmology, but is part of the Division, so I will update you, is that we've been fortunate enough to attract a new Branch Chief for our Ear, Nose and Throat Branch who is Eric Mann who is an otolaryngologist who comes to us from NIH and you will not have the opportunity and the pleasure to work with him, unless there's a combined device in which ENT and Eye is developed.  I just wanted you to know that he has joined us and we are overwhelmingly delighted that he has agreed to accept the post.

                        DR. SUGAR:  Thank you.  Dr. Beers, Donna Lochner and Dr. Saviola, do you want to -- Donna is not here?  Okay.

                        DR. BEERS:  I'm Everette Beers, Chief of the Diagnostic and Surgical Devices Branch.  I just want to update you on some recent PMA approvals.  We approved the VisX for Lasik mixed astigmatism, that was P930016, Supplement 14.  And we approved the LaserSight for Lasik myopic astigmatism, P980008, Supplement 5.  I won't go into all the indications on that, but those are approvals, supplemental approvals since our last meeting. 

                        The Diagnostic and Surgical Devices Branch has been extraordinarily busy with clinical trials that I can't discuss here and with other issues that may not be of interest to you, but we are trying to work in everyone's best interest.  Thank you.

                        DR. SUGAR:  Thank you, Dr. Beers.  Dr. Saviola?

                        DR. SAVIOLA:  Good morning.  As the former Acting Chief of the ENT Branch, as well as Branch Chief of the EDB I'm also delighted that Dr. Mann has joined us in the division.

                        I'd like to update the Panel on recent approvals of two 30-day extended wear contact lenses and give you a little bit of information about what we're doing with them.  The Focus7 NIGHT & DAY/otrafilcon contact lens was reviewed at the July Panel Meeting and it was approved October 11th.  This soft contact lens is indicated for the correction of refracted ametropia and also a number of alternate designs such as toric and progressive designs were approved with the spherical design.  The lens may be prescribed for daily or extended wear for up to 30 nights of continuous wear, for removal -- with removal for disposal or cleaning as recommended by the eye care professional.

                        A precaution statement was included in the labeling that states at the extremes of the power range above +10.00 or -15.00 diopter oxygen transmissibility is slightly below the established threshold level required to prevent overnight corneal edema.  We did not put a power restriction in the indication itself.

                        In the clinical study section results there are a few bullets about other important safety results of this study and I'll just read three of those that 14 of the FOCUS7 9-day subjects experienced infiltrates during the first month of extended wear compared to five of the control and that the FOCUS7 9-day subjects experienced more than one endpoint, excuse me, the FOCUS7 9-day subjects experienced more than one endpoint 70 percent during the first month of the trial.  And for both groups if the subject experienced an infiltrate event in one eye, the risk of a second event in the same or fellow eye was six times more likely as compared to having a first event.

                        The Bausch & Lomb Purevision balafilcon A contact lens was approved on November 20th under a supplemental submission to the existing PMA.  This lens is indicated for daily or extended wear from 1 to 30 days between removals for cleaning and disinfection or disposal.  We did put a power restriction on this one.  It's approved from +8.00 D to -2020.00D when prescribed for up to 30 days of extended wear and it already had approval for + or -20.00 for daily wear or extended wear up to 7 days.  And again, a precaution statement is included in the labeling that addresses extremes of the power range above +3.00 and -5.00 diopter.  Also that the rate of infiltrative keratitis was found to be higher with higher lens powers.

                        Now although this PMA was a second of a kind, it was originally scheduled for discussion at the September 21st Panel Meeting to discuss the need for post-market study and to provide the Panel an opportunity to review clinical data from a contralateralized study.  Two primary Panel Reviews have been completed in preparation for the meeting.

                        Due to the tragic events of September 11th, the September 21st meeting was canceled.  During subsequent discussion, it was decided that the primary clinical issues in the PMA did substantially duplicate information previously reviewed by the Panel.  Additional homework assignments from two Panel Members were obtained to corroborate the recommendation of the two primary reviewers in lieu of full Panel discussion.

                        All four Advisory Panel Reviews recommended approval of the supplement from 1 to 30 days.  Therefore, we did not refer to the full Panel for a meeting and discussion.

                        As to our plans to better communicate the risks to both patients and practitioners, we have placed a variety of restrictions on these two extended wear lenses.  For advertising, the advertising restriction was put into the approval order.  Similar to drug advertisements, print ads for the new extended lenses must include a company information to describe the indications, contraindications, warning and precautions.

                        The company, in conjunction with FDA, developed a consumer information leaflet in a question and answer format similar to information available for some prescription drugs in order to address this restriction for consumer advertisements, rather than to print the whole technical information from the package insert.

                        For labeling, practitioners will receive additional information in professional labeling.  The package insert will consider a clinical study result section that describes the study and provides information on demographics, primary safety and efficacy outcome measures and also provides a quick reference to better understand the details of the preapproval study.

                        A brief description of the study and outcomes of the study will also appear in the patient information booklet as well.

                        As far as post-approval clinical studies, as a condition of marketing approval, each manufacturer must conduct a post-market study to characterize the risk of microbial keratitis and subsequent loss of best corrective visual acuity in the general population.  Both the Ciba and B & L studies will involve about 100 sentinel monitoring sites.  These prospective active monitoring studies are designed to provide data on 4500 to 5000 patient years of subjects wearing their 1-month lenses during a 1-year period.

                        The protocols call for monitoring subjects every six months for the one year, without the detailed evaluation of all the parameters usually measured in pre-approval study.

                        While the scope of these post-approval studies does fall short of the 20,000 subjects it would take to do a statistically rigorous clinical study, they will still provide an early indication for risks in the real world setting and help to answer the questions of long-term safety in the general population.

                        These labeling initiatives provide a better opportunity for practitioners and patients to make a wearing schedule decision based on an individual patient's response to lens wear and their acceptable level of risk.

                        Thank you very much.

                        DR. SUGAR:  Thank you.  If there's no other information to be updated from the Agency, I'd like to move ahead to discussion and review of PMA P010018.  We'll begin with the sponsor presentation.  The sponsor has one hour.  I'd like each presenter to identify themselves at the beginning of their presentation.

                        DR. GORDON:  Good morning.  My name is Dr. Judy Gordon.  I have the pleasure of representing Refractec today as a regulatory consultant.  Together with Dr. Jon Hayashida, Refractec's Vice President of Clinical Affairs, we will present to this Panel the clinical trial results submitted to the FDA in P010018 for the ViewPoint Conductive Keratoplasty system.  We will be joined by two of the clinical investigators who participated in the CK trial, Dr. Marguerite McDonald who has also served as Medical Monitor for the study, and Dr. Peter Hersh, who is an investigator.

                        Dr. Dan Durrie, another of the CK study investigators, has also joined us today add his clinical perspective as a refractive surgeon is involved in multiple clinical trials of new refractive surgery procedures.  We appreciate the opportunity to present to this Panel and hope that our presentation elucidates the clinical data presented in this PMA.

                        Dr. Hayashida will begin the presentations with a brief discussion of the indication and the technology.

                        DR. HAYASHIDA:  Thank you, Judy.  Good morning.  I am Dr. Jon Hayashida.  I would like to share with you today some background information on the correction of hyperopia and the conductive keratoplasty procedure.  Historically, the surgical correction of hyperopia has been considerably more challenging than myopic corrections in that it requires steepening of the central cornea.  Currently, this is accomplished by means of excimer laser ablation and collagen shrinkage procedures that apply treatment to the peripheral cornea. 

                        Thermal keratoplasty alters the cornea curvature by heating the stromal tissue in the periphery, causing collagen to shrink.  Achieving an optimal collagen shrinkage thermal profile is critical.  If the temperature profile is too low, minimal collagen shrinkage results.  If the temperature profiles are too high, excessive tissue damage and eventual remodeling and regression of the effect occur.

                        The heating of corneal tissue can be accomplished by utilizing either laser light energy or radio-frequency energy. 

                        As shown in this photograph, the viewpoint conductive keratoplasty system consists of a portable console that generates the radio-frequency energy, a lid speculum and a handpiece in which a small tip called the keratoplast tip is held.  The keratoplast tip is used to deliver the energy for treatment, while the lid speculum serves as the return.

                        Conductive keratoplasty, or CD, involves the controlled interstromal delivery of

radio-frequency energy to a depth of approximately 500 microns in the corneal periphery.  RF energy passes from a generator to a probe tip which is 450 microns in length by 90 microns in diameter into the corneal stroma and returns via the lid speculum.

                        The impedance of the corneal tissue results in a thermal effect that is controlled to  achieve the optimal thermal profile for collagen shrinkage temperature along the entire length of the probe.  This provides a homogenous and uniform cylinder of optimally constricted collagen to a depth of approximately 80 percent of the peripheral corneal thickness.

                        To demonstrate the column of constricted collagen, histology was performed on pig corneas.  The image shown here is a transmission polarization micrograph of a CK treatment spot in a pig cornea which a corneal thickness of about 650 microns as 7 days post-operative.  The CK footprint has also been measured post-operatively in humans, using ultrasound biomicroscopy.  On average, the CK cylindrical footprint measured 405 microns wide by 509 microns deep.  We believe that it is the uniformity and depth of this footprint which contributes to the effectiveness of the CK procedure.

                        To achieve the optimal configuration for safe and long-lasting collagen shrinkage the CK treatment applications are of consistent power with an increase in the number of rings of applications to achieve greater levels of corneal steepening.  The procedure spares the visual axis, offering an important potential safety feature.

                        As shown in this videoclip of a CK procedure, the optical zone marks of 6, 7 and millimeters act as a template for the treatment appoliation.  Once the optical zone marks are applied, the surgeon begins applying treatment spots superially and continues in a cross cornea fashion for each ring, moving from the most internal ring at the 6 millimeter zone to the outside ring at the 8 millimeter zone until all of the rings of treatment are complete.

                        The stop or cuff on the keratoplast tip aids in ensuring that the tip is inserted into the cornea perpendicular to the corneal surface for each spot.

                        Stria then begin to form between the treatment spots creating a circumferential band of tightening.  It is this tightening of the tissue which results in the steepening of the central cornea.

                        In fact, with confocal microscopy, we have been able to establish the continued presence of stria between treatment spots at 12 months post-operatively.  These observations are consistent with the clinical effects observed post-CK.

                        In conclusion, we believe that the application of radio-frequency energy in the conductive keratoplasty procedure has clinical advantages over other methods of collagen shrinkage based on the mechanism of action.  In support of this, Dr. Marguerite McDonald will present the safety and effectiveness data generated in the IDE clinical trial of conductive keratoplasty.

                        DR. McDONALD:  Thank you, Jon.  Good morning.  I am Dr. Marguerite McDonald and I served as both the Medical Monitor and as principal investigator for the IDE clinical trial of conductive keratoplasty.  I wish to share with you the clinical results of this phase 3 clinical trial designed to evaluate the safety and effectiveness of the Viewpoint CK system for the correction of hyperopia.

                        This is a list of the principal investigators who participated in the CK trial.  This group represents many leaders in corneal refractive surgery and also represents a mix of private practitioners and academic centers so several types of surgeons contributed to the CK clinical trial and to the understanding of this procedure.  The CK clinical trial was designed and conducted in accordance with FDA guidance for hyperopia treatment.  Eligible eyes within +0.75 to +3.25 diopters spherical hyperopia and had no more than -0.75 diopters refractive cylinder, translating into baseline cycloplegic spherical equivalent of +0.75 to +3.00 diopters.  All treatments were based on pre-op cycloplegic refraction spherical equivalent with a treatment goal of full correction of spherical hyperopia.  No cylinder corrections and no retreatments were performed in this study.

                        The standard effectiveness measures were improvement in uncorrected acuity, predictability of the refractive outcome, refractive stability, and patient satisfaction. 

                        Safety parameters included measurement of best corrected vision, induced cylinder, endothelial cell loss, patient symptoms and as far as any clinical trial complications and adverse events.

                        A total of 401 eyes of 233 subjects were enrolled in this study and demographics for this population are shown here.  Consistent with other clinical trials of refractive surgery procedures, a larger number of women than men were enrolled and the mean age of the study population was approximately 55 years.

                        Critical to any hyperopia study is the exclusion of latent hyperopes, therefore entry criteria for the study required that no more than >.05  diopter difference between the pre-op MRSE and CRSE would be allowed as demonstrated in this slide.  Please note that in the original study protocol, 54 eyes with CRSE of 1.00 to 4.000 diopters were enrolled.  Additionally, you will note that two ineligible eyes were enrolled, accounting for the MRSE range extending to -0.38 diopters.

                        Approximately half of all eyes enrolled had baseline MRSE and CRSE between 1.00 and 1.99 D and over a third of eyes had baseline MRSE of greater than or equal to 2 D.  As I mentioned on the previous slide, eyes with up to 4.00 diopters of spherical equivalent were enrolled in the initial phase of study prior to a nomagram adjustment that limited the upper range of treatment.

                        This nomagram adjustment was based on the results of the 54 eyes treated in the initial phase of the CK clinical trial.  Analysis of the outcomes of these eyes revealed overcorrection at the low end of the treatment range and under correction at the upper end of the range.  On the basis of these data, Refractec implemented a reduction in the maximum treatment from 4.00 to 3.25 diopters of spherical hyperopia and the addition of an 8 spot treatment pattern for eyes with base.line CSRE of 0.75 to 0.85 D.

                        Accountability in the study was excellent with at least 97 percent available eyes examined at each visit.  Ninety-four percent of all eyes enrolled were available for analysis through the 9-month examination and just over 50 percent of eyes had reached the 12-month examination at the time the data base for this PMA was locked.  As the medical monitor for this study, I've been very impressed with the effort to ensure that patients' follow-up is complete.

                        This flow chart shows the total population of 401 eyes enrolled and the relevant cohorts.  Thirty-eight eyes were not treated with the current nomagram and are therefore not included in the effectiveness cohort of 363 eyes.  The safety cohort includes all enrolled eyes with the exception of a single that was discontinued from the study prior to treatment.

                        Effectiveness data will be reported for the 363 eyes treated with the current nomagram while safety instability will be presented for all 400 treated eyes. 

                        We will now move on to a review of the effectiveness data generated in the CK clinical trial.  Before describing the effectiveness outcomes in detail, I would like to review this summary of effectiveness.  As you can see from this slide, key effectiveness targets established in FDA guidance were met.  Uncorrected visual acuity of 20/40 or better exceeded the FDA target of 85 percent from the 6-month visit forward as did the proportion of eyes with MRSE within .50 diopter and within 1.00 diopter of plano.  Targets were exceeded for change in MRSE less than or equal to a .50 diopter and less than or equal to 1.00 diopter.  Mean change per month was small, 0.03 diopters between 6 and 9 months and increased nonsignificantly to 0.04 diopters per month between 9 and 12 months. 

                        We will now expand on the effectiveness parameters which included improvement in uncorrected visual acuity, predictability and stability of the refractive outcome and patient satisfaction.

                        As shown in this slide, uncorrected visual acuity improved over the course of follow-up with the FDA target of 85 percent of eyes with 20/40 or better achieved at the 3-month examination.  While the proportion of eyes with uncorrected acuity of 20/20 or better was low at the 1-month examination, this is likely a result of the slight overcorrection in refraction observed at 1 month.  Additionally, it should be noted that these data reflect the outcomes of a single procedure since no retreatments or enhancements were performed in this study.

                        As shown in this graphical representation, uncorrected acuity improved from 1 in 3 months to the later examinations and excellent levels of uncorrected acuity were achieved at 9 and 12 months post operative with the FDA target of 85 percent 20/40 or better achieved from 3 months forward.

                        The FDA targets for predictability of the refractive outcome are defined as MRSE within a .50 diopter of plano for 50 percent of eyes and within 1.00 diopter for 75 percent of eyes. 

                        Accuracy of the CK procedure exceeded the FDA targets at all study visits from 3 months.  At 12 months, close to 60 percent of eyes were within a .50 diopter of plano and 91 percent were within 1 diopter.  This level of accuracy of the refractive outcome is very good, particularly when considering that these results reflect the outcome of only a single procedure with no retreatments.

                        As shown in this graphical representation of predictability, the FDA targets for proportion of eyes within a .50 diopter of plano and within 1.00 diopter of plano were met and exceeded by the 3-month visit with 56 percent of eyes with .50 diopter of plano and 83 percent within 1.00 diopter.  These values increased at 6 months to approximately 60 percent within a .50 diopter of plano and close to 90 percent within 1.00 diopter of plano for the remaining visits through one year.

                        When examining a consistent cohort of 158 eyes with all visits through 12 months, the predictability of the CK procedure is further established with approximately 60 percent of eyes within a .50 diopter of the target refraction and 90 percent of eyes within 1.00 diopter of target.

                        Predictability of the CK procedure is presented here graphically to display the proportion of eyes that were under-corrected and over-corrected.  This shows clearly that the proportion of eyes initially over-corrected decreased substantially after one month and under-correction was limited to a small number of eyes throughout the course of the study.

                        Refractive stability is another key effectiveness parameter and the FDA has identified four criteria for achieving stability.  These include the proportion of eyes with a change of less than or equal to MRSE of .50 diopter and less than or equal to MRSE of 1.00 diopter.  Mean change in MRSE of less than or equal to .50 diopter on an annualized basis and decreasing to an asymptote of 0, and inclusion of 0 in the 95 percent confidence interval for mean change in periods preceding and after stability is established.

                        The stability target of 95 percent of eyes with a change of less than or equal to 1.00 diopter in MRSE between two refractions performed at least 3 months apart identified in FDA guidance was achieved at both the 6 to 9 and 9 to 12 month intervals.  Additionally, a paired analysis of mean change per month in MRSE shows very small changes in this parameter over time.  Between months 6 and 9, the mean change per month in the manifest refraction was 0.03 diopters while mean change was 0.04 diopters between 9 and 12 months.  However, these data did not achieve the remaining two FDA criteria for stability, including successive decreases in mean change over time and the confidence interval encompassing zero.

                        Stability of the cycloplegic refraction is shown in this slide.  It is noteworthy that both the proportion of eyes within the stability parameters and mean change in MSRE over time are consistent with the same measures just shown for manifest refraction.  The close match between the manifest and the cycloplegic refractive stability suggests that eyes with latent hyperopia were effectively screened out of the study, preventing masking of poor visual and refractive outcomes by accommodation.

                        Consistent with the analysis of stability of MSRE, mean change in CSRE by paired analysis was very small between 6 and 9 and between 9 and 12 months.  The upper limits of the confidence intervals were the same for both 3-month intervals and the standard deviation of the mean decreased over time.

                        When plotting both mean MSRE and mean CSRE over time, the close match between the manifest and cycloplegic refractions is again observed.  As with all corneal steepening procedures there is an initial overcorrection, but this is relatively small following the CK procedure.  This overcorrection has generally been acceptable to study patients.  Emmetropia is reached at approximately 6 months and there is less than a .25 diopter of change between 6 and 12 months.

                        To more fully characterize the stability of the refractive outcome following CK, we have also examined how much of the intended correction is retained over time and, as you will see, approximately 90 percent of the intended correction remains at 12 months.

                        As for any elective surgery, patient satisfaction is a very important measurement of the procedure's effectiveness.  Overall satisfaction is summarized in this slide.  A large majority of patients were very satisfied or satisfied with the outcome of CK treatment.  Approximately 9 to 12 percent of patients were dissatisfied or very dissatisfied at 9 and 12 months.  It should be pointed out that these findings are consistent with reports from other studies of refractive correction of hyperopia.

                        This summary slide once again demonstrates the strong effectiveness outcomes following CK with study outcomes meeting targets identified in FDA guidance for uncorrected acuity and predictability of refractive outcome. 

                        As we move to a discussion of safety parameters, please note that safety is reported for 400 treated eyes. Key safety outcomes are summarized on this slide.  As shown here, following the CK procedure, all FDA limits for safety were met in the study population.  Only 1 percent of eyes lost more than two lines of BSCVA and best corrected acuity was 20/40 or better in all eyes at 6, 9 or 12 months

post-operative.  Finally, the incidents of greater than 2D increase in induced cylinder was well below the current FDA guidance of less than 5 percent and consistent with the limit of 1 percent in the proposed draft ANSI guidance.

                        As shown on the previous summary of safety, this slide specifies the safety parameters evaluated following the CK procedure and we will provide additional detail in each of these parameters beginning with preservation of best corrected acuity.  The limits established in FDA guidance for preservation of best corrected acuity are a loss of more than two lines of BSCVA in less than 5 percent of eyes and a decrease to worse than 20/40 of less than 1 percent in those eyes with pre-op BSCVA of 20/20 or better.

 

                        In addition to the limits established by FDA guidance, we are also reporting loss of BSCVA of two lines and BSCVA worse than 20/25 for eyes with pre-op BSCVA of 20/20 or better.  As you can see from this slide in the CK study, loss of best corrected acuity was very low across each measure of this parameter.  A loss of more than 2 lines of BSCVA was reported for only 1 percent of eyes from the 3-month visit.  By 12 months, no eye had this level of loss of BSCVA.  None of the study eyes had best corrected acuity worse than 20/40 on any of these visits.

                        Of the eyes with BSCVA 20/20 or better at baseline, 1 percent at BSCVA worse than 20/25 at 6 and 9 months, but none was worse than 20/25 at 12 months.

                        If we look specifically at the population of eyes which lost 2 or more lines of BSCVA over the course of the study, you can see that the majority of these eyes had best corrected acuity of 20/32.  No eyes had BSCVA worse than 20/40.

                        I will now turn the podium over to Peter Hersh who will present information related to induced cylinder.

                        DR. HERSH:  Thank you, Marguerite.  Mr. Chairman, Panel Members, I'm Dr. Peter Hersh and I serve as a principal investigator for the conductive keratoplasty clinical trial.  My goal in this section is to present data on induced cylinder following the CK procedure.

                        FDA's guidance states that less than 5 percent of eyes are allowed to have an increase from baseline of greater than 2 diopters of cylinder.  We will also report the incidents of induced cylinder greater than 1 diopter since this is the limit reported in labeling for all refractive surgery devices used in the treatment of hyperopia.

                        Finally, at FDA's request, we will report a similar analysis using a stratification of greater than or equal to 1 diopter of induced cylinder. 

                        Since concerns have been raised regarding induced cylinder following conductive keratoplasty, and since we will be addressing these with a number of analyses, I first wanted to provide you with a summary of this information.  First, you will see that the incidents of induced cylinder after CK meets the current FDA limit of less than 5 percent of eyes with greater than 2 diopters of induced cylinder.  The cylinder decreases significantly over time and resolves in a large proportion of the eyes. 

                        In eyes with induced cylinder, there was on average one line less improvement in uncorrected visual acuity.  However, uncorrected visual acuity improved over time as the astigmatism resolved.

                        Finally, and importantly, best spectacle corrected visual acuity was not affected by induced cylinder. 

                        So let's begin here.  As shown in this slide, the absolute change in refractive cylinder remained well below the FDA guidance of less than 5 percent of eyes with induced cylinder greater than 2 diopters at all follow-up examinations.  From 6 months on, the proportion of eyes with induced cylinder of greater than 2 diopters also met the more stringent proposed limit of less than 1 percent.  Whereas, the frequency of astigmatism was relatively high at the early examinations, this decreased significantly over time.

                        The same information on absolute change in refractive cylinder is also shown here for the cohort of eyes with all visits through 12 months further demonstrating that induced cylinder decreases over time and meets FDA guidelines.

                        In a further effort to understand both the magnitude and course of astigmatism after CK, we also examined the mean induced cylinder over time.  Here you can see that the mean induced cylinder decreases to less than .50 diopter at months 9 and 12 and this decrease was statistically significant.  We also performed statistical modeling to determine whether the resolution in induced cylinder over time was associated with a loss of refractive effect with regard to historical hyperopia since this obviously would be of concern.

                        This modeling revealed that the resolution of induced cylinder was not attributable to regression of the spherical correction.

                        Next, we attempted to understand the actual clinical impact of induced cylinder.  To do this, the study population was stratified into those eyes with greater than 1 diopter of induced cylinder as compared to eyes with less than or equal to 1 diopter of cylinder.

                        Now as you can see from the slide, there was no difference between the two groups with regard to loss of spectacle corrected visual acuity at 12 months.  Indeed, there were no eyes in the induced cylinder group that lost 2 or more lines of best corrected vision.

                        We also examined of the effects on best spectacle corrected vision of manifest cylinder greater than 0.75 diopters combined with an axis shift of 30 degrees or more which the FDA considers clinically significant.  Eyes with this level of cylinder and axis shift had no change in spectacle corrected vision, while there was a loss of lines in 6 percent of eyes in the group with less than 0.75 diopters of manifest cylinder, or no significant axis shift.

                        In order to evaluate the impact of induced cylinder now on the efficacy of the procedure, we performed an analysis comparing mean lines of improvement in uncorrected visual acuity between eyes with induced cylinder and eyes with less than or equal to 1 diopter of induced cylinder.  This analysis first was performed using two stratifications.  Induced cylinder by absolute magnitude and induced cylinder by vector analysis.  As shown here, the mean UCVA in the induced cylinder group was 20/32 compared with 20/27 in the low cylinder group.

                        Furthermore, in the induced cylinder group improvement in uncorrected visual acuity was 3.3 lines compared with an improvement of 4.4 lines in the low cylinder group.  As you can see, results of this comparison using the stratifications by vector analysis yielded similar results.

                        In addition, an analysis was performed for eyes with any increase in cylinder over baseline and axis shifts of 30 degrees or more which was considered by FDA again to be clinically significant.

                        As shown here, significant shifts in axis combined with any increase in cylinder from baseline had minimal effect on uncorrected vision and no effect on lines of uncorrected visual acuity improvement.

                        These data thus suggest a difference of approximately 1 line of improvement in uncorrected visual acuity as a result of induced cylinder of greater than 1 diopter.  But only a minimal effect on uncorrected vision of any increase in cylinder over baseline when combined with significant axis shift.

                        To look further into the effect of induced cylinder on uncorrected visual acuity the change in uncorrected visual acuity over time was evaluated for those eyes with induced cylinder of greater than 1 diopter at the 1-month visit.  Consistent with the resolution of induced cylinder over time, uncorrected visual acuity improved substantially in these eyes from 1 through 12 months.

                        As shown in this graph, while the proportion of eyes with uncorrected visual acuity of 20/20 or better was low, 79 percent of eyes had uncorrected acuity of 20/25 or better by 12 months and 84 percent had uncorrected visual acuity of 20/32 or better at 9 months.

                        The FDA target of 20/40 or better in 85 percent of eyes was achieved beginning at 3 months post-operatively.

                        We next wanted to compare uncorrected acuity of 20/20 or better in eyes with induced cylinder to the eyes with less cylinder at 1 month.  The light blue bars that you see here show the low cylinder group at 1 month, whereas the dark blue bars represent the induced cylinder group.  Consistent with the resolution of induced cylinder over time, uncorrected visual acuity improved substantially in time for both groups and the proportion of eyes achieving UCVA of 20/20 or better was similar for both groups at 12 months.

                        The same comparison of eyes with induced cylinder versus eyes with less cylinder is now shown here for uncorrected visual acuity of 20/25 or better.  As you can again see from this slide, the proportion of cylinder eyes with uncorrected vision of 20/25 reached 50 percent at 3 months and there was virtually no difference between groups in uncorrected visual acuity at 9 months and at 12 months.

                        Now finally, when looking at uncorrected vision of 20/40 or better, the low and the high cylinder groups are very closely matched from 3 months forward with virtually no difference in uncorrected visual acuity.  The FDA target of 85 percent at 20/40 or better was achieved at 3 months for both groups.

                        Now we're going to shift gears a little bit and look at the data a somewhat different way.  FDA expressed an interest in looking at eyes with greater than or equal to 1 diopter of induced cylinder rather than simply greater than 1 diopter of induced cylinder and comparing these eyes to less than 1 diopter of induced cylinder.  So we're dealing here with a different stratification.

                        Consistent with the previous comparison, using the induced cylinder stratification of greater than 1 diopter there was no significant difference in the loss of spectacle corrected vision between these two groups.

                        As before, we again performed an analysis comparing mean lines of improvement in uncorrected visual acuity between eyes with induced cylinder and those with less induced astigmatism.  Here again, the data suggests approximately a difference of 1 line less improvement in uncorrected visual acuity in the induced astigmatism group and again no effect on uncorrected visual acuity when you look at a group of manifest cylinder greater than 0.75 diopters combined with an axis shift of 30 degrees or more.

                        Change in uncorrected vision over time was also evaluated for the eyes with one or more diopters of induced cylinder at one month.  Again, consistent with resolution of induced cylinder over time, uncorrected acuity improved substantially through the 12-month follow-up.

                        Finally, to complete the examination of the impact of induce cylinder after CK we looked at those eyes with induced cylinder at 1 year.  Of the total population of eyes at 1 year, there were 203; 25 had 1 or more diopters of induced cylinder and 13 eyes had greater than 1 diopter of induced cylinder.  Of these, 21 of the 25 and 9 of the 13, respectively, were treated with the current nomagram and therefore could be evaluated for effectiveness.  But first turning to safety, let's look at best spectacle corrected visual acuity.

                        Looking at safety, best corrected visual acuity was very similar for the two groups of eyes with induced cylinder.  The UCVA was 20/32 or better for all eyes and all by one eye had best spectacle corrected visual acuity of 20/25 or better. 

                        Looking now at uncorrected visual acuity, there was a substantially lower proportion of eyes with uncorrected vision at the 20/20 and 20/25 levels in the presence of induced cylinder compared with eyes with less cylinder.  However, the proportion of eyes with uncorrected vision, 20/40 or better, was 81 percent for eyes with 1 diopter or more of induced cylinder approximating the FDA guidance target.

                        Finally, let's look at the astigmatism outliers at 12 months.  A total of 9 eyes treated with the current nomagram had induced cylinder greater than 1 diopter at 12 months.  This listing presents the uncorrected and best corrected acuities as well as the satisfaction grading for these outlier eyes.

                        As you can see, post-operative, spectacle corrected visual acuity was 20/25 or better for all of these eyes and the majority of eyes, indeed, had spectacle corrected visual acuity of 20/20 or better.  Uncorrected visual acuity was 20/32 or better in 6 of the 9 eyes, whereas the remaining 3 eyes had UCVA of 20/50.

                        It's of interest to note that 5 of the 9 eyes were satisfied or very satisfied with the procedure and 2 were neutral.  One was dissatisfied and finally, one was very dissatisfied.  Overall then, as you can see, uncorrected visual acuity and best spectacle corrected vision, even in these outliers, was quite good.

                        In summary then the incidents of induced cylinder reported in the CK clinical trials meets the current FDA limit of less than 5 percent of eyes with greater than 2 diopters of induced cylinder as well as the more stringent limit of less than 1 percent which has been identified in the draft ANSI guidance.  The frequency and the magnitude of induced cylinder decreased significantly over time, resolving in a large proportion of the eyes.

                        Importantly, this resolution of induced cylinder was not attributable to regression of the spherical correction.

                        Induced cylinder assessed by absolute magnitude, vector analysis and in conjunction with access shift was associated with approximately one line less improvement in uncorrected visual acuity.  UCVA in these eyes improved over time as the induced cylinder resolved.

                        Finally, induced cylinder had virtually no effect on best corrected visual acuity, irrespective of the analyses performed and therefore does not raise any safety concerns.

                        Thank you very much.  Dr. McDonald will now continue with her presentation of the safety and effectiveness data.

                        DR. McDONALD:  Thanks, Peter.  Other safety parameters evaluated included endothelial cell loss, patient symptoms, complications and adverse events.

                        Specular microscopy, using the noncontact Conan Robocon was performed on a subgroup of eyes enrolled in the CK study and endothelial cell density was analyzed for images obtained centrally,

mid-peripherally and peripherally.  As shown in this slide, endothelial cell density remained relatively constant over the course of follow-up from baseline to 3, 6 and 12 months in all regions evaluated.

                        The percentage change in endothelial density was similarly constant over the course of follow-up with no changes observed in any of the regions evaluated.  This absence of any change in endothelial cell density or morphology over the course of follow-up, irrespective of the region examined, establishes the safety of radio-frequency energy delivered to the cornea via the keratoplast tip. 

                        Analysis of patient symptoms in determination of the clinical importance of reported symptoms, presented a reporting challenge since no limits had been established by the FDA.  Nor are there standards for collecting and reporting these data. 

                        In the absence of pre-established limits, we have utilized a level suggested by FDA during review of our PMA, an increase of 5 percent or more in moderate to very severe symptoms. 

                        A subjective questionnaire was administered to all study patients pre-operatively and at follow-up examinations.   Patients were asked to rate each of the symptoms  listed on this slide as either none, mild, moderate, marked or very severe.

                        As mentioned, FDA indicated an interest in subjective symptoms which increased from baseline levels by 5 percent or more in the categories of moderate, marked or very severe.  The symptoms which met this criteria are highlighted on this slide and include dryness, glare, halos, double vision and changes in vision. 

                        The actual incidents reported for each of these symptoms is shown here.  Again, this represents those symptoms for which a 5 percent increase from baseline and moderate and marked symptoms was reported.  It is noteworthy, that there was no significant increase in the very severe rating for any symptom.

                        When considering the actual percentage increase in the moderate and marked symptoms listed here in detail, it can be observed that all symptoms reported as moderate had an increase of 5 to 7 percent, thus just exceeding the threshold of 5 percent identified by the FDA as clinically relevant.

                        More importantly, the increase in marked symptoms reported at 6 months decreased at 9 and 12 months and as previously noted, there was no significant increase in the very severe rating for any symptom at any time during the study.

                        The final component to be evaluated for safety is reports of complications and adverse events.  FDA guidance limits the occurrence of adverse events to not more than 5 percent of eyes, with any single adverse event occurring in less than 1 percent of eyes during the study.

                        Information on complications and adverse events was collected at each study visit, using the extensive lists of reportable events identified in FDA guidance.  As you can see from this slide, the complication rate for the study was very low, with only a small number of complications reported at any time during the study.

                        Further confirmation of the safety of the CK is provided by the low incidence of adverse events.  There were only three device or procedure-related events.  In one case, a corneal perforation occurred during the procedure.  Investigation revealed that the glue bond attaching the Teflon top to the CK tip was fractured from a lateral force which may have occurred during removal from packaging allowing the stop to separate from the tip.  This subject was subsequently treated and has had excellent outcomes with uncorrected acuity of 20/16 at 12 months. 

                        Random sampling and testing of keratoplast tips indicates that this occurrence is not design or manufacturing-related and was an isolated event.  To prevent further possible occurrences, additional instructions have been added for the surgeon regarding the safe removal of the keratoplast tip from its packaging.

                        In two cases, no energy was applied during the initial treatment.  In both cases, an internal connection was found to have a poor solder joint, resulting in no delivery of radio-frequency energy.  A design change to address this was developed and tested and has been implemented following review by the FDA.  This design modification has prevented any additional occurrences.

                        Of the two eyes that were affected by this complication, one was successfully treated 3 weeks later.  The second eye was determined to be illegible for participation in the study, due to narrow angles and was therefore exited from the study.

                        Other adverse events are summarized in this slide, including IOP greater than 25 millimeters of mercury in 3 eyes of 2 patients; 1 eye with mild iritis; a retinal break that was successfully treated with argon laser; and a decrease in BSCVA secondary to optic atrophy and inferior attitudinal hemianopsia.

                        Several non-ophthalmic events were also reported including cancer, heart attack, temporal arteritis, and miscellaneous other unrelated events.

                        This slide summarizes the safety outcomes following CK and as we've seen from the data presented to this point, the study outcomes meet all limits identified in FDA guidance. 

                        Summary and indications for use.  To summarize the effectiveness data presented, the study results for uncorrected visual acuity and accuracy of the refractive outcome exceeded FDA targets for accuracy of MRSE and uncorrected visual acuity.  Furthermore, from the 6-month examination, change in MRSE was less than or equal to a .50 diopter for 85 percent of the study population and the mean in MRSE change per month was small, 0.03 diopters to 0.04 diopters for a total mean change of less than a .50 diopter per year.  Ninety-four percent of the intended correction remains at 12 months by a matched pair analysis.  This is compelling effectiveness data considering that no re-treatments were performed in this study.

                        All safety limits established by the FDA and the study protocol were achieved in the study population.  Specifically, all criteria related to the preservation of BSCVA were met.  With regard to induced cylinder, the proportion of eyes with more than 2 diopter was below the FDA target throughout the course of the study and induced cylinder decrease in frequency and magnitude over time.  There was no effective induced cylinder on BSCVA and the effective induced cylinder on UCVA was reflected largely in the slightly lower proportion of eyes with UCVA 20/20 or better.

                        Finally, the incidence of adverse events was very low and all resolved without sequelae.

                        On this basis, we respectfully request that this Advisory Panel renders an approval determination for this PMA for the conductive keratoplasty procedure with the following indication for use:  CK treatment for the reduction of spherical hyperopia in the range +0.75 to +3.25 diopters of cycloplegic spherical hyperopia; -0.75 diopters or less of refractive astigmatism; +0.75 to +3.00 diopters cycloplegic spherical equivalent; in patients with less than or equal to .50 diopter difference between pre-op, manifest and cycloplegic refractions; in patients 40 years of age or older.  The magnitude of correction diminishes over time with an average loss of approximately 6 percent by MSRE paired analysis of the intended correction at 1 year.  The proportion of intended correction retained beyond 12 months is undetermined.

                        Thank you for your time and attention.

                        DR. SUGAR:  Does that end the sponsor's presentation?  Please stay at the table then.  We are running ahead of time and what we will do is continue -- the program has lunch designated at noon.  We still intend to do that, but we will move head.  First, we'll have the Panel questions for the sponsor and then we will try to move ahead with the FDA presentation, if we can, prior to lunch.

                        So questions?  Dr. Pulido?

                        DR. PULIDO:  Yes, thank you very much.  Jose Pulido.  Thank you very much for a very nice presentation and I'm sure that my colleagues will be, from what I've been reading, will be delving into the statistics, so my question isn't in the statistics.  My questions are first, the safety of radio-frequency energy in patients with pacemakers or cochlear implants.

                        DR. GORDON:  It's a contraindication.  We were looking back to the Refractec technical --

                        MS. THORNTON:  Can you identify yourself, Judy, and speak into the microphone?

                        DR. GORDON:  I apologize.  Judy Gordon and we were referring to Refractec technical personnel who were here and who have communicated that those patients would be contraindicated for this treatment.

                        DR. PULIDO:  Okay, because that wasn't in the contraindications and these are elderly patients and these are the people that will have pacemakers and cochlear implants.  And so that needs to be put in there if it ultimately will be accepted.

                        DR. GORDON:  That can be corrected in the labeling.

                        DR. PULIDO:  Secondly, slide 22 and slide 79 alluded to a patient that was supposed to have originally received the treatment, but first the machine wasn't working and then it was determined the patient had narrow angles and therefore did not receive treatment.  That wasn't one of the contraindications and yet, you said well, he didn't receive it because the patient had narrow angles and therefore it was determined that that was contraindication.  So are you saying narrow angles is a contraindication?

                        DR. GORDON:  Judy Gordon again.  Narrow angles is not a labeling contraindication, but it was an exclusion criterion identified in the entry criteria for the study population, so that patient was inappropriately enrolled, meaning it would have been a protocol deviation if the patient had been successfully treated, but in re-screening the patient after the initial failed treatment to re-perform another baseline examination, it was determined that the patient was not eligible and should not have been enrolled in the first place and so the patient was discontinued without treatment.

                        DR. PULIDO:  How many patients enrolled did have narrow angles and how can you be sure that that is not a contraindication?

                        DR. GORDON:  I think the issue of narrow angles on a hyperopic population, particularly in the studies, the refractive surgery studies of hyperopia really relate to at least in part the number of cycloplegic refractions that are required in the

post-operative period and the risks therein of the cycloplegia and so it's pretty typical to exclude those patients from these studies, but I think it doesn't necessarily imply that it would be an appropriate contraindication, but I'll rely on my clinical advisors here to add commentary on that.

                        DR. McDONALD:  I think that, as with all studies --

                        DR. SUGAR:  Again, please identify yourself, Marguerite.

                        DR. McDONALD:  Dr. Marguerite McDonald.  As with all studies, we were trying to just have the cleanest possible entry criterion be exceedingly careful.  Judy's comment is correct that we cyclopleged the patients repeatedly, so we were a little worried there an also you know, we really don't know what happens to the peripheral profile.  Just to be extra careful.  I really don't think the angle would be affected, but just to be extra careful in the study.  We excluded them.

                        DR. PULIDO:  Right.  But again, is there

-- I don't have any indication from what I've read that there isn't a change to the peripheral profile into the trabeculum meshwork.

                        I thought maybe you would have data otherwise that I wasn't able to find.

                        DR. DURRIE:  This is Dan Durrie and I've been involved in several of these studies and there hasn't been any evidence in any collagen shrinkage procedure that there is narrowing, but there's not a good way, we didn't do ultrasonic measurements.  There's just not a good way to measure it.

                        Being involved in the design of these studies it's exactly true what Judy has said.  This really is a contraindication in the study because we're going to cycloplege these patients multiple times and that has really been the contraindication on putting patients in, but there's nothing in this study or other ones that I've been involved in that are shown that the angle structure is changed with collagen shrinkage procedures and periphery.

                        DR. PULIDO:  One other question that I had and that relates to patients, patient number -- the hospitalization for tonsillectomy an nasal septum repair.  Now it lists that -- if you could turn to -- is it Volume II, page 191 and in it, it has the manifest refraction at the 6-month visit with -2.00,

-0.75 at 20 in the right eye and plano -0.5 at 165 in the left.  So this patient had, if he or she was very hyperopic, a marked myopic shift.

                        We don't have her pre-op refraction.  What was it?

                        DR. GORDON:  We can look that up.  Judy Gordon.  We'll have to pull that information.

                        DR. PULIDO:  I'd like to know what that was.

                        DR. GORDON:  We'll get to you in a few minutes with that information.

                        DR. SUGAR:  The issue being?

                        DR. PULIDO:  The issue being just want to make sure the patient was properly enrolled in the study.

                        DR. SUGAR:  Are there other questions for the sponsor? 

                        Go ahead, Dr. Matoba, and then Dr. Grimmett.

                        DR. MATOBA:  I would expect, this is Alice Matoba.  I would expect some increase in intraocular pressure immediately following the procedure since you were causing shrinkage of collagen.  I wondered if you had taken an IOPs and if you had some idea of what the magnitude of the change might be?

                        DR. GORDON:  Judy Gordon.  Intraocular pressure measurements were made at every examination, including post-operative Day 1 and there was no evidence of any change.  We can show you the --

                        DR. MATOBA:  Actually, I'm talking about acutely, immediately after the procedure, I would expect a rise in pressure.

                        DR. GORDON:  Measurements were not made in the first 24 hours.

                        DR. MATOBA:  Okay.  And then my second question is in terms of your endothelial cell loss data which looked great, the n was only 162 and that subsequent patients, I wondered what the treatment parameters were if you had enough patients who had the 32 spot or the higher level of treatment in those patients?

                        DR. GORDON:  Judy Gordon.  That's an excellent question and we'll take a look at that, but again, I can't answer without looking.

                        DR. MATOBA:  Okay, then my third question is in regard to patient satisfaction data.  It appeared to me that as you go towards 12 months the percentage of patients who were dissatisfied or very dissatisfied, the combined total appeared to increase compared to the earlier study points and the n was only 198 for 12 months.  I wonder if that trend toward slightly increasing percentage of dissatisfied and very dissatisfied patients holds up, if you look at more patients or it could increase, continue to increase over time?

                        DR. GORDON:  Judy Gordon, again.  There tends to be considerable variability in these types of subjective questions and I will check with the statistician, but I think that the variances that are observed in those tables were nonsignificant.  We did some extensive statistical testing there, so we can check on that, but we haven't seen any trends that would indicate any change, dramatic change over time.

                        DR. GRIMMETT:  Michael Grimmett.  I have one comment and two questions.

                        DR. SUGAR:  I guess there's a follow-up comment.

                        DR. McDONALD:  I'm sorry, Marguerite McDonald.  One last thing, the cyclometric testing pulls different things out.  At one year, Dr. Matoba, 95 percent of patients felt that their quality of vision was improved.  Five percent said no improvement, so those questions pull out different things, but we will look for you.

                        DR. GRIMMETT:  Mike Grimmett again.  One comment, two questions.  I had a similar thought to Dr. Pulido regarding the pacer issue and I would just add that the FDA or sponsor consider implantable defibrillator devices as well.

                        Question.  On slide 8 of your presentation that outlined how the spots are placed on that corneal marker, for the last 8 spots when you move from 24 to 32, is there any identifying marker or anything how you pick in between or is it best estimate and how hard is that to do with precision?

                        DR. McDONALD:  Dr. McDonald.  That's an excellent question.  The hand-held marker does not have dashes or elements to indicate the last 8 spots.  If you're doing a maximum treatment of 32, but several things.  The little distance that you're bisecting is so short, it's very, very easy to dissect it.  Placement doesn't actually matter of the last 8 as long as you're somewhere on that ring because what you're doing is cinching the periphery, so even if you're a tiny bit off on dissecting the short distance which would be hard to do, you are still circumferentially shrinking the ring.

                        Last, but not least, if you add more elements to the marker and then you ink it up with one of the FDA-approved dyes, you start to get a big blue smear and you really can't see anything, so that's the maximum that you can practically put on one marker.

                        DR. GRIMMETT:  Thank you.  And another question, I just want to clarify or reconcile some data in your slides that went by too fast for me to reconcile it.  Slide 64 of Dr. Hersh's presentation that goes over this cylinder with uncorrected visual acuity, we have in the latter column eyes with greater than or equal to 1.00 diopter of induced cylinder and we see the rates of certain levels of vision, for example, 29 percent have 20/20 or better.

                        I want to reconcile that with slide 61 that I think is showing the exact same data, trying to show induced cylinder greater than or equal to 1.00 diopter at various vision levels.  The vision level, at least the way I'm reading it on slide 61 says 20/20 or better in 49 percent.  Yet, slide 64 says 20/20 or better in 29 percent.  And the other categories are different as well.  20/25, slide 64, says 52 percent; slide 61 says 80 percent at month 12.

                        DR. HERSH:  These are --

                        DR. GRIMMETT:  Go ahead.

                        DR. HERSH:  Dr. Peter Hersh.  These are actually different groups of patients.  Slide 61 is that group of patients who had greater than or equal to 1.00 diopter of cylinder at the 1-month visit.  So all patients who we saw at 1 month, who had greater than or equal to 1.00 diopter of induced cylinder, we then followed on for the subsequent visits to look at the natural history of the induced cylinder.

                        Now slide 64 is a snapshot of the group of patients who have reached 12 months.  So it's simply the group of patients who have reached 12 months looking at those with induced cylinder and those without induced cylinder, so they represent different patient groups.

                        DR. GRIMMETT:  Great.  Thank you very much.

                        DR. SUGAR:  I have a question.  In terms of the pattern, you prescribe a pattern of placing the spots.  Was that derived empirically or arbitrarily or how was it derived?

                        DR. DURRIE:  The pattern -- this is Dan Durrie.  The pattern was done off of international investigation that was done previously and then very importantly, the first 54 patients that were done before the nomagram adjustment and I think that that's why you have a clean group of data done with one pattern that was evolved not only on international experience, but then the experience of the first 54 eyes to come up with the suggested patterns.

                        DR. SUGAR:  So -- Joel Sugar.  So you're implying that you tested different patterns and this was the most effective and the pattern does make a difference?  Is that the implication from what you just said?

                        DR. DURRIE:  No.  The situation as far as this particular pattern of only adding one spots and not changing energy, a lot of those things were looked at before, but in this particular thing is the only thing that the surgeon does in which makes this quite easy is adding an additional number of spots for higher diopter correction.

                        DR. SUGAR:  That, I understand.  I'm talking about the pattern in which they're applied, given that you decided that you're going to do 24 spots on a patient with 2 diopters. 

                        DR. McDONALD:  Dr. McDonald.  This pattern was established by the international investigative team, but it's also the pattern that's been used historically in the PERK study and other studies because if, for whatever reason, you have to abort a procedure in the middle, you will have induced less cylinder.  If you go around from one spot to the next you could induce a huge amount of astigmatism, if for whatever reason you had to abort.

                        DR. SUGAR:  Thank you.  Dr. Weiss?

                        DR. WEISS:  I had three questions.  The first one was that 80 percent and I think in the September document, it was indicated that 80 percent of patients did not need glasses after the procedure.  Considering that two-thirds of patients had 1.9 diopter of hyperopia or less, do you have a percentage of patients who wore glasses at a distance before the procedure, so that we can compare the two numbers?

                        DR. GORDON:  Dr. Judy Gordon.  No, we did not collect preoperative spectacle correction usage.

                        DR. WEISS:  Okay.  In the list of side effects patient subjective complaints, mild diplopia increased from a level of 5 percent pre-op to 14 percent subsequently.  Was that correlated with pupil size or refraction?

                        DR. GORDON:  Judy Gordon.  I can speak to this because I had the pleasure of addressing the challenge of looking at symptoms that are rated on a 5 point scale about 20 symptoms over 6 visits and so in trying to do a meaningful analysis of this and because we had collected pupil diameters, we actually just did a statistical comparison of an overall type of symptomatology for smaller pupils versus larger pupils and we were really gratified to see that there were no differences observed at all.

                        DR. WEISS:  So we don't really know why they had that complaint of diplopia.

                        DR. GORDON:  Correct.

                        DR. WEISS:  Finally, this is in regard to the indications for the procedure.  On the last slide, you indicated that the proportion of intended correction retained beyond 12 months is not determined, undetermined, and in the physicians reference guide it's indicated that there is some loss of refractive effect with time.

                        Are you not saying that this is a temporary procedure?

                        DR. GORDON:  This is Judy Gordon again.  I think we were attempting to articulate in some fashion that have a body of information and a clear understanding of what occurs during the initial

12-month of follow-up, but not beyond and we've attempted to somehow quantify or semi-quantify to patients and physicians what proportion of the effect or the intended effect is retained at 12 months and for that reason we have suggested the 94 percent retained.  But beyond the 12-month period in the absence of data, we've added language suggesting that the continued course of refractive correction is undetermined.

                        DR. WEISS:  Would not the 24-month data, although limited, give you some more indication as to what happens in the patients in whom you have 24-month data?

                        DR. GORDON:  Yes, absolutely.

                        DR. SUGAR:  Go ahead, Dr. Mathers.

                        DR. MATHERS:  Dr. Mathers.  I have a couple of questions.  You mentioned something about that this data was, of course, a single application.  Do you think that there will be for some patients several applications as there are with other refractive procedures and how would you approach that?

                        DR. GORDON:  Judy Gordon.  The purpose of the study was to evaluate the outcome of a single procedure and we have no information at this time on the effects or benefits of additional applications of spots.

                        DR. MATHERS:  And some patients will have smaller corneas.  Was there any exclusion criteria regarding the size of the cornea and would you have difficulty in treating more peripheral lesions or making more peripheral lesions in smaller corners.  Some of these hyperopic people might have smaller corneas?

                        DR. McDONALD:  Dr. McDonald.  We did not measure pre-op corneal diameter, but no one that I'm aware of, none of the investigators complained that they had difficulty placing the spots in any of the corneas.

                        DR. SUGAR:  Dr. Matoba?

                        DR. MATOBA:  In your presentation you stated that the induced cylinder resolved over 12 months, but your spherical induced change was stable and why do you think that is?

                        DR. HERSH:  It seems to be a wound-healing effect that we really see in all refractive surgery procedures that we do.  Wound remodeling, particularly epithelial remodeling has been shown in any number of procedures we do now, PRK lasik tend to resolve astigmatism in topography abnormality over time and I would suspect that it's a similar case here where wound healing particularly, possibly epithelial remodeling diminishes the cylinder and we so retain the spherical effect.

                        DR. SUGAR:  Go ahead, Dr. Bradley. 

                        DR. BRADLEY:  Dr. Bradley.  In a lot of the statistics you just presented, the most troubling case was the 1-month data set where some of the FDA marks were not met.  It makes me wonder what happened prior to 1 month.  Do you have data collected during that period, particularly I'm interested in the manifest refractive error, the uncorrected visual acuity and best spectacle visual acuity.  And my concern, of course, is that the patient will be suffering some, albeit temporary, visual disability due to the procedure.

                        DR. GORDON:  Judy Gordon.  The standards for reporting in these refractive surgery studies is pretty much what we've shown and so uncorrected acuity is manifest and we also performed cycloplegic refractions to have more confidence in our outcomes were collected and were reported at 1, 3, 6, 9 and 12 months.

                        We'll have further discussion later relative to some additional comments in labeling and we've shown that the uncorrected acuities, given the initial overcorrection could lead to some challenges in uncorrected vision.  None of the patients in the studies, either requested or required spectacle correction during the early period, but we'll propose labeling to suggesting that that may be a concern and that physicians and patients should be aware of that.

                        DR. BRADLEY:  Can I just come back on that?

                        DR. SUGAR:  Dr. McDonald wanted to further respond.

                        DR. BRADLEY:  Can I just clarify something?  You didn't answer the question.  I asked you if you had any data prior to one month.  You've just told me you presented the 1-month data which I've seen, of course.  I'll repeat the question.  Do you have any data prior to one month?

                        DR. GORDON:  I'll have to check and find out.  I think that we don't.

                        DR. McDONALD:  Dr. McDonald.  Dr. Bradley, we looked at the people at one month who had an MSRV of -1.00 or worse.  Also, the people who at one month were 20/40 or worse than 20/40 uncorrected.  In the first group, the people with an MSRE of -1.00 or greater at one month, that was 23 percent of the population, 81 eyes.  Six patients had same day bilateral in that group.  Of the six patients, two were very satisfied, two were satisfied, two were neutral, but none were dissatisfied or very dissatisfied.  At one month, the 21 percent, n equals 73, who had worse than 20/40 uncorrected.  There were nine patients same day bilateral.  Three of the nine were very satisfied, three of the nine were satisfied, and three of the nine were neutral and no one was dissatisfied or very dissatisfied.  So although they are briefly, either as a percentage of the population, almost a quarter that are briefly more myopic or have worse than driving vision, they are not dissatisfied or very dissatisfied.

                        DR. BRADLEY:  If I could just comment on that.  In some ways it seems reassuring, but to me it seems quite alarming that the criteria of 20/40 that we are holding out as being so important you find those people who have worse than 20/40 are quite satisfied.  Likewise, people who are 1.00 or more diopter myopic are satisfied and makes one wonder how to interpret the satisfaction data.

                        DR. McDONALD:  Dr. McDonald.  I think they're well aware that it's temporary and I think that's the key to their satisfaction.

                        DR. SUGAR:  Dr. McMahon and then Dr. Weiss.

                        DR. McMAHON:  Tim McMahon.  There was no data presented in your presentation and only minimal data presented in supplemental submission with regard to the near vision.

                        DR. SUGAR:  Is that microphone on?

                        DR. McMAHON:  Yes.  Let me repeat that.  Tim McMAhon.  There were two graphs presented in the red book with regard to near vision.  My question is two-fold.  One is can you describe your methodology for correcting for best corrective near vision and how that was measured?

                        DR. GORDON:  Judy Gordon.  Perhaps I can just comment.  Because near vision was not identified as a primary outcome in this study, we have concerns in evaluating the data as we were preparing the PMA in the rigor of the method and there was inconsistency in the near cards used, so we don't feel it would be the basis for any claims.  It can give us an indication though of what did occur and that is that we did not see any effect of conductive keratoplasty on best corrected near acuity and there was a pretty substantial improvement in near uncorrected visual acuity from pre-op where about 4 percent of eyes had Yager* 3 or better and that improved to about 40 percent.  We could show you that data.  It's in one of the later submissions to FDA.  But again, we were reluctant to present that and over-represent it in any way, given that there was not necessarily an adequate level of standardization of the methodology for collecting the information.

                        DR. McMAHON:  All right, the second one is help me get over my amazement that a substantial percentage of the patients had induced cylinder and/or shifts in cylinder axis with this procedure, yet the percentage of patients who had excellent best corrected acuity seems to defy logic to me.

                        When you have a focal procedure that affects local areas of the cornea, it seems to me that it would be nearly possible not to have a substantial increase, the amount of irregular astigmatism, yet with a very high percentage of patients having best corrected acuity of 20/20 or close to that, it implies an orthogonal or regular astigmatism.  Can you help me explain how that is?  To me, that just doesn't wash.

                        DR. DURRIE:  This is Dan Durrie.  You really bring up an important point and that's why I wasn't very impressed with this data, is that this is best corrected spectacle acuity and you would expect if it was irregular astigmatism that they would be losing best corrected vision and in this particular procedure, we have seen that the astigmatism deduced was at least correctable with spectacles and it did not have the induced or regular astigmatism you expect from focal correction.  So I think the data really speaks for itself is the fact that we can't correct regular astigmatism with spectacles.  We know that.  And the fact that we did preserve best corrected vision I think is a sign that the irregular astigmatism was very small.

                        DR. McMAHON:  Do you have topography data with this data set?

                        DR. HERSH:  I've done a few analyses simply on my own patients and can't comment on the entire patient set.  We did not find any correlations, thus far, with topography and a number of outcomes.  We looked at procedure centration which indeed was quite good and that showed no correlation with any outcomes including induced astigmatism.  We looked at loss of spectacle-corrected vision and again, did not find a correlation.  Indeed, the topography, anectdotally, look good and the kind of irregularities that one might see or one saw in PRK, for instance, during the wound healing phase didn't really again, in my patient subset, appear to obtain.  So potentially working in the periphery, rather than removing tissue essentially gives you a more regular response and the wound healing effects that could lead to irregular topography might be precluded in a peripheral technique like this.

                        DR. McMAHON:  Thank you.

                        DR. SUGAR:  Okay, Marguerite and then Dr. Bradley.

                        DR. McDONALD:  Marguerite McDonald.  Just to add a little more to that comment, I think working in the far periphery is the key and whenever we've seen a hand-held procedure very close to the visual axis like hexagonal keratotomy, the incidence of irregular astigmatism goes sky high.  So I think it's the fact that we're out in the far periphery.

                        DR. SUGAR:  Dr. Bradley, then Dr. Huang and then Dr. Jurkus and then Dr. Grimmett.

                        DR. BRADLEY:  It's sort of a carry-on question from Dr. McMahon's question.  If I recall in the data, the subjects who had the largest amount of induced astigmatism did have slightly lower best spectacle corrected visual acuity.  Perhaps you could either confirm or deny that.  If that is the case, my interpretation was, in fact, that along with astigmatism, which we are calling regular astigmatism, there was some induced irregular astigmatism, which was not correctable by the spectacles and in the modern parlance I think we might refer to that as some higher order aberration, probably kerma which one might imagine from some hand-held device which doesn't have precise positioning.  But I may have misrecalled the data.  Can anyone confirm or deny what I just --

                        DR. SUGAR:  I thought that they showed that the acuities were actually quite similar.  I'm waiting really for them to give their own data.

                        DR. BRADLEY:  Then we can forget what I just said if it's the same, but I thought I remember seeing them differently.

                        Dr. Weiss is suggesting that maybe my recollection is from the original data set and not the revised data set.

                        Perhaps if you could just check on that anyway, but the idea being -- you're right, if it is correctable with spectacle lenses, remarkably the induced cylinder is just that, it is induced astigmatism whereas we might have imagined that the measured induced astigmatism is just one component of a myriad of aberrations that are induced by the procedure, and therefore we would imagine that some of these would not be correctable with something we call correcting lens and therefore we would imagine those with large amounts of induced astigmatism would presumably have larger amounts of other aberrations which would not be correctable and therefore best spectacle corrected visual acuity would not quite be as good in that group.

                        DR. SUGAR:  Is there a comment from the sponsor?  Okay, Dr. Huang?

                        DR. HUANG:  Andrew Huang.  My concerns the long-term stability of your results.  From 6 to 9 months the regression was .09 diopter and from 9 to 12 months the regression is .12 diopter.  Do you have any evidence suggesting that this rate of regression is stabilized after one year of follow-up or do you think the data in whatever, 24 months, patients you have collected suggesting that this rate of regression is progressive?

                        DR. GORDON:  We have 24-month data and updated 12-month data that's been submitted to FDA as we indicated, but they were submitted quite recently, not in anticipation of planning for this Panel meeting.  So we had no plans to show those data, but we can comment that in a very small number of eyes with data through 24 months, the rate of change is quite small, between 12 and 24 months, but it's a very small population and for that reason we've taken the position in our proposed labeling that the loss or the change in refractive effect after 12 months is undetermined at this point in time, based on the data that you have reviewed.

                        DR. SUGAR:  Dr. Jurkus, I think is next.

                        DR. JURKUS:  My question goes to the patient satisfaction from draft 1 of pages 26 and 27.  And in looking at them it appears that 1 in 3 people showed an increase of some sort in complaints of halos, fluctuation in vision and variation in dim vision from pre-operative to post-operative.  And to me, this seems like quite a large amount of increase.

                        Is there any correlation to pupil size or to power or reasons why that, again, 1 in 3 would say that they have more problems with halos and fluctuation in vision after surgery than they did before?

                        DR. GORDON:  I think there's two separate issues here.  One is, as I mentioned before, we did do a very thorough statistical analysis relative to pupil size because obviously that would be a concern that one would want to label for and we did not see any effect of pupil size on symptoms.  The other comment is more general and that, as I mentioned, we collect information on a sale, a 5-point scale of 0 to 5 at six periods in time and for about 20 symptoms.  So you tend to see all kinds of changes all over the place.  For that reason, as we struggle to somehow define what would be considered clinically relevant we came up with an -- FDA had suggested looking at a greater than or equal to 5 percent increase in the categories beyond mild, so the marked, moderate and very severe.  You see the biggest changes over time in both directions and across these types of studies in the mild where you just get a lot of people marking these things on these forms.  You get the sense of, if you look at these individually as I have over a number of studies and I think Dr. Durrie could comment to that effect as well, so I think the data that we think is clinically relevant is what we showed in terms of greater than or equal to 5 percent increase from baseline and those symptoms that you measured did fall into that category, although they did improve to some extent over time.

                        DR. JURKUS:  Was there any correlation -- Dr. Jurkus again -- to the amount of correction?  Did the people who had like the +3 people have more fluctuation than +75 people?

                        DR. GORDON:  This is Dr. Gordon again.  I would have to confirm that, but I believe that was not the case and one of the things that we noted as we looked at some of the key parameters by dioptric group was that it was in the higher range of hyperopes, that we have the higher levels of satisfaction.  More positive, I think it just has to do with more perceived benefit perhaps, but I don't believe we saw any difference across dioptric range and symptom reporting that was at any statistical level.

                        DR. SUGAR:  Dr. Grimmett?

                        DR. GRIMMETT:  Mike Grimmett.

                        DR. SUGAR:  I'm sorry, Dr. Ho hasn't spoken yet.  I'd like to give him an opportunity.

                        DR. HO:  Allen Ho.  Just a question with respect to the long-term data.  Can you tell me approximately when the last patient was recruited and does our lack of 24-month data indicate a fall off in follow-up compliance or does that indicate that they have not reached those milestones yet?

                        DR. GORDON:  Judy Gordon again.  Having been very close to this study, but not having managed it myself, I'd have to say and Dr. McDonald commented that the level of compliance was one of the highest I've seen, 97 percent.  Over 95 percent at each visit.  And the data that we do have available at 24 months is again 95 percent of the eyes that have hit that window, but a small number of eyes have gotten to that point and I'll have to defer to when was the last patient enrolled, but in any case, we have at every interval examined accountability because in the absence of having more than 90 percent of data available, we have not reported, we would not report on a parameter, and in all cases wherever we've reported, we've had more than 95 percent of eyes that were eligible for the examination come in and be examined.

                        DR. HO:  Allen Ho again.  So in other words, when can we expect to anticipate that the last enrolled patient will have 24-month data if they come?

                        DR. GORDON:  The last patient was enrolled in December of 2000, so that patient hits one year shortly and two years in about a year from now.

                        DR. HO:  Thank you.

                        DR. SUGAR:  And now, Dr. Grimmett?

                        DR. GRIMMETT:  Mike Grimmett.  I apologize if this was previously stated or if it's redone -- regarding the 24 patients who lost greater than or equal to two lines of best corrected vision in 6 months or later, were any of them contact lens

over-refracted as a diagnostic step to rule in a regular astigmatism?

                        DR. GORDON:  Dr. Gordon.  We'll find out and get back to you on that.  I don't have the answer on that.

                        DR. GRIMMETT:  Okay.

                        DR. GORDON:  We're making a list of questions.

                        DR. GRIMMETT:  Okay, I thought I had missed it.  Sorry.

                        DR. GORDON:  We didn't say anything to that effect.

                        DR. GRIMMETT:  Okay.

                        DR. SUGAR:  Jayne?

                        DR. WEISS:  Jayne Weiss.  What did you find the mean dioptric change was on a monthly basis between 12 and 24 months in those patients who you do have data on?

                        DR. GORDON:  Judy Gordon.  Dr. Rosenthal is shaking his head in a negative direction, so I'm hesitating to respond.

                        DR. ROSENTHAL:  Dr. Weiss, we normally have data presented here related to what was presented in the PMA submission.  If the Panel feels that they require additional data to be looked at by the Agency, that is one of the things you can consider in your deliberations.

                        DR. SUGAR:  Dr. Bradley.

                        DR. BRADLEY:  I just wanted to add a few comments to Dr. Gordon's reply to Dr. Jurkus' question about the subjective data.  I would concur with Dr. Gordon that they're very difficult to interpret and really without an effective placebo group, I really have a lot of trouble making much of those data in the sense that there were no alarming signs in the data set.  But being fully aware that there could be huge biases either plus or minus in that data set, you can easily imagine that patients who just had something done to their eye are extremely observant of any nuance in their sight from that day on and therefore the reporting of adverse symptoms might go up.

                        Conversely, you can imagine the opposite bias.  They've just committed themselves to an irreversible surgical procedure on their eyes, so they're really biased to think good of what they've just done, so that you can imagine bias going either way in that data set and I think when, as I think you've observed and reported quite nicely this morning, very small changes or what seemed like very small changes in the reporting, given the potential for bias either way, it's very difficult to make much of those.  That was my interpretation.

                        DR. SUGAR:  Dr. Huang and then we're going to move in about two minutes into the FDA's presentation.  We also -- do you have answers to the earlier questions like endothelial cell count?  After Dr. Huang's question, we'll ask for those.

                        Go ahead, Dr. Huang.

                        DR. HUANG:  I have two questions regarding the quality of life issue.  Given the fact that greater than 50 percent of the patient went 6 months, still have a significant amount of induced cylinder and a residual undercorrection, and is there any data suggesting some of the patients may need remedial service such as contact lenses or spectacle corrections?

                        DR. DURRIE:  This is Dan Durrie.  And this is actually the seventh hyperopic clinical trial that I'm involved in so I think that one of the things that I think I'm bringing a perspective of the biases over multiple studies, but I think it was very interesting to me in this study is we didn't have -- I personally did not have a single patient during this time of overcorrection or induced astigmatism that even asked for spectacle correction or asked for a retreatment which has not happened in other clinical trials.  So these patients did not need additional help, did not request it and I think that that was a lot because the overshoot was not that great.  They were always within three quarters diopter on average of the plano mean and also the induced astigmatism did not seem to be that clinically significant to the patients. 

                        You have to remember, these patients, a lot of them were +1.50, +2.00, +3.00 diopter hyperopes who were used to some very poor vision.  The average age was 53 and these patients really weren't seeing very well.  Any of you who have gotten hyperopic like I did over the years understand that.  I think that these patients were not needing any remedial -- not even spectacles, let alone contact lenses during that period.

                        DR. SUGAR:  Go ahead.

                        DR. McDONALD:  Marguerite McDonald. We pulled some data, proportion of eyes using distance corrective lenses, eyes treated with current nomagram.  This is 14 percent at 6 months and across all time points, 80 percent of the eyes and more reported no use of corrective lenses for distance vision.

                        DR. SUGAR:  Did you have --

                        DR. HUANG:  Could you repeat that? 

                        DR. SUGAR:  Could you go ahead and repeat that?

                        DR. McDONALD:  Mcdonald again.  Proportion of eyes using distance corrective lenses, eyes treated with current nomagram.  This was 14 percent at 6 months and across all time points, 80 percent of eyes and more reported no use of corrective lenses for distance vision.

                        DR. SUGAR:  Have you finished with your question, Dr. Huang?

                        DR. HUANG:  That's fine, thank you.

                        DR. SUGAR:  Then do you have a response to the endothelial cell question and the question on contact lenses?

                        DR. GORDON:  Yes.  We have a couple of responses here.  First of all, this is Judy Gordon again.  Dr. Pulido asked about a specific patient that had nasal septal repair.  The preoperative manifest refraction for that eye was +1.75, -1.75 cell.  So the MRSE was 1.3 and the patient was eligible for enrollment.

                        DR. PULIDO:  And then she ended up at

-2.00 for a while?

                        DR. GORDON:  That was the 6-month observation.  We'll check.  I don't have the full line listing, but we'll pull that and see what additional follow-up we may have on that patient.  We have almost all 9-month follow-up at least, so there should be another examination.

                        DR. PULIDO:  That's very predictive.  Thank you.

                        DR. SUGAR:  Then the two other.

                        DR. GORDON:  With regard to endothelial cell density, we did not examine those data by dioptric power.  It was a fairly small number of eyes.  It's a sub-study.  But we do know that 40 percent of the eyes are somewhere in that neighborhood, were in the higher dioptric range at entry, meaning we had a pretty good distribution of eyes that were greater than 2, up to 3 and a quarter diopter spherical hyperopia, so we would anticipate that there would be a pretty even distribution of those eyes in the endothelial cell study.  And in fact, those eyes were enrolled in the initial phase of study when we were enrolling up a baseline CRSE of 4 diopters, so there should be perhaps even more eyes there that were at the higher range.

                        DR. SUGAR:  Okay, and then the contact lens question?

                        DR. GORDON:  Yes, Judy Gordon again.  With regard to contact lenses, contact lens over-refraction was required by the study protocol for eyes with best corrected acuity worse than 20/40 and since all of these eyes were better than that, 20/32 and 20/25, there were none performed.

                        DR. SUGAR:  Thank you.  I'd like to have the sponsor then move back from the table and have the FDA group come up and give their presentation.

                        (Pause.)

                        MR. GLOVER:  Hi, I'm Joel Glover.  I'm the FDA Team Leader for the application.  Since it's already been introduced, I just have a few brief comments.  First, I want to thank the Panel for reviewing and discussing the application today.  I want to thank the sponsor for being so responsive during the rest of the review and also I'd like to thank the nonclinical review team in FDA for all their work and lastly, I want to introduce Dr. Sherri Berman, the clinical reviewer.

                        DR. BERMAN:  Okay, good morning.  I'm Sherri Berman, an ophthalmologist and I was the clinical reviewer for this PMA.  First of all, I'd like to thank Refractec for their cooperation in providing us here at FDA in advance with their Panel presentation.  I have for you today six questions for the Panel to consider as part of their discussion today and rather than reiterate what has already been presented by Refractec I have put together myself a few summary tables that I feel are relevant to each of these questions and I'd like to just go through them briefly right now.

                        The first question that the Panel will be asked is for their concerns regarding the incidents of induced cylinder with significant axis shift and its consequent effect on efficacy.

                        As part of the surgical procedure with this device, the positioning and angle of the handpiece as it enters the cornea as well as the centration on the pupil are performed manually by the surgeon.  I've put together this slide to summarize the difference between pre-op and post-op cylinder magnitudes.  I'll give you a minute to look it over and as you can see here, for the more than or equal to 1.00 diopter and the greater than 1.00 diopter stratifications, the incidence of induced cylinder was 20 to 30 percent at month 1 and declined over time, but at month 9 and month 12 still a significant proportion of eyes have this level of induced cylinder.

                        Here you can see a summary of the change in the vector magnitude and again, there's a significant proportion of eyes that had more than or equal to 1.00 diopter of induced change. 

                        In this table, you can see that approximately 40 to 50 percent of eyes had a shift in cylinder axis of more than 30 degrees and approximately 25 percent had an outcome shift of greater than 60 degrees.  The direction of the final post-op axis appears to be somewhat unpredictable and widely variable.

                        In this slide of post-op cylinder magnitude, I first want to point out that all eyes as an entry criteria had a baseline cylinder magnitude of three quarters of a diopter or less.  It is of clinical significance that the magnitude of post-op residual cylinder of greater than or equal to 1.00 diopter was 40 percent of eyes at month 6 and 32 percent of eyes at month 12.

                        Finally, with respect to this first question for the Panel, in order to further assess the clinical significance of induced cylinder, an analysis was requested by FDA of the sponsor and was performed as such. 

                        I want to clarify that the percentages that I've put together in this table differ very slightly from those presented in the Panel presentation by Refractec because they presented data on the -- I believe 21 eyes from the current nomagram treatment, whereas these numbers represent the total 25 eyes that were treated, but the percentages did not differ by more than a few percentages and here the stratification is eyes with less than a diopter of induced cylinder at 12 months and eyes with more than or equal to a diopter of cylinder and you can see that almost double the proportion of eyes achieved 20/20 with less than a diopter cylinder and significant differences at 20/25 level and the 20/40 level, although not as significant as the difference at the 20/20 level.

                        And as well, was presented the mean uncorrected visual acuity which I don't think gives the whole picture.

                        The second Panel question is as follows:  Is 12-month follow-up sufficient to provide reasonable assurance of safety and efficacy?  There are 21 eyes available at 20 months.  Should data for these eyes be required in the labeling?

                        In addition, the third question, does the refractive correction obtained with this device in light of the rate of change of mean MRSE over time and the incidence of over and under-correction justify potential risks.

                        For example, from one of the sponsors PMA analyses, it was presented that only 32 percent of the 363 eyes in the efficacy cohort achieved a final UCVA greater than or equal to their baseline BCVA.

                        The stability data was presented earlier and I won't focus on this for too long, but I do just want to point out some numbers because they are pertinent to the requested indication statements and that is when you look at the mean change over time and the extrapolated annual change, I just want to point out that over the 6 to 9 month interval and the 9 to 12 month interval and the 12 month consistent cohort that there certainly is no demonstration of the fact that the rate of refractive regression is slowing down.  And this is confirmed with the larger cohort with two consecutive visits.

                        Further data to look at for these two questions for the Panel, focus on accuracy of the MRSE and here you can see that the rate of undercorrection was as follows here and when the sponsor stratified this data by the degree of pre-op hyperopia there was a suggestion of a trend of decreasing efficacy with increasing pre-op CRSE. 

                        Here you can also see that a significant percentage of eyes developed early clinically significant myopia, the incidence of which declined dramatically over time.  These patients were like to require spectacle or contact lens correction at least part-time.  Overall, these outcomes are consistent with the post-operative hyperopic shift over time.

                        The fourth question that the Panel will be asked to consider is as follows:  Are there concerns regarding the increased incidence of visual symptoms from pre-op levels? 

                        As this was also presented extensively by the sponsor, I won't deliberate here, but you can look over these numbers and I also want to point out that in addition to the moderate and severe symptoms reported, it was also clinically interesting that the proportion of eyes that reported none for each of these symptoms decreased over time for many of the symptoms including halos, diplopia, visual fluctuation and night driving problems so that eyes did not have any symptoms pre-operatively did develop symptoms post-operatively.

                        In addition, the subjective assessment of overall satisfaction revealed that a rating of dissatisfied or very dissatisfied was reported by 8 percent of subjects at month 6 and 12 percent of subjects at month 12.

                        The fifth question:  Do the safety and efficacy data presented in this PMA support approval of this device for the requested indication?  Is the requested indication appropriate as worded, based on the study outcome? 

                        I prepared these slides and they were accurate up until about a week ago.  The sponsor had modified somewhat the requested indication down in this area so I'm apologizing that it's not 100 percent accurate, but I've highlighted in yellow the areas of the requested indication statement that I'd like the Panel to address during their deliberations.

                        And these basically are the upper limit of the cycloplegic spherical equivalent and the wording or such of the statement that the magnitude of correction decreases over time and how much it does so.

                        In one of the amendments to the PMA, Refractec provided an additional analysis in response to one of the primary Panel reviews which is summarized here.  In this amendment, they concluded a highly significant correlation between baseline CRSE and induced cylinder.  Most pronounced in eyes with a baseline CRSE more than 2.50 diopters.  Due to the small sample size of the eyes with treatment size of eight spots, these numbers cannot be used to make statistically valid conclusions.  The sponsor proposed that these outcomes be addressed by them in the device labeling or alternatively by modification of the upper limit of the refractive range.

                        At this time I have no further clinical data to present. 

                        Okay, the final question for Panel consideration is a general question, what are your recommendations for labeling regarding regression of effect, induction of cylinder and incidence of visual symptoms?  Are there any additional labeling recommendations?

                        DR. SUGAR:  Thank you.  Are there questions for Dr. Berman or for the Agency?

                        If not, I'd like to -- go ahead, I'm sorry.

                        DR. BRADLEY:  Arthur Bradley.  You were apologizing for one item on that segment from last slide being out of date.

                        Would you mention what has changed?

                        DR. BERMAN:  Yes.  At the time that I prepared these slides, the requested indication for use from the sponsor, the final bullet here they requested was the statement that the magnitude of correction diminishes over time with an average loss of approximately 10 percent of the intended correction at one year.

                        I wold have to defer to sponsor --

                        DR. SUGAR:  It would be slide 85 from the sponsor's package you have in front of you, where they changed that to 6 percent of the intended correction at one year and they added the statement the proportion of intended correction retained beyond 12 months is undetermined. 

                        If there are no other questions for the Agency, the sponsor will have additional time right after lunch, whether that means we'll be better able to attend or less, I'm not sure, but I would like to have everybody really get back here at 1 o'clock so that we can proceed to pace.

                        (Whereupon, at 12:01 p.m., the meeting was recessed, to reconvene at 1:00 p.m.)

 

 

 

 

 

 

 

 

 

 

 

 


 

            A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N

            (1:06 p.m.)

                        DR. SUGAR:  Okay, if there's no objection, I'd like to proceed with the additional comments from the sponsor.  They've asked for a few more minutes than the 5 minutes on the program and I think that that's reasonable.  So go ahead.

                        DR. McDONALD:  Thank you, Dr. Sugar.  We would like to specifically address Dr. Berman's questions to the Panel.

                        Question 1 relates to concerns regarding induced cylinder.  As you have seen both in our presentation and presented by Dr. Berman, induced cylinder was observed in a fairly high proportion of eyes at the 1-month examination.  However, the frequency and magnitude decreased significantly over time and was well below the current FDA limit of less than 5 percent.  From 6 months, the proportion of eyes with induced cylinder of greater than 2D also meets the more stringent proposed limit of less than 1 percent. 

                        This graph shows UCVA over time in eyes with greater than 1D induced cylinder at 1 month, consistent with the resolution of induced cylinder over time, uncorrected acuity improved substantially from 1 through 12 months.

                        Induced cylinder had no affect on BSCVA, with all eyes at 20/32 or better at 12 months.  The magnitude of effect of induced cylinder greater than 1.00 diopter on UCVA was on average one line less improvement, irrespective of whether the analysis was performed using absolute magnitude of induced cylinder or vector analysis.  Similar results were obtained when considering induced cylinder greater than or equal to 1.00 diopter.  There was no effect on UCVA in eyes with manifest cylinder greater than 0.75 D with an axis shift of 30 degrees or more.

                        In summary, we've shown that induced cylinder meets the current FDA limit and decreases significantly over time, resolving in a large proportion of the eyes.  This resolution of induced cylinder was not attributable to regression of the spherical correction.  The presence of induced cylinder greater than 1D and greater than or equal to 1D was associated with a difference of approximately one line of improvement in UCVA.  UCVA improved over time as induced cylinder resolved, and the difference in UCVA translated into a lower proportion of eyes with UCVA of 20/20 or better.  Induced cylinder had no effect on best corrected visual acuity irrespective of the analysis performed.

                        Question 2 relates to whether a 12-month follow-up is adequate to support safety and effectiveness.  Because the 9-month population of 376 eyes presented in our PMA represents 94 percent of all eyes, and the 12-month population of 203 eyes represents 51 percent of all eyes treated, but 97 percent of the eyes eligible for examination, we believe the available data provide reasonable assurance of safety and effectiveness.  Updated

12-month data and the available 24-month data have been submitted to the FDA for review and the results for key parameters of safety and effectiveness are consistent with the data reviewed by the Panel.  Refractec is more than willing to update all labeling information to reflect the additional data.

                        Question 3 asks whether the refractive correction effected by CK justifies the risks.  Predictability of the CK procedure is presented here graphically to display the proportion of eyes that were under-corrected and over-corrected.  The proportion of eyes initially over-corrected decreased substantially after one month and under-correction was limited to a small number of eyes throughout the course of the study.

                        The stability target identified in FDA guidance of change in MRSE within .50 or 1.00 diopter was achieved at both the 6 to 9 and 9 to 12 month intervals.  Using a paired analysis between months 6 and 9, the mean change per month in the manifest or fraction was 0.03D while mean change was 0.04D between 9 and 12 months.  However, these data did not achieve the remaining two FDA stability criteria of decrease in mean change over time to an asymptote and the confidence interval encompassing zero.

                        As shown in this graph, there was a very close match between the manifest and cycloplegic refractions over the course of the study.  This graph also shows the relatively small initial

over-correction following the CK procedure, particularly in comparison to other refractive procedures for hyperopia correction.  This over-correction has generally been acceptable to patients and that it is mild and temporary.  Hyperopia is reached at approximately 6 months and there is less than a .25 diopter of change between 6 and 12 months.

                        FDA poses the very fundamental question of whether the potential risks of the CK procedure are justified in light of the rate of change in MRSE over time and the proportion of under-corrections and

over-corrections.  The first point to be made in response to this question is that hyperopic patients seeking correction of their distance vision in this study experienced a significant improvement in UCVA.  Fifty percent of all eyes had UCVA of 20/20 or better and over 90 percent had UCVA of 20/40 or better.  This was accomplished with no serious adverse events or complications, no incursion into the visual axis and no removal of tissue.  Additionally, 95 percent of patients felt that their quality of vision was improved.

                        We have shown you data establishing the rate of change in MSRE to be very small, less than a .50 diopter per year, based on the mean change from 9 to 12 months.  The concerns regarding

under-corrections and over-corrections are valid, but are also pertinent to all refractive surgery procedures for correction of hyperopia.  As with all corneal steepening procedures, there is an initial over-correction following CK, but those are relatively small and resolves early.  Only a small number of eyes were under-corrected over the course of the study. 

                        To speak to the issue of whether the potential risks of the CK procedure are justified, we ask you to consider the risks associated with Lasik as described in the FDA's website for patients considering Lasik surgery.  These risks include under treatment or over treatment, loss of vision that cannot be corrected with spectacles or contact lenses and loss of effect over time.  As a refractive surgeon, I can also tell you that I continue to have concerns with regard to Lasik complications such as "Sands of the Sahara" or DLK, micro and macro striae, aborted flaps, lost flaps and of course, the most serious of Lasik complications, entry into the anterior chamber with the microkeratome blade. 

                        We believe that CK offers patients considering vision correction a viable alternative to Lasik and other modalities for the correction of hyperopia with a comparable risk to benefit ratio.

                        Question 4 relates to the visual symptoms reported in our study.  The increase in symptoms reported as moderate and marked was limited to 5 to 7 percent, thus just exceeding the threshold of 5 percent defined as clinically relevant.  More importantly, the increase in marked symptoms reported at 6 months largely resolved at 9 and 12 months.  Finally, there was no significant increase in very severe symptoms at any time during the study.

                        Question 5 asks whether the safety and efficacy data support approval of CK for the indication proposed.  To summarize the effectiveness data, you have seen that the results for UCVA and accuracy of the refractive outcome exceeded FDA targets for these parameters.  Stability was not achieved, but the average change per month in MSRE was small, annualized to less than a .50 diopter per year.  Ninety-four percent of the intended correction remains at 12 months and 80 percent of patients reported being satisfied or very satisfied with the results of the procedure.

                        All FDA limits for safety were met in the study population.  Only 1 percent or less of eyes lost greater than 2 lines of BSCVA and no eyes had best corrected acuity worse than 20/40 at 6, 9 or 12 months post-op.  Finally, the incidence of induced cylinder was considerably below the current limit in FDA guidance.

                        To summarize, we believe that the results of the clinical trial of CK serve to establish the safety and effectiveness of this procedure and also serve to support the proposed indication for use. 

                        Question 6 speaks to recommendations for labeling.  While we welcome further recommendations from the Panel and from the FDA for labeling, we have proposed for your consideration labeling information that serves to address concerns that should be communicated to physicians and patients considering the CK procedure.  Specifically, we suggest that loss of effect over time be communicated by reporting the proportion of intended correction retained at one year in this study population, while noting that loss of effect may continue beyond one year.

                        With regard to over-correction, it should be communicated that patients may experience an initial over-correction and that this may affect distance vision such that spectacles are required for driving.  Next, although we have not specifically discussed this during our presentations, we have already included information in the labeling, stating that accuracy of the intended correction was slightly lower for eyes in the higher dioptric range.  We will also address the lower proportion of eyes with UCVA 20/20 or better in the higher dioptric range.

                        With regard to induced cylinder, we propose communicating that induced cylinder greater than 1D was associated with less improvement in UCVA at the 20/20 and 20/25 levels and that achievement of UCVA of 20/40 or better was somewhat delayed.  Information on symptoms has already been included in the labeling in our PMA and can be revised as determined appropriate by Panel and the FDA.

                        Finally, as suggested in the Panel review, we will add to our labeling a statement indicating that no data are available on re-treatment. 

                        This concludes our presentation.  We would like to thank the Panel Members, particularly the primary reviewers and the FDA personnel for the significant time and effort invested in their thorough and insightful review of the clinical data in our PMA.  We also thank you for your consideration of the CK procedure as a safe and effective refractive surgery option for hyperopic patients.

                        DR. SUGAR:  Thank you.  We will, I think, reserve the option of asking questions as they arise from you, but it's fine to go back to the audience.

                        Now we proceed with the committee deliberations and begin with the primary Panel reviewers.  First will be Dr. Arthur Bradley.

                        DR. BRADLEY:  Arthur Bradley.  A couple of things to remind everybody here, that I'm not a clinician and the original review of this PMA was done back in August and I had to re-frequent myself with this document a few days ago and some of my comments relate to some of the frustrations experienced at that time.

                        I want to go through several points here.  First, an issue about presentation of the data.  This really applies to the sponsor and also to the FDA.  I'm trying to think of more effective ways of communicating complicated data sets because I found the current document really quite difficult to manage.  I'm then going to concentrate on what I call the main effect, as the change in manifest refractive spherical equivalent.  The issue there, of course, is over or under correction and much has been said already about stability.  I'm going to add a few comments about stability and we then get into this issue of induced astigmatism and in particular, I'm going to comment on how this might be presented in a more easy to understand way.

                        I'm then going to talk about interactions with any procedure.  We always look for significant interactions and I found that very difficult to extract from the data set and finally some issues about patient information which, in many ways, don't stem from my expertise as a scientist, but my position as a potential customer.

                        Let's go through one by one.  Presentation of the data.  Indeed, a complicated data set, but hundreds of tables, I'm not really sure exactly how many tables I looked through but my mind was spinning.  I think in the last document I was at Table 109.2, entitled "Induced Cylinder Residual Astigmatic Error at Stability time Point.  All Eyes Treated at Month 12."  Really, 109 data tables makes me wonder if this is just an inefficient way to present the data.  There might be better ways to do it.  And certainly as a teacher of graduate students, I have to communicate all the time that numerical effectively communicated in a graphical format -- tables often do a very poor job of communicating data.

                        Still, sometimes the main data are never presented or are hidden or are inadequately.

                        (Laughter.)

                        Here's a good example of that.  Look at that.

                        (Laughter.)

                        I don't know what that was all about.  I think the system is reacting to having a McIntosh attached to it, basically.

                        What have we got here?  The sponsor has presented the data in terms of -- yeah, so this last comment really is I think the way the data have been presented.  I think the sponsor has done a fabulous job, by the way of communicating to us what proportion of the data meets certain criteria and the criteria are really, have been dictated by the FDA, a certain number of people have to have uncorrected VA of a certain level.  Residual refractive error must be less than a certain percentage and have more than 1.00 diopter, etcetera.  And in the end, that's how the data have been communicated and in the teaching environment in which I work, the one thing that I continually have to remind my students of is that before I know the statistics on a data set, I really want to know the data set.  In the end, I think that was what really bothered me and gave me so much trouble with this particular proposal and that was the data were perhaps not presented.  More the analysis of the data was presented.  So if I had an opportunity here to encourage the FDA and the sponsor or future sponsors, is to first present the data and then we'll have a look at the analysis and if we could see the data directly, I think we would learn quite a bit more.

                        Here's just an example.  The most important thing really for us to know is the issue of how much did the refractive error change.  And I looked really hard and I think as my son could tell you, I'm not the best searcher of things in the world, but I couldn't find a graph that showed the mean spherical equivalent refractive error for this patient set and we've seen it this morning, by the way.  A couple of presenters from the sponsor presented this graph.  But it isn't in the report and that would have helped tremendously.  It turns out the data are shown on Table 69 at page 154 of Volume II, but only after amendment 11, dated September 7th, did the pre and post MRSE appear together as Table 1D.1.  And as far as I could tell the original narrative didn't even provide that information and it seems to me that is the main reason for doing the procedure.  Surely, this should have had a very prominent position in the report.

                        Well, I did my own analysis and actually graphed the data and this is the graph we've already seen.  It's the pre-1 month, post 3-months, 6 months, 9 months, 12 months and we've got the manifest and the cycloplegic refraction there and you see, as the sponsor has shown us this morning that these are really essentially identical and a couple of things to point out here.  This is the myopic overshoot we're a bit worried about.  At month 1, it's still there at month 3.  The mean is about plano at month 6 and drifting slightly into hyperopia by 12 months and that's exactly the result we've seen already.

                        And these are the average data, so on average we've got over-correction early on, under correction later on, but this is for the whole sample.

                        From the most recent data set, I took out the standard deviation data and simply added those.  That should say one standard deviation here.  And there's the mean again that I've just shown you and that's one standard deviation in one direction, two standard deviations.  One standard deviation, two deviations.  And there are a couple of important things to note here, particularly in that early time period of one month.  Although the mean is only about .50 diopter here, once we get out at two standard deviations and really that encompasses the whole distribution of plus or minus 2 standard deviations, some people are hovering out there at 2.00 diopters of myopia and these are the ones that worry me the most, these particular patients.

                        Something that's quite hard to see in this graph, but I'll show you in the next graph and something that you should think about is notice the pre-op range of data.  That's the data here we'll call time zero.  Time zero here.  It's ranging from about +2.8 down here to about +.3 or .4, that's the range.  Notice that the range doesn't get any smaller.  It turns out the standard deviations actually climb as we -- after the procedure.  So the post-op standard deviations are actually larger than the pre-op.  I've got a little note down here, expectation.  First of all, we expect the refractive error to converge towards emmetropia after appropriate levels of CK, the idea being is that CK can come, you can have 32, 8, 16, 24 different amounts of the procedure done, all designed to accommodate the pre-op refractive error and target everybody towards emmetropia.  So that's the goal of having different levels of CK.

                        We know the mean is myopia and as I said, it's very significant for some eyes, but here's the -- unusual result.  The refractive error distribution is wider after the procedure.  Now how could that happen because everybody should be targeted to the same results, starting from different locations and the fact that the distribution after the procedure is wider than it is before makes one realize that this is not a highly controlled procedure in which irrespective of starting point we can converge the distribution down on to zero, on to plano.  In fact, the distribution spreads, a larger distribution after than before the procedure, indicating significant course of variability in the procedure.

                        This is just a graph plotting that. Standard deviation is a function of time, zero being pre-op, standard deviation .6 diopter.  It climbed 60 percent up to that point, 95 percent.  Thing to remember, if you gave every eye the same CK procedure, identical, you would expect the standard deviation to remain constant, but by selecting the appropriate levels of CK we expect the post-op standard deviation to be significantly lower.  In fact, it's higher.  We really have no explanation for that, except that the procedure is introducing a huge amount of variability and maybe the sponsor could comment on that at some point.

                        Next issue on my list.  Stability.  Well, we've seen lots of talk about it and we've seen a variety of numbers thrown around but most striking to me is the commentary and the commentary is this.  We've got data at 1 month, 3 months, 6 months, 9 months and 12 months.  And that's exactly the graph I've shown you before and all I've done is extrapolated the 9 to 12 month data on out.  So these are all from -- that's real data.  This is extrapolation, extrapolation.  Just to remind everybody, another word for extrapolation is speculation.  We don't have the data here, here and here, but I'm just extrapolating the last two data points on out.

                        A couple of things to note.  Indeed, the change from here to here is quite small and we've heard the sponsor tell us it's very small, insignificant, tiny.  In fact, in the original submission this was called stable.  So all I did was extrapolate that.  I remember these are not real data here.  This is all me speculating, based upon a linear extrapolation of the data between 9 and 12 months, the point being that as the sponsor in its amendment 11 or submission 11 gave us this result as a percentage of the targeted refractive change and it was something like 90 percent so there had been a bit of regression, got down to about 90 percent.  The important point to note is you continue that out at four years, the percentage of the refractive error change will be zero.  Like I said, these are not real data.  This is just me making it up.  It would be nice to have these data and if there was some indication of stability here, that is, this change asymptoted out to a flat line, then I think extrapolating that out will be in this direction and indeed, we would be concluding that there was not significant regression, but because the last data set had this slope, if we are extrapolate which I never liked to do, but I'm just doing -- my McIntosh will come back.

                        (Pause.)

                        Okay, so any way that's just a little story about stability and I don't quite know what to say about that.  There is no evidence of stability and you know the alarming thing is that would keep on and we'd have zero correction, but like I say I don't know that's going to happen.

                        Astigmatism.  Does the procedure induce significant amounts of astigmatism?  Now, astigmatism is an inherently two dimensional variable.  We all know that, axis and magnitude.  But the presentation always reduces that down to a one dimensional number.  And it turns out when you do that you end up with some problems and they can be misleading and I'm quite familiar with astigmatism data sets and I really in the end was struggling to understand what had actually happened with induced astigmatism.  For example, did the procedure introduce random astigmatism, was it consistent?  How did the induced astigmatism vary with clinician and number of treatment spots, etcetera?  These are all interesting questions I would have liked to have seen answers to, but I didn't get them.

                        This is really by way of tutorial.  I apologize for those of you who know this.  It's me as a teacher coming in here.  This is the one way we typically present astigmatic data.  It's called vector analysis in the proposal and in some of the reviews and it's worth making a couple of points about it so we, in future, maybe could use this as a standard.

                        This is a little graph and in the graph it's a two dimensional graph, as you can see, horizontal, vertical axes.  I've called this J0 which is sort of vertical horizontal astigmatism, J45 which is oblique astigmatism.  Plus J0 is with the rule, -J0 is against the rule and this over here is one type of oblique astigmatism and this is the opposite oblique astigmatism.  I've put three sets of data on here.  One, two and three.  These are three different eyes.  The yellow circle is the astigmatism pre-treatment, pre-CK. 

                        Now again this is all hypothetical, just to make a point.  If the procedure introduced an astigmatism and that was a procedurally introduced astigmatism so we've talked about induce astigmatism, let's say this is it and it's the same for every eye.  What you could imagine could happen with a stable procedure.  Then that would transfer this data point to there.  This one to there.  This one to there.  It would be a constant effect here.  That is a vector change from here to here. 

                        Well, let's look at what happens as a result.  Let's take Case No. 1, a certain amount of astigmatism.  That was that black line here.  We could describe that as its vector.  It changes to this one.  So clearly, there's a change in axis and there's a small change in magnitude.  Well, let's take Case 2.  This is the astigmatism to start with, you add it, you get this.  There is no change in axis at all, none at all, but a large change in magnitude.  Let's take Case No. 3.  Starts off with this astigmatism.  We add the procedural astigmatism and end up with this.  The actual magnitude is exactly the same as what we started with, but a very large axis change, in this case -- plotted here it's 180, but it ends up being a 90 degree axis change.  So you can see, depending on where you start a constant procedurally induced astigmatism produces quite different results.  Sometimes you get a change in axis, sometimes you get a change in power, sometimes you get both.  Presenting just one of those dimensions alone does not allow us to understand what really happened.  It's very important with two dimensional data that you present both dimensions.  Otherwise, we can misinterpret it.

                        Is this academically interesting, but clinically irrelevant?  Good question to ask, especially when I'm talking, but let me give you an example.  Let's imagine this really is what happened.  Again, this is all just speculation, just an example, but imagine you knew that this patient had this amount of astigmatism and you knew the procedure did this.  The residual astigmatism in this case is going to be much greater than it was at the start.  Whereas for this patient, you know that the final astigmatism is going to be basically the same as it was when it was started, just a different axis.  So this patient might be discouraged from having the procedure.  That would be one direct clinical application of this knowledge.  But without this knowledge, you can't make that recommendation to a patient.  So it's very important to present the data in a complete way.

                        A couple of things to be thinking about, astigmatism can be induced by two very obvious things.  Any meridional anisotropy in the procedure.  This is a hand-held device.  This is an eye.  The eye is moving, the angle at which you enter the needle into the cornea can vary.  Clearly, there's a lot of opportunity for this and maybe that is the reason for some of the results we see.

                        The other one is that the misalignment of the procedure axis from the visual axis and really it's the foveal line of sight.  There are a few details that I would have liked to have seen in the presentation that we didn't learn about how this procedure axis, that is, the little ring that is inserted, that is painted out of the cornea is lined up with the eye.  Is it really lined up on the foveal line of sight?  How accurate is that misalignment of that as the people who are involved in laser refractive surgery know will induce astigmatism.  So both of these can induce astigmatism.  It would be nice to know which of these is actually involved, but I couldn't find any data that examined the root cause of the induced astigmatism and because the astigmatic were presented in a one dimensional way, I couldn't get a handle on what was going on.

                        Interactions.  With refractive surgery there are always -- we're always very concerned about the procedure, how the procedure interacts with other parameters in the patient.  For example, how does accuracy vary with pre-CK RX.  How does induced astigmatism vary with pre-CK astigmatism?  How does post-CK BSCVA vary with pre-CK VA, etcetera, etcetera.  I mean there are lots of interactions we'd like to know about.  And there is a very effective graphic tool for identifying and visualizing such interactions.  We call it the scattergram and I would have loved to have seen some of these scattergrams, but again, I say no graphs, but I can't recall seeing a graph and certainly not these scattergrams.  Again, to get a handle on what the actual data were, not whether they met the FDA criteria, it would have been very helpful to see these and I just show again a hypothetical example here.  If this is pre-procedure, MRSE and this is post-procedure MRSE and here's a little scattergraph of us, so we're plotting one against the other.  This graph is a very familiar territory for us.  We know if the data fall along the Y equals X line, CK has no effect.  If the data fall along the post-refractive area equals zero, CK is perfect.  If the data fall up here, we've got 

under-correction.  If it falls down here we've got over-correction.  We would have known this right away by looking at that graph.  But we don't have that graph and I found that difficult to extract and that's just one example, but I could list tons of these.

                        Final point, again, this is not really me speaking as a scientist, but as a potential patient, I really feel very strongly about this, the informed consent issue and having dealt with complicated optical effects and trying to communicate those to patients I realize that this is not an easy thing to do.  I just pull out a couple of things.  If I recall in the patient document there was some effort to make sure that the patient knew that they weren't going to have a laser irradiating their eye which is, of course, a very important thing for the patient to know and patients are quite concerned about lasers, justifiably so.  But it paints the current procedure in a very reassuring light and talks about "gentle heat".  I wonder what "gentle heat" really meant anyway, but you know I think if you're going to bring up the alarm bells of lasers, then I think to be fair, maybe you should explain that a sharp needle is going to be inserted into their eye up to 32 times, just to give balance there and so the patient really can make a judgment call.  Do I want a laser or do I want a needle?  As opposed to a laser versus "gentle heat".  That just didn't seem to me a very accurate way to prevent a procedure to a patient.

                        Finally, and I think the sponsor has just discussed this in their final presentation, they are going to and I think it's essential, that the patient who undergoes this procedure has a very good indication of the likelihood, the magnitude and the consequences of the post-procedure myopia and astigmatism that they are going to experience.  The myopia particularly concerns me because -- but I would really like that because I think patients who have been hyperopic all their life to be converted to a myope, even if it's for a short period of time, they need to know about that and they need to appreciate the consequences, particularly as the sponsor has now conceded with regard to driving and particularly driving at night.

                        Thank you.

                        DR. SUGAR:  Thank you.  The  next reviewer is Michael Grimmett.

                        (Pause.)

                        DR. BRADLEY:  The system survived a McIntosh.  Only just so.

                        DR. GRIMMETT:  The following is not intended as a comprehensive substitute for my written comments dated August 11th, but I feel it necessary to highlight some of the notable features of the PMA, primarily as a foundation for my conclusions for the public record.

                        Regarding the study population, the original PMA only had 20 percent of eyes available at the 12-month interval, increasing to approximately 50 percent at the 12-month interval.  There are no data submitted for the 24-month interval. Therefore, the study is submitted as incomplete.

                        As we've seen the accountability was quite good throughout the study, a greater than 97 percent at all time intervals. 

                        First, I'll discuss issues related to safety.  An important indicator of the safety of a refractive surgical procedure is no change in the best corrected visual acuity following a surgery.  A month 6, approximately 5 percent lose greater than or equal to two lines of best corrected visual acuity, not an insignificant rate in my book.  Presumably, the higher rates of best corrected visual acuity loss at the earlier time periods are due to corneal irregular astigmatism.  Fortunately, the rates do decrease with time as we see in the graphical presentation that I hope meets Dr. Bradley's standards.

                        (Laughter.)

                        Looking over some subjective symptoms, pre-operatively, 26 percent of patients were complaining of mild, moderate or marked glare symptoms, while post-op 38 percent complained of the same symptoms, an increase.  Pre-op, 10 percent complained of mild, moderate or marked halo symptoms, while post-op, 35 percent complained of the same symptoms, a 3.5 fold increase.  Pre-op, 10 percent complained of mild and marked double vision symptoms, while post-op 24 percent complained of the same symptoms, a 2.4 fold increase.  Regarding fluctuation of vision, 16 percent pre-op complained of mild, moderate and marked fluctuation of vision symptoms, while post-op 40 percent complained of the same symptoms, a 2.5 fold increase.

                        Pre-op, 25 percent complained of mild, moderate or marked variation of vision symptoms, while post-op, 44 percent complained of the same symptoms, a 1.8 fold increase.  Pre-op, 36 percent complained of mild, marked or very severe night time driving vision problems, while post-op, 42 percent complained of the same symptoms, an increase. 

                        Hence, an increase in glare, halos, double vision, night driving problems, suggest the induction of higher order visual aberrations as a consequence of the procedure, that is, the induction of regular astigmatism, irregular astigmatism or the detrimental alteration of the normal corneal prolate asphericity among others. 

                        An increase in variation of vision and fluctuating vision may be the patient symptom and harbinger of refractive instability as we previously discussed.  Appropriate labeling should include these symptom data.

                        A large percentage of patients, approximately 1 in 4 had the induction of greater than or equal to 1.00 diopter of astigmatism at the 6-month interval.  Up to one third had the induction of greater than or equal to 1.00 diopter of cylinder at month 1.  By month 12, there's an approximate two fold increase in the mean cylinder, .32 diopters pre-op to .68 diopters at month 12.  If experiencing induced cylinder greater than or equal to 1.00 diopter, the uncorrected visual acuity declines as shown in Dr. Berman's slide 8 where 51 percent had 20/20 or better uncorrected vision of less than 1.00 diopter of cylinder and half of that or 24 percent had uncorrected visual acuity of greater than or equal to 1.00 diopter of cylinder.

                        Presumably, the induction of cylinder is related to asymmetric corneal shrinkage as a consequence of the procedure.  Looking at greater than or equal to 1.50 diopters, approximately 1 in 15 had that level of cylinder induction at the 6-month interval.  Therefore, based on the cylinder data, appropriate labeling should include specific data regarding cylinder induction rates greater than or equal to 1.00, greater than or equal to 1.50 and greater than or equal to 2.00 diopters.  Also include data regarding the loss of uncorrected visual acuity associated with the induced cylinder, and number three, it should delineate the instability of the induced cylinder with time.

                        Regarding cylinder axis, shifts in axis are somewhat random and generally spread across the range 0 to 90 degrees, a slight weighting towards shifts less than 15 degrees.  Approximately 70 percent at Month 12 shift in axis greater than 10 degrees indicating there's a high probability that the direction of cylinder will be different post-op as compared to pre-op.  Approximately 50 percent at month 12 shift greater than 30 degrees.  Labeling should therefore indicate that the precise direction of induced cylinder is unpredictable and highly variable.  The labeling should indicate that the axis shifts are more probable than not.  Based on the data submitted, I was unable to determine if the astigmatism meridian is refractably stable in the long run.

                        Regarding the etiology of the induced cylinder, we can speculate that the high rate of induced cylinder may be due to a combination of factors.  Number one, inaccurate spot placement.  The technique requires a manual spot-by-spot placement on a corneal mark.  It's improbable that any surgeon can place each spot with 100 percent precision in perfect symmetry.  Also, if the optical zone markers is decentered, treatment asymmetry is a given.

                        Number two, asymmetric energy uptake, differing corneal thickness we can postulate may lead to asymmetric energy uptake and therefore may lead to asymmetric steepening, for example, the temporal cornea is thinner.

                        Number three, nonperpendicular needle tracks.  Given the prolate asphericity of the cornea and the manual spot-by-spot placement technique, it's improbable that any surgeon can place each spot with 100 percent precision regarding perpendicularity. 

                        Number four, a non-uniform needle dept, we can theorize that differing pressure by the surgeon with each spot placement and patient to patient tissue variability may indeed lead to differing treatment depths.  All four of these factors may contribute to the induced cylinder seen with this technique.

                        Now on to some efficacy issues.  As shown in Donder's table, accommodation at younger age is significant and can skew uncorrected visual acuity measurements toward better visual outcomes in a hyperopic population.  Importantly, stratification by age in this study did not show a trend toward better uncorrected vision with the younger age group. 

                        The Refractec data did disclose improved uncorrected visual acuity following the procedure as compared to pre-op levels.  If we stratify this by dioptric group it appears reasonably matched at month 6, but the levels achieving 20/20 appear to decline by month 9 and month 12 disclosing lower rates of achieving these visions.  Labeling should incorporate this fact.

                        For this procedure, as Dr. Bradley pointed out, emmetropia was intended in all cases.  If the predictability of the procedure were good I would certainly expect the post-op standard deviation values to be lower than the pre-op standard deviation values and this is clearly not the case.  Pre-op standard deviation of the mean post-op values are all higher.  This would indicate that a wider spread of the data was created and suggests poor predictability of the procedure.

                        Looking at intended versus achieved correction.  Fifty-eight percent achieved plus or minus half of intended while 91 percent achieved plus or minus 1 of intended.  These exceed the relevant guidance document target values.  I would simply point out that a patient with a low amount of hyperopia is likely interested in plus or minus a half.  Certainly, a patient entering the study with 1.00 diopter of hyperopia, for example, is not going to care about a 4.00 diopter spread of predictability.  I just want to make sure that labeling includes the range of the data for analysis.

                        If stratifying by the degree of hyperopia, there's declining predictability as the level of hyperopia increases as we can see here for both plus or minus a half and plus or minus 1.  This is a find similar to many refractive procedures.

                        The proportion of under-corrections greater than +1.00 diopter is increased in the higher hyperopic group suggesting decreased efficacy with increasing levels of hyperopia.  Appropriate labeling should delineate the declining procedure effectiveness as the pre-op level of hyperopia increases.

                        There was an approximate 1 in 10 rate of no or slight improvement in the quality of vision and an approximate 1 in 10 rate of dissatisfaction.  There were no differences found between differing hyperopic groups regarding satisfaction rates.  Appropriate labeling should reflect these data.

                        Regarding stability, the proportion of over-corrections for the entire cohort decreases with time over the study periods suggesting refractive instability or loss of surgical effect as shown here graphically with time.

                        Additionally, as we've seen this data on a previous slide, the declining levels of induced cylinder with time also argues for refractive instability. It's reasonable to assume that shifting  astigmatism may lead to complaints of fluctuating vision.

                        For a consistent cohort of eyes through month 12, the mean refraction does show a continuous rise as shown here, supporting refractive instability of loss of surgical effect.  Over this particular study period, there was a .8 diopter loss from month 1 to month 12 or approximately 30 percent of the refractive effect was lost between month 1 and month 12.  Of note, physiologic drift has been estimated to be less than .08 diopters per year and is therefore not likely to play a significant role in the hyperopic drift seen in this particular study.

                        If analyzing the mean rate of change per year, there is a 1.00 diopter change per year if you utilize the data between 3 and 6 months.  There's a .4 diopter change per year if looking at the data from 6 to 9 and a .48 diopter shift per year if looking at the data between 9 and 12 months.  Importantly, the rate of shift is increasing at the latest study interval whose confidence interval does not include zero, indicating that a definitive stability point has not been reached.  The stability of this procedure is therefore unproven.

                        As a historical perspective, the 10-year PERK Study results caused widespread concern regarding refractive instability when it disclosed a refractive shift of only .06 diopters per year, a rate of refractive change 8 times smaller than the current CK refractive shift from 9 to 12 months.

                        In support of refractive instability then we have the following features:

                        1.  Increased variation of vision complaint.                    

                        2.  Increased fluctuation of vision complaint.

                        3.  Progressive declines in astigmatism magnitudes.

                        4.  Progressive declines in the percentage of over-corrections.  

                        5.  Progressive increase in the mean manifest refraction spherical equivalent in a continuous month to month refractive shift that increases at the latest time interval and whose confidence interval excludes zero. 

                        Hence stability of this surgical procedure has not been established on the basis of these data.  It is therefore mandatory that the study be completed with careful FDA analysis of the completed data set.  There is no doubt that the seemingly temporary nature of the refractive effect is an important material fact for a given patient to understand prior to undergoing or considering this procedure.

                        The refractive procedure likely causes irreversible structural changes to the collagen fibers of the cornea, making the suitability for future refractive procedures unknown.  There are no data in the submission regarding retreatments.  Appropriate labeling should indeed mention this fact and especially in the light of the substantial refractive drifts seen in the study.  In other words, options to later correct a seemingly temporary nature of the effect are unproven.

                        Given all the foregoing, if I were advising a patient in a doctor-patient relationship considering this procedure, I would feel obligated to disclose at least the following material facts.

                        1.  There may be up to 32 individual corneal needle sticks placed manually at 90 percent corneal depth.

                        2.  Twenty-five percent of patients have greater than or equal to 1 diopter of induced cylinder at 6 months.

                        3.  A shift in astigmatism axis is more likely than not.

                        4.  Five percent of patients lose greater than or equal to two lines of best corrected visual acuity at 6 months.

                        5.  Patients report increased symptoms of glare, halos, double vision, fluctuation of vision, variation of vision and night driving problems following the procedure.

                        6.  The procedure is unstable with a substantial progressive loss of surgical effect.

                        7.  The current PMA discloses that the duration of the hyperopic drift is unknown.

                        Assuming that the patient was competent, had adequate comprehension of the issues and was exercising voluntary choice, I'm hard pressed to say that a reasonably prudent individual would want the particular procedure.  Nonetheless, it's the charge of this Panel to determine if the data proffered give a reasonable assurance of safety and efficacy if a patient was indeed interested in this procedure.

                        This Panel is once again faced with a device that has a seemingly temporary refractive effect.  From a prior Panel Meeting, it's the Agency's position that "it's quite reasonable for an Advisory Panel to evaluate a submission which has a nonpermanent use.  There are devices that are just temporary.  There are a lot of them."

                        In the past, a marginally effective procedure for hyperopia, the Sunrise LTK procedure, was indeed FDA approved, "for the temporary reduction of hyperopia in 2000." 

                        Given that refractive instability is a major shortcoming of this procedure, the primary indication statement should delineate two crucial material facts. 

                        1.  Significant hyperopic shift or loss of surgical effect occurs over the study period.

                        2.  The study fails to prove refractive stability in the long run, that is the drift may be on-going.

                        It's important to realize that just as the data do not prove final stability, the data similarly do not prove that the surgical effect completely regresses.  That is, the data are insufficient to prove that the effect is either temporary or permanent, albeit we do know that the surgical effect diminishes over the study period and we do know that it does not stop at a defined point in time.  Rather than a single word like "temporary", I'd suggest a statement that describes both the loss of surgical effect and the unknown duration of drift such as "refractive stability is unproven for the CK procedure with progressive loss of refractive effect over time."

                        I'll certainly be interested to hear Panel wordsmithing on this particular issue.

                        In the PMA's current state, with the major shortcoming of refractive instability, I don't believe that the application is approvable without conditions.  Therefore, I'd recommend the following conditions for approval. 

                        1.  Complete all enrolled eyes to the

12-month interval with FDA review of all stability analysis and if stability cannot be proven at that time, hold approval and reanalyze at longer time intervals.

                        2.  Submit all available 24-month data for FDA review prior to considering approval.    

                        3.  The study must be completed to 24 months given all the aforementioned issues.

                        4.  Post-market surveillance is mandatory to document if and when the regression stops with appropriate labeling revisions.

                        5.  The labeling should include all relevant material facts.

                        And rather than listing them I went ahead and put a Panel handout on everybody's table at the end of my slides listing the types of labeling recommendations that I would like to see for consideration.

                        6.  If not already done, eliminate the adjustable energy duration controls as this study was really only tested with .6, .6.

                        That concludes my initial comments.  Thank you so much for your attention.

                        DR. SUGAR:  Thank you.  Next, Dr. Weiss?

                        DR. WEISS:  I think my colleagues have very effectively discussed the concerns about this procedure and in the interest of not being repetitive and in the interest of time I will not repeat their comments, but I'll limit myself to the questions that are before the Panel for discussion.

                        The first question was are there concerns regarding the incidence of induced cylinder with significant axis shift and its consequent effect on efficacy?  I think all the -- Dr. Berman, Dr. Grimmett, Dr. Bradley and myself all have concerns about this.  The best corrected visual acuity is only one criteria to evaluate the efficacy and as Dr. Berman has shown us, of the patients who had more than or equal to 1 diopter of astigmatism induced, they had half the rate of achieving 20/20 as those who had less astigmatism induced.  So even one line of uncorrected visual acuity difference is very significant when we're dealing with such small amounts of hyperopia.

                        Nevertheless, I think the way to address this concern is in the patient labeling because there are strict criteria that the FDA has put forward and that the device meets these criteria in terms of the amount of percentages of induction of 2.00 diopters of astigmatism, so this is a patient labeling question that we will sort of hash out.

                        The second issue is is 12-month follow-up sufficient to provide reasonable assurance of safety and efficacy and should data for the 21 eyes available at 24 months be required in labeling?  We have to apply the FDA criteria for all these questions and in this case we have to admit that the sponsor has met only 2 of the 4 stability criteria at 12 months.  Consequently, stability has not been achieved.

                        This is a very important question for any patient who's going to decide to choose a particular type of refractive procedure and they're entitled to know whether this is a temporary or permanent procedure and we have applied these criteria, namely deciding whether something is temporary or permanent effect to other devices that have come before Panel as was just mentioned the Sunrise laser most recently.

                        So I think it is incumbent on the FDA and the sponsor to have analysis of the 24-month data to decide at what point, if we can determine, stability is reached and I think this very important to put as well in the labeling that stability has not been reached by 12 months and I would actually prefer to say at 12 months the effect of this device is temporary just so the patient can understand and compare this to other devices that are out there and they are going to be making a selection between.

                        The third question, does the refractive correction obtained with this device in light of the rate of change of mean MRSE over time and the incidence of over and under-correction justify the potential risk?  And to this I would answer yes.  The criteria that the FDA has put forward have been met by the sponsor and the risk of adverse effects are quite low and so I think that the risks are certainly justified.

                        Question 4, are there concerns regarding the increased incidence of visual symptoms from pre-op levels?  Well, here I have a slight concern.  The moderate to marked complaints subjectively were a little bit higher than FDA criteria have mandated in the 5 to 7 percent range and I think it's very important to have in the patient booklet a better reflection of exactly what these complaints have changed from pre-op to post-op values.  For example, mild complaints of halos, blurred vision, double vision, fluctuation of vision actually doubled between the pre-op visit and the month 6 visit and continued at month 9 and month 12 and it's very important for patients to know not just the percentages, but that these things may be affecting them.

                        Also, as has been pointed out at the Panel, there appeared to be a slight trend toward increasing dissatisfaction with time, although statistical parameters were not applied and this follows the effect of regression and decrease in

over-correction with time.

                        Question 5, do the safety and efficacy data presented in the PMA support approval of this device for the requested indication?  I would say yes, with the concerns that I've mentioned about the 12 and 24 -- bring the data out to 24 months and deciding whether we are going to call this a temporary effect or when stability is defined.

                        And as to Question 6, the recommendations for labeling regarding regression of effect, induction of cylinder and incidence of visual symptoms, I would address myself again to the question of stability.  I do believe the sponsor is being a little disingenuous by playing around with not being able to see whether this is permanent or temporary and not needing to choose those words, yet at the same time including in the patient labeling a statement saying that LTK reshapes the cornea to temporarily treat hyperopia, as if to make a distinguishing characteristic that LTK is a temporary procedure with this indeed may not.  I think you have to basically decide is this temporary of if you don't want to say it's temporary at the 12 months, then bring it out to 24 months and give us a stability time point, but to say that another procedure that a patient may be choosing instead of this is temporary by comparison, I think is a little bit deceptive, just as deceptive as saying you could be treated with a laser versus a warm heat.  That has to be described in a little bit better detail as well.

                        The incidence of the axis shift and the magnitude of induced cylinder as well as the duration that this is occurring for should also be included in the labeling because this could cause significant visual symptoms, even if the best corrected visual acuity is minimally affected and even if there's only a line of uncorrected visual acuity deficit, still I think most of us would not have any problems believing that if a patient has an axis shift of 45 degrees they may have a problem with this.

                        And in addition, the subjective symptoms the patients should have in the patient booklet, the degree of increase between pre-op and post-op of the symptoms.

                        DR. SUGAR:  Thank you. 

                        DR. ROSENTHAL:  Mr. Chairman?

                        DR. SUGAR:  Please.

                        DR. ROSENTHAL:  I think I should say this now before you start your deliberation that as you all know and I think you've been very good about it, each PMA has to stand on its own and this data has been discussed on its own.  There has been reference to other decisions the Panel has made.  I think that's reasonable to make a reference to it, but I think no comparison either by you, the Panel or certainly by the company in its labeling will be appropriate.  So I think you all are aware of that and I think it's reasonable to point out in historical perspective that the Panel in the past has approved refractive corrections for quote temporary as you have done, but to compare them in any way would be inappropriate.

                        Thank you.

                        DR. SUGAR:  Thank you.  I'd like to suggest a format for proceeding, of going through question by question unless there's objection, and then using that discussion to then come to a motion and discuss motions.

                        Do you have a comment, Jose?

                        DR. PULIDO:  Yes, since Dr. Rosenthal brought up the historical perspective, we should also realize that the first time that the LTK came up to Panel it was not accepted.  It was only after the FDA pushed us to saying that temporary is allowed that the Panel then allowed the LTK to go through.

                        DR. ROSENTHAL:  I think Dr. Grimmett made that clear.  I think he was quoting me.

                        DR. GRIMMETT:  Yes, I was.

                        DR. SUGAR:  Okay.  Does anyone object to proceeding question by question?

                        Then the first question is what are the concerns regarding the incidence of induced cylinder with significant axis shift and its consequent effect on efficacy?  And I'd like to have one of the primary reviewers be the first to answer each of these.

                        Dr. Bradley, do you want to begin?

                        DR. BRADLEY:  Well, I think there has to be concern we have a procedure that is inducing cylinder.  We don't know what the root cause of this induction is and clearly those patients with larger amounts of this induced cylinder are not achieving the uncorrected VA that is achievable by those patients who have lower amounts of the induced cylinder.  So I think whenever that happens we have to be concerned about it and it certainly is compromising the efficacy.  I think as I alluded in my presentation the thing that  concerns me is we have no idea where it's coming from and there seems no indication in the near future that it could be improved or remedied.

                        DR. SUGAR:  Thank you.  Other comments concerning this issue? 

                        I think that the Agency has a sense of our concern about the induced cylinder.  In terms of how specific we need to get beyond what's already been discussed I'm not sure.  Can you comment, Ralph?

                        DR. ROSENTHAL:  If the Panel feels they've discussed this sufficiently --

                        DR. SUGAR:  I'm not saying we have.  I'm not exactly sure what direction you want us to go.

                        Bill Mathers?

                        DR. MATHERS:  Yes, Bill Mathers.  I'm a little concerned, like my colleagues, that we don't really know why this is occurring and there certainly are several possibilities.  I think it could be possible to find out.  I think that, for instance, topographic ought to indicate if we have a kind of generalized regular astigmatism or if it's highly irregular and where it is on the cornea and if there's a possibility of improving this or if the procedure is just intrinsically going to do this.  And so I don't think the astigmatism is terrible, but I think we don't know why it's occurring.  It may be because we're treating in some cases on visual axis, but some of that is closer to the periphery than -- because of the shape of the cornea.  There's lots of questions here that remain unanswered.

                        It may not preclude us from granting some kind of approval because of its safety and efficacy, but we don't know what's happening.

                        DR. ROSENTHAL:  May I just interject?  I think there are certain interesting scientific questions that are always raised by devices and Dr. Mathers has raised them, but whether or not -- I do not feel that it's this Panel's responsibility to try to come to some conclusion as to why there are problems, except if it influences the decision making process and certainly, hopefully, for devices, in general, when they are finally out in the community many of these questions get answered.

                        DR. SUGAR:  In general, the way we answer these is by dumping them into labeling and the suggestion has been made that the labeling includes cylinder induction by degree of induction, loss of acuity related to cylinder induction, instability of cylinder induction and the unpredictability of cylinder axis and I think it's important that if these are put in the labeling that the labeling for the patients not say cylinder axis because that's not meaningful to a patient, but that there be wordsmithing such that it's understandable to a patient what's being talked about.

                        Alice?

                        DR. MATOBA:  Also in the labeling we should add that the original study only included patients with astigmatism up to .75 diopters and we don't know whether this effect would be magnified or not in patients with higher levels of astigmatism.

                        DR. SUGAR:  Although my presumption is we're considering approval only in the range that's been studied.

                        Other comments on cylinder?  Does everyone agree that this needs to be addressed in labeling?  Any other comments on -- that's Question 1.

                        No. 2, is 12-month follow-up sufficient to provide reasonable assurance of safety and efficacy?  There are 21 eyes available at 20 months.  Should data for these eyes be required in the labeling?

                        It's a two-part question, that is, do we have enough follow-up and (2) what should we do with the data that we have?

                        Jayne?

                        DR. WEISS:  I think 12-month data is sufficient to assure safety, but I think part of efficacy is whether the effect is stable or not.  So I think I would have questions about efficacy at only 12 months and consequently would like the data from 24 months to be included in the labeling.

                        DR. SUGAR:  Go ahead.

                        DR. GRIMMETT:  Michael Grimmett.  As I made in my concluding remarks, with the final interval showing a .48 diopter shift per year whose confidence interval excludes zero and is increasing, I feel that the 12-month data collection should ensue with FDA analysis of that stability to see if it is now decreasing and if the confidence interval includes zero.  I would hold approval until that's met.

                        DR. ROSENTHAL:  Excuse me --

                        DR. SUGAR:  You said 12 months.  In your presentation you said 12 and then you had another clause about 24-month data.

                        DR. GRIMMETT:  I'd like to see the

24-month data that's available or have the FDA look at it, but I believe the 12-month data should show stability by the current criteria before it's let loose.

                        DR. SUGAR:  So you're suggesting that we get more complete 12-month data?

                        DR. GRIMMETT:  Yes.

                        DR. SUGAR:  And have that re-reviewed --

                        DR. GRIMMETT:  By the FDA.  That's correct.

                        DR. SUGAR:  Dr. Huang?

                        DR. HUANG:  I have a real reservation about Mike's final recommendation.  So we know this is going to be a temporary procedure would that be reasonable to impose on the post-market surveillance rather than defer the PMA, otherwise, I don't think we will ever get enough data.

                        DR. SUGAR:  Other comments?  Dr. McMahon?

                        DR. McMAHON:  Tim McMahon.  One of my concerns and maybe one of my questions is with the supposition that this is a transient effect, that if Dr. Bradley's supposition is even remotely correct has somewhere in the neighborhood of a 4-year duration, then there's going to be a tremendous stimuli for retreatment and we have absolutely no idea about this.  And I have -- do we have the capacity in the labeling to prevent retreatments in the absence of subsequent study data?

                        I'm worried that additional treatments will increase irregular astigmatism, reduce the best corrected visual acuity and all the things that have escaped this procedure thus far.

                        DR. SUGAR:  I think in the labeling we can approve it for the indications and say that this has not been -- we say that there is not data on retreatment.  What a physician practicing medicine chooses to do is a different issue that I don't think we can control. 

                        Am I wrong, Ralph?

                        DR. ROSENTHAL:  That's -- you can put, you can certainly put in labeling that there's no data on retreatment.  If you have valid scientific justification, you can include in labeling that you do not feel retreatment is warranted, but --

                        DR. McMAHON:  That's like proving the negative.

                        DR. SUGAR:  But it's hard to do in the absence of data either way.  But your point, I think is well taken.

                        DR. ROSENTHAL:  Excuse me, Ralph Rosenthal.  You can use precautions and warnings to clarify your issue, but to contraindicate retreatment without having any data and any scientific basis of that is very difficult to do.

                        DR. SUGAR:  Jayne?

                        DR. WEISS:  I think we've returned to the issue of temporary versus stable and that's why I think at some point sponsor, as well as FDA has to put our money down and determine which one this is and that will let us go forward in terms of deciding whether delay approval will go ahead with approval. 

                        I would be of the mind to say to go ahead with approval with the 12-month data that we've been supplied by saying at this point the effects are temporary and we will need the 24-month data to determine stability as opposed to holding up approval waiting for that stability to happen.

                        DR. SUGAR:  I would like to wait until Question 5 in terms of that would be the indication rather than labeling, but the use of the word "temporary" and I assume we'll have a moderately gently heated discussion.

                        DR. WEISS:  I was just addressing that to Mike's comment.

                        DR. SUGAR:  Dr. Huang?

                        DR. HUANG:  Andrew Huang.

                        DR. SUGAR:  And then Dr. Ho.

                        DR. HUANG:  I have a question for the Panelists.  I'm still not clear if the Panel's responsibility is to approve the device based on the safety or based on the efficacy.

                        DR. SUGAR:  Both.  And to comment on both and we recommend to the Agency, the Agency then approves or doesn't approve the device.

                        Dr. Ho?

                        DR. HO:  Allen Ho.  My only comment would be that there may not be anything magical about

24-month data and if stability is established prior to that that would be much more comforting to me.

                        DR. SUGAR:  Okay, so last comment on this question.

                        DR. BRADLEY:  It's actually a question.

                        DR. SUGAR:  Dr. Bradley.

                        DR. BRADLEY:  I'm surrounded by such esteemed clinicians and I think the sponsor has already mentioned that treatments for hyperopia tend to have the characteristics we've seen with this particular treatment, that is, initially there's an over-treatment and the patient ends up with myopia.  Subsequently, there's a regression and arguably the regression is greater than some of the earlier devices that have been approved.

                        I'm just wondering what patients do with that?  I mean surely we have now a data base of how patients handle this.  Are patients opting for some of these other techniques that are out there or are they saying no, I don't want temporary myopia and I'm not going to have a surgery is then going to regress away.  I'm going to lose the effect.  Because if that's the case, then I would say perhaps we shouldn't approve this one, but if patients are quite happy with that, then my opinion would change.  But I have no knowledge of that.

                        DR. WEISS:  I think our decision should really be made at the Panel just on safety and efficacy requirements and whether or not an individual patient opts for this is a whole separate question which I don't think we really have to address.  The company and its stockholders will have to address that one.

                        DR. SUGAR:  Although we can say let the buyer beware and do that in the labeling.

                        Next is Question 3.

                        I'm sorry, Bill?

                        DR. MATHERS:  Bill Mathers.  We can say that it's effective temporarily at this point because there is some demonstration of efficacy, but we certainly can't say that we know the nature of the permanent correction and we may not at 24 months either.

                        DR. SUGAR:  Again, we'll get to that in the indications and we can also, in addition to these questions, we can recommend post-marketing surveillance and re-review -- we cannot recommend post-marketing --

                        DR. ROSENTHAL:  Rosenthal.  Surveillance, I don't think is the word.

                        DR. SUGAR:  I'm sorry.

                        DR. ROSENTHAL:  You can recommend a post-market evaluation of a cohort.

                        DR. SUGAR:  No. 3.  Does the refractive correction obtained with this device in light of the rate of change of mean Manifest Refractive Spherical Equivalent over time and the incidence of over and under-correction justify the potential risks.

                        Go ahead, Dr. Grimmett?

                        DR. GRIMMETT:  I interpret this question to mean is it reasonably safe despite the limitations of effectiveness.  I believe the answer is yes.  It's reasonably safe despite the stability questions.

                        DR. SUGAR:  It's sort of worded a little ambiguously.  It also says in light of the rate of change of mean Manifest Refractive Spherical Equivalent.  So this is really asking, I think, both of us stability and safety.

                        DR. GRIMMETT:  Okay.  Well, stability I believe I've made my opinion clear that I don't think the current PMA meets the current FDA definition of stability and I'm uncomfortable approving unstable procedures that don't meet current FDA definitions, but I do believe that the procedure is reasonably safe.

                        DR. HUANG:  Andrew Huang.  I feel that the regression is really biphasic as shown by the graph from the presenters.  There's initial over-correction and there's later under-correction and so therefore I think the generalize statement by the sponsors generalizing the statements it is 6 to 10 percent decrease loss of the intended correction, I don't think it's a fair statement.  I think the sponsors should clarify the issue and report a natural course of this regression to the consumers.

                        DR. SUGAR:  Again, that's in terms of how we define the indications, because they're suggesting, I think that being the indications and I agree, we can suggest rewording. 

                        Other comments?

                        Arthur?

                        DR. BRADLEY:  We're trying to assess whether this procedure justifies the potential risk given what we've seen in terms of its effectiveness and it just seems to me that in some ways we're a bit -- we're forced to make this decision prematurely.  I mean the data, as I show, the procedure itself actually increases the variability in the refractive error distribution.  I can't imagine how such a procedure can be successful, given in every eye there was a single target end result which is emmetropia.  So it seems to indicate there's a huge amount of uncontrolled variability in this procedure which is very worrying to me.

                        We also know that not only the mean, but a significant proportion of the patients are going to have significant, and I mean clinically significant levels of myopia after the procedure, albeit this is a temporary situation for most of those patients.  Again, that worries me in terms of safety, particularly, as I said, these patients have not experienced myopia before.  So this is a first time for them.

                        In the end, I just worry that we have a procedure that has a lot of uncontrolled variability to it.  It fails to hit its target in the short term and maybe only hits the target at 9 to 12 months because it so happens the regression is passing through zero at that point.  And I just -- I'm looking for evidence to say yes, this is an effective procedure.  It actually can render emmetropia is some reasonable way in a large percentage of the people who are treated and I can't find that.  I'm really having trouble with that.

                        DR. SUGAR:  Dr. Mathers?

                        DR. MATHERS:  This is a surgical procedure and all surgical procedures are unstable immediately after the procedure.  We take this to a higher standard with a refractive procedure because we're dealing with somebody that can see beforehand, as opposed to say an unstable knee that needs a total knee.  But nevertheless, it is a surgical procedure and the fact that it's not perfect immediately after I think it would be to a higher standard to hold that to make it perfect immediately, in general terms.

                        DR. BRADLEY:  Maybe I can respond to that.  I think it would be true, if this patient was rushed to the hospital and needed treatment, but that's not the case.  I mean these patients have alternative modalities which they can use to correct their farsightedness.  So this is an elective procedure and I think we should hold it to a much higher standard.  I'm quite comfortable with that higher standard.

                        DR. SUGAR:  Additional comments on Question 3?  If not, we'll move on to Question 4.  Are there concerns regarding the increased incidence of visual symptoms from pre-op levels? 

                        We're back to you, Arthur?

                        DR. BRADLEY:  Well, I know we're not allowed to mention other refractive procedures, Ralph, so I'm not going to.

                        (Laughter.)

                        But we clearly know this is a ubiquitous result.  Any time a refractive surgery is done to the cornea, we have loss of best corrected visual acuity which is, by the way, symptomatic of some optical imperfection.  We have increased optical manifestations, also visual manifestations of optical problems:  halos, glare around light sources, transient visual, unstable vision, I mean.  And it seems like this particular procedure is no different.  So it just fits in with the crowd.

                        DR. SUGAR:  Go ahead.  Janice?

                        DR. JURKUS:  Janice Jurkus.  I have some very serious concerns regarding the changes from when people were pre-op and they said they had no symptoms to post-op and they said that they did have symptoms, even though they may be mild symptoms.  I think the person can quite easily tell if they have a symptom or not and I understand that the subjective information that patients given can vary from day to day, but when you get the amount of change that was noted in the submission that's concerning to me, particularly in terms of the halos around lights and the patients having fluctuating vision and having fluctuating vision in dim illumination because again, the age population that this treatment is for is also the age population that may be developed in cataracts and these can be exacerbated to even a further degree.  So that is a very serious concern to me.

                        DR. SUGAR:  Go ahead, Dr. Ho.

                        DR. HO:  Allen Ho.  I'm less concerned about those.  Any symptomatology that's reported in an uncontrolled fashion and I would say that the bottom line here on satisfaction, 9 out of 10 patients were satisfied.

                        DR. SUGAR:  Okay, other comments?  I think Mike and then Jose.

                        DR. GRIMMETT:  That's okay, Jose can go.

                        DR. PULIDO:  Dr. Ho, where was the -- Jose Pulido -- where was the 9 out of 10 satisfaction rate?

                        DR. HO:  Can you guys confirm that?

                        DR. GRIMMETT:  The relative figure was 1 out of 10 were dissatisfied or very dissatisfied and then the satisfaction rate, you'd have to subtract the neutral category out.

                        DR. HO:  Right.

                        DR. GRIMMETT:  So satisfaction may be, if my memory serves me correctly, 70 percent?

                        DR. PULIDO:  Yes, it wasn't 9 out of 10.

                        DR. GRIMMETT:  But you'd have to look at the tables.

                        DR. HO:  Okay, Allen Ho. I'm corrected, but the point is you have to be very careful about looking at rates of symptoms in the context of an uncontrolled setting.

                        DR. GRIMMETT:  Mike Grimmett again.  I think -- I agree with Dr. Jurkus' concern over the symptom data and I think those issues can be dealt with in the labeling as given an example of a nice table that Dr. Berman presented on the very next slide, Slide 15, as well as delineating the percent of patients that had no symptoms pre-op, versus no symptoms post-op.  That was the type of data I presented in my presentation.  I just reversed the numbers to yes rather than no, but I think both ways of presenting the data would be appropriate in the labeling.

                        DR. SUGAR:  I'd like to move on then to Question 5.  Do the safety and efficacy data presented in this PMA support approval of this device for the requested indication?  That's getting back to the wordsmithing we were talking about.  Is the requested indication appropriate as worded, based on the study outcome? 

                        And then the last page of the sponsor's presentation, I think, had their recommended wording if I'm correct.

                        This is CK treatment for the indication of spherical hyperopia in the range of +0.75 to +3.25 diopter for cycloplegic spherical hyperopia, -0.75 diopters or less of refractive astigmatism, +0.75 to +3.00 diopters of cycloplegic spherical equivalent.  In patients with less than .50 diopter difference between pre-operative manifest and cycloplegic refractions who are over 40 years of age, that's the up front indication in terms of patient refractive error and age.

                        The magnitude of correction diminishes over time with an average loss of approximately 6 percent by paired analysis manifest refractive spherical equivalent of the intended correction at 1 year.  The proportion of intended correction retained beyond 12 months is undetermined.

                        I guess I'd like to deal with first the two main bullets, the dioptric correction for sphere and cylinder and the difference between pre-manifest and cycloplegic refractions in patients 40 years of age or older.

                        Are there comments suggesting to modify those.  Please, Jayne?

                        DR. WEISS:  Well, I would agree with the three bullets as listed, except would want to -- if the device was going to be approved today, I would like to add CK treatment for the temporary reduction and just add the word temporary which can be changed if the 24-month data which will be reviewed by the FDA shows stability at that point.

                        DR. SUGAR:  Okay, I sort of tried to separate these so that we can -- I'm not trying to avoid anything, but -- in a way I am, but that's different.

                        The last two bullets are really discussing that wording and it could be put up front or at the end that I think ultimately FDA will decide.

                        DR. WEISS:  Jayne Weiss again.  The erst of the bullets as listed that you're referring to I would agree with.

                        DR. SUGAR:  Dr. Huang.

                        DR. HUANG:  Andrew Huang.  I have a little bit reservation about the proposed three indications.  I think the data presented by the reviewers are stratified patients of pre-operative hyperopia, so you can see there's a drastic difference between the efficacy between the +2.00 of greater or the +2.00 or lower hyperopia.  So I think maybe we can review the data if the sponsor can stratify the information according to the pre-operative information and then show the efficacy is indeed much better in one group and then we probably can narrow the indication of +.75 to +2.00 or +2.50 instead of all the way to +3.25 to increase the safety margin.

                        DR. SUGAR:  Okay, there are two different ways that we've dealt with this.  One is to change the indication.  The other is to leave the indication, but include in the labeling and physician information require that it be in -- that information that there be stratification and demonstration of efficacy and that the patient be told that there are different efficacious at different rates.  I think Mike and then Alice.

                        DR. GRIMMETT:  Mike Grimmett.  I would favor the latter option that Dr. Sugar discussed of dealing with it in the labeling.  We all know that most of the refractive procedures have decreasing efficacy as the level of emmetropia increases.  I don't think it would be exactly fair or right to chop it off at the higher range unless there was such a paucity of data at the higher range that it wouldn't warrant the approval.

                        I would leave the first three bullet points alone and deal with the decreasing efficacy in the labeling.

                        DR. SUGAR:  Dr. Matoba?

                        DR. MATOBA:  Dr. Alice Matoba.  I agree with Dr. Grimmett.  I think the patients who had the higher levels of pre-operative hyperopia were more satisfied and happier with the procedure.

                        DR. HUANG:  But have less effect.

                        DR. SUGAR:  That's correct.  Bill?

                        DR. MATHERS:  Bill Mathers.  But that is the group actually that needs -- that is most interested in having the procedure, so I think that whereas the efficacy, the effect may not be quite as great, it would be unfortunate to remove that group from this.

                        DR. SUGAR:  Okay, I'd now like to deal with the indication, the wording in the indication for our concern about stability or loss of effect.  The sponsor suggests the magnitude of correction diminishes over time with an average loss of approximately 6 percent of the intended correction at 1 year.

                        DR. BRADLEY:  I'm a bit worried by this because if we replace one year, perhaps 11 months and 3 days it would be zero percent because there is some point at which that function crosses zero and it may just be fortuitous that the cross over one is close to 1 year and what is misleading about that is the implication that boy, it's right on target and there is no indication that, in fact, that was a moving target.  So I'm a bit worried about an incorrect implication of that statement.

                        DR. SUGAR:  Please, Dr. Grimmett?

                        DR. GRIMMETT:  I agree with Dr. Bradley's concerns.  I think the comparison to intended correction with the moving target is misleading to consumers.  The way that I looked at it or analyzed it, at pre-op, these patients had a mean hyperopia of 1.86 and at month 1 they were corrected to a mean of

-.56 diopters for a mean total of 2.42 diopters of surgical effect at the 1 month visit.  They lost .8.  That's about a third of the effect was being lost with time, so in my presentation when I said they lost about a third of the surgical effect, that's the way I was looking at it and I feel the 6 percent figure would give misleading reassurance to consumers.  I'm not in favor of the comparisons to intended correction because it is a moving target.

                        DR. SUGAR:  Bill?

                        DR. MATHERS:  Bill Mathers.  I think it would be more accurate at the present time for the public to understand that it's at about a .50 diopter per year in -- but this is only an estimate.  Because they care what happens in the immediate time, but really in terms of what they can look forward to once things settle out, it looks like it's going to be somewhere on .50 a diopter a year.  And that's perhaps a closer understanding to -- although we don't know this.

                        DR. SUGAR:  Jayne?

                        DR. WEISS:  I would like to put this in terms that anyone could understand and I think without looking at the numbers, basically at one year, this is not stable.  The effect is not stabilized at one year.  I'm not sure that all patients would understand the significance of the .50 diopter versus 1.00 diopter whereas if you say it's not stable, well, it's not stable.

                        DR. SUGAR:  So you're suggesting?

                        DR. WEISS:  Well, I would still -- I don't know if I dare to go back to the first line and put in "temporary", but I won't say that, but I thought it.  But I would agree with the other two reviewers, the last two statements by the sponsor sort of sanitize and minimize what our concern is that at one year time stability of the refractive effect has not been achieved for the consumer advocate might wordsmith a better way to put this for consumers, but that's basically what I'd like to convey.

                        DR. SUGAR:  Rich McCarley?

                        MR. McCARLEY:  Just a comment.  I mean I don't know if we're actually trying to wordsmith it here, but it seems like three comments can solve, I think, at least in my mind, you know, the results may diminish over time or the stability has not been established over time.  Average loss at one year is 6 percent.  Long term stability has not yet been established.  I mean essentially you're telling them what the truth is.  The long-term stability hasn't been established.  What we do know at least with the data we have is that at one year it appears to be 6 percent and up front you tell them it may diminish over time.  You don't know -- I'm not sure whether the statement that they have even presented is correct because it says that there's an average or a mean loss of 6 -- a regression of 6 percent, but did all patients regress?  So I think it's simply being up front and telling them the results may diminish over time, the average loss at one year was 6 percent and the long-term stability has not yet been determined.

                        DR. SUGAR:  My recommendation would be that if we have a statement similar to where there is significant likelihood of regression of effect over at least 1-year period, over at least a 1-year period of time, which may be too nebulous, but I don't think -- I think that 6 percent is too specific and misleading.

                        Bill?

                        DR. MATHERS:  Yes.  I would agree with you.  If you're going to say something, you can't say the 6 percent.  I think that that's too soft.  You either need to be more nebulous or you make it a little more accurate, according to what we currently think.

                        DR. SUGAR:  Too gentle.  Tim?

                        DR. McMAHON:  Two things.  I'd actually like to put in Dr. Weiss' comment on the first line that we do put in the point of the temporary reduction of spherical hyperopia and then to address the bullet point with regard to the 6 percent.  I think you can accomplish that by actually posting what the ranges are for both change from maximum correction as Dr. Grimmett was discussing as well as from intended correction and if you show the breadth of the range, then both physician and patient will have some idea of what that spread is.

                        DR. SUGAR:  Jose?

                        DR. PULIDO:  Going back this morning, Joel, you asked me why I brought up that case of the patient with that adverse event.  It was a patient that had a -2.00.  Dr. Bradley later talked about the -2.00 situation as well and my concern and it's been brought up by the Panel reviewers is the unpredictability and nowhere in this yet have we discussed the fact that it's not a very predictable procedure.  Do we need to put that somewhere in the labeling?

                        DR. SUGAR:  I think that there will be agreement to that. Right now, I think we're still dealing with the indications, but I agree with you wholeheartedly.

                        Arthur?  I guess I'm not supposed to agree.  I'm supposed to be neutral.

                        MS. THORNTON:  You can agree.

                        DR. SUGAR:  I can?  Thank you.

                        DR. BRADLEY:  I'll try to preface the agreement with -- I'll try to agree with Joel and with Jose here.  This is Arthur Bradley.  Yeah, I think that second from last bullet is unique, really, compared to the other ones and one wonders if it's appropriate in the indications for use.  Because really it's sort of an apology for a statement of the inaccuracy of the procedure.  And it's only one of the inaccuracies is as I spoke before, the procedure itself has a lot of variability, so inherent inaccuracy and this is just mentioning one summary statistic of a whole variety of errors produced by this procedure and I think if in the indications it's appropriate to put a summary of the inaccuracies of the procedure, I think that would be fair enough, but this is completely inappropriate as such a summary, but I'm not sure that that would be an appropriate thing to put in the indications, but it seems to me that's what it is.  It's a statement of the inaccuracy of the procedure and I think there are a variety of things we'd like to put in such a summary statement.

                        DR. SUGAR:  Jose?

                        DR. PULIDO:  So, Joel, you castigated me for putting, for talking about the unpredictability --

                        DR. SUGAR:  I enjoyed it.

                        (Laughter.)

                        DR. PULIDO:  But really, I think it should say something to the effect of CK treatment for the unpredictable and temporary reduction of spherical hyperopia in the range of dah, dah, dah.

                        DR. SUGAR:  No comment.  Jayne?

                        DR. WEISS:  I know we're not supposed to speak about other lasers or other procedures, but I do think we have to apply standard criteria to the devices that we evaluate here and I think putting that in would hold it to a higher level than we've been applying to any other device.  I think the indications are meant for what you use it for and the sponsor has indicated that.  We're discussing how we can indicate in a clearer fashion that there's not stability at one year, but to talk about the variability, I think that should be put into the labeling as opposed into the indications because that's the way we usually do it.

                        DR. SUGAR:  Mike and then Bill.

                        DR. GRIMMETT:  Mike Grimmett.  I'm not in favor of a single word temporary or permanent.  I just don't think that the data are sufficient to prove it one way or the other.  We simply don't know.

                        What we do know is that the refractive effect diminishes over the study period and we don't know where it stops, so I would with those two points I would somehow like them in a sentence and I suggested one, but there's numerous ways to do it to communicate those two particular points.  I'm not a fan of the word temporary.

                        DR. SUGAR:  Can you restate yours?

                        DR. GRIMMETT:  Sure.  My was "refractive stability is unproven for the CK procedure, with progressive loss of refractive effective over time."  I'm certain that can be wordsmithed to something better.

                        DR. SUGAR:  That's worded more as a labeling thing rather than as an indication thing, unless you add CK treatment for the reduction of spherical hyperopia, where --

                        DR. WEISS:  This is just a question to yourself or Dr. Rosenthal.  In terms of the devices that we look at ordinarily, ordinarily does it have permanent versus temporary in the wording?

                        DR. ROSENTHAL:  This is Rosenthal.  No.  It says for the -- I forget what the exact word is -- for the correction of, which implies for the correction of.  And for the temporary correction of implies for the temporary correction of.

                        DR. WEISS:  So this is -- Jayne Weiss again.  This is where my concern lies is by not putting the word "temporary" are we implying "permanent"?  And that's why I'm going back to past experience with other devices, just so that the consumer can have a uniform way of comparing things?

                        DR. SUGAR:  My sense of the committee is that we all agree that there needs to be some modifier that says -- that based on the information we have now it does not appear to be stable and how we say that is what we're discussing.  I agree.

                        Bill, I think, was next.

                        DR. MATHERS:  Well, it was a couple of comments ago, but I think that all of our assessment of both the stability and the accuracy is based on a relative effect and that we -- although we don't talk about other systems, I mean none of this is accurate to the point at which we -- and to the level that we can measure.  They're all inaccurate and this is inaccurate as well, but in my opinion it isn't so wildly inaccurate that we should particularly characterize it as being an inaccurate approach.

                        But I do think it is important to address, to not let it stand either through labeling or through this indication use, that it is intended to be permanent because other systems of this are permanent, so this is a little different and somehow we ought to indicate that.

                        DR. SUGAR:  How would you suggest that we indicate that in the indications?

                        DR. MATHERS:  Well, if we put temporary in here now or if we recommend that -- and we learn later that it is different would it be removed?  Because -- I mean we don't have a complete data set here.

                        DR. SUGAR:  It could be.

                        DR. ROSENTHAL:  Rosenthal.  Dr. Mathers, yes.  The company could come back with 2-year or

18-month or 3-year or 6-year and ask for the elimination of the word or change in the indication based upon the data.

                        DR. MATHERS:  Because if I'm being intellectually honest about how this is now, it is the temporary effect in my mind now.

                        DR. SUGAR:  Go ahead, Alice.

                        DR. MATOBA:  Alice Matoba.  I think permanent is actually a relative term when you're speaking about these sorts of procedures and my question is are these last two bullets really indications?  Shouldn't they actually belong in another part?  Isn't it really more like a warning or a labeling?  Couldn't we just approve the first three bullets and then move on?

                        DR. SUGAR:  I think that the last two bullets modify the first bullet and certainly that information, this is opinion, should be in the labeling.

                        DR. MATOBA:  Okay.

                        DR. SUGAR:  The question is whether we approve this for treatment for the reduction -- approve this treatment for the reduction of spherical hyperopia or we approve this treatment for temporary or permanent, whatever.

                        DR. MATOBA:  Okay, my opinion is that the last two bullets are not indications and they're just modifications.

                        DR. SUGAR:  I personally -- I said this when we reviewed another hyperopia correction.  I think temporary implies that it is never permanent and I think temporary is an inadequate word to describe what we're trying to say, but I don't know what the right word is and I made a suggestion and I think there have been other suggestions.

                        Is anyone willing to take the bull by the horns, as it were?

                        Bill?

                        DR. MATHERS:  If you left the initial bullet to say "for the reduction" and you left the second to the last bullet to say "the magnitude of the correction is temporary" down there, it would still do the same thing, although I do agree both those are --

                        DR. SUGAR:  Does "diminishes over time" say temporary sufficiently for you or not?

                        DR. MATHERS:  I think it should say temporary.

                        DR. SUGAR:  Jayne?

                        DR. WEISS:  I understand Dr. Matoba's confusion with the last two statements because I think it's a way of skirting the issue of whether it's temporary or not.  And I think they sort of imply it's temporary, but don't say it's temporary and I think it would just be easier to call it for what it is.  At the present point it's temporary and if we have a

24-month data, if the FDA is now reviewing that and they see that indeed it stabilizes at 18 months, then that can be easily taken out even before it's on the market.  But if the sponsor is going to come forward to us with incomplete data, then we can only act on what we see and I think it is temporary at 12 months.

                        DR. SUGAR:  Bill?

                        DR. MATHERS:  I guess that I kind of agree with you that temporary is a little bit too harsh a statement and if we just said the magnitude of the correction diminishes over time period, then we are vague, but we are conveying that as a statement and you don't really have to say it's temporary because temporary really means it's never permanent.  I agree with you about that.

                        DR. MATOBA:  We don't know that.

                        DR. MATHERS:  No, we don't know that.

                        DR. MATOBA:  It could go down for another year and then just -- Alice Matoba.  We don't know that it's temporary.  It could keep going -- the effect could go down for another year and then stabilize completely.

                        DR. WEISS:  That's only because we've been forced to meet here without the complete data set.

                        DR. MATHERS:  Correct.

                        DR. WEISS:  That's why we don't know it and the data set is out there, so someone knows it.

                        DR. MATOBA:  Alice Matoba, so I think we can say neither temporary nor permanent.

                        DR. WEISS:  That's my --

                        DR. SUGAR:  Joel?  Tim?

                        DR. McMAHON:  I disagree with that.  We're faced with a set of data that we're supposed to comment on and it doesn't show stability on that basis.  The description is more temporary than anything else.  Now whether it's going to be like years down the line is something we can speculate on, but we're being asked to advise on and it is not stable and the effect is going away.

                        DR. SUGAR:  Dr. Ho?

                        DR. HO:  Allen Ho.  I just wanted to make a specific suggestion to include the first three bullets as indication and then the last two bullets, I would be personally comfortable with, "the magnitude of correction diminishes over time."  And then the last bullet stands as is.

                        DR. SUGAR:  Jose?

                        DR. PULIDO:  Well, Jose Pulido.  Treatment for the unstable reduction of spherical hyperopia.

                        DR. SUGAR:  I wonder if it's appropriate or not to mention in another review this committee looked at a suggested indication where the magnitude of correction diminishes over time, where it said treatment for the reduction of hyperopia where the magnitude of correction diminishes over time and we changed that to temporary.  Yeah, I personally favor where the magnitude of correction diminishes over time, but putting it up in the first sentence.

                        I suspect we've given you a sense of where we are.  We haven't?  Okay.

                        DR. ROSENTHAL:  Dr. Rosenthal.  You've given us a sense.  You're going to have to vote.  The sense of the Panel has been clarified, but you're going to have to ultimately vote.

                        DR. SUGAR:  I understand.  We're still discussing.

                        DR. BRADLEY:  The suggestion of Dr. Ho that we simply just include the very first part of that second from last bullet, the magnitude of correction diminishes over time period seems to me a way which accurately describes the result.  It doesn't put any potentially misleading statistic in there like 6 percent and we don't have to call it temporary.  We don't have to call it permanent.  We don't have to get embroiled in any of that.  We're just stating a very simple fact.  The fact is the magnitude of the correction diminishes over time.  And then the next bullet comes along basically saying well, we don't know what's going to happen beyond 12 months which is correct.  So --

                        DR. SUGAR:  Although it's been suggested that that be taken out of the indications, that last bullet and be put in the labeling.

                        DR. BRADLEY:  I don't think either of them are indications, but we're discussing them as indications.  I personally think they should be dropped completely and put in the labeling.  But if we want something like this in the indications, I think what Dr. Ho suggested is a very good suggestion.

                        DR. SUGAR:  Dr. Weiss?

                        DR. WEISS:  Jayne Weiss.  The concern or the issue that you just brought up is the concern that I have that we're applying for similar phenomena to different companies, different wording and some of them may be much more favorable and some of them are less favorable and for a patient who is comparing two potential procedures they can have, I would think it would be clearer for the consumer to have similar wording to convey similar issues.  And that is where my concern is as we recently looked at another device whose name won't get mentioned because I'm not discussing other devices, but we dealt with the issue of stability and because it was not stable at the time point that was given to us, we said it was temporary.  Now of course, no one knows that's going to be in 50 years or 20 years.  You can get ridiculous as far as final time points.  Yes, at some point -- but all the Panel can do is look at the data we have.  So if we have data at 12 months and it's not stable at 12 months, then why should we be giving different sets of wording for the same phenomena to different companies?

                        DR. HUANG:  Andrew Huang.  In addition to the wording, I think that that's a fair statement, but I think the indication we should look into the substance of the indication.  If we think that two or three similar devices provide similar effect, then if we provide a different range of the allowable correction, then that will be a disfavor to one of the companies.

                        DR. SUGAR:  Could you clarify?

                        DR. HUANG:  Well, I'm not sure about an indication of other companies, but obviously --

                        DR. SUGAR:  That's not relevant to this.

                        DR. HUANG:  That's what I'm saying, but the whole point is if we take into Dr. Weiss' discussion into consideration that we have to give the fair wording to the indication, labeling for this company, then we should also take into the other factors into consideration in terms of --

                        DR. SUGAR:  I think we should be fair based on the data that's presented to us and what Ralph is going to say is not relative to another product.

                        DR. HUANG:  That brings to mind another point on Dr. Grimmett's Slide 22 and obviously the amount of under-correction greater than 1.00 diopter is significantly more in the patient in the

pre-operative hyperopia of greater than 2.25 diopters.  The difference is 5 or 6 orders of magnitude, so I think that narrowing of the indication probably, should be discussed.

                        DR. SUGAR:  Actually, we did discuss that earlier and at least the --

                        DR. HUANG:  I know I may be in the minority.

                        DR. SUGAR:  No, but that should certainly be in the labeling.  But I think we also -- we're going to go back and vote on these one by one.

                        Janice was next.

                        DR. JURKUS:  I just wanted to say that I agree with Dr. Weiss.  I think it should be stated right up front that this is a temporary reduction.  We don't know if it's permanent.  And if you don't put that in it would appear to the consumer and the person buying this device that it would be permanent.  And it can be removed if it needs to be removed at a later time.  I think it's quite important that it's put right in the very front.

                        DR. SUGAR:  Okay, the sixth -- I'm taking the prerogative of moving on to the sixth question.

What are your recommendations regarding regression of effect, induction of cylinder and incidence of visual symptoms?  Are there any additional labeling recommendations?

                        And I'd like to ask Mike to go through this since he listed them I think in his presentation.

                        DR. GRIMMETT:  Sure.  Mike Grimmett.  On the last page of the copy of the slide handouts I listed suggested labeling considerations.  Everyone should have it in front of them.  We've already discussed 3, 4 and 5.  Joel Sugar mentioned about the induction of cylinder data. 

                        These pretty much speak for themselves.  Number 1, include the spectrum of best corrected visual acuity loss at each exam interval and state that of those 24 patients losing best corrected vision at 6 months or beyond, half of those patients are dissatisfied.

                        No. 2, include the subjective symptom data.  I would suggest to include a slide like Dr. Berman suggested in Slide 15.  And also include those patients who had no symptoms pre-op versus no symptoms post-op.

                        No. 6, include predictability data.  I don't think there's any argument there.

                        No. 7, I would include a statement regarding Dr. Bradley and my concern regarding the predictability that the post-operative standard deviations of the mean refraction actually increase after this procedure.

                        No. 8, is getting to Dr. Huang's concern of including a statement of decreasing efficacy as a pre-op hyperopia increases supported by several features:  (a)  uncorrected visual acuity data showing lower rates of 20/20 or better for higher hyperopes.  (2) the proportion of undercorrection is greater than 1.00 diopter is increased in the higher hyperopic group and (3) the proportion of eyes achieving plus or minus .50 or plus or minus 1.00 of intended decreases as the range of hyperopia increases.

                        No. 9 was regarding the instability and I listed the five or six features I listed in my slide that we've discussed at length already.

                        No. 10 was an additional issue regarding the reduction in spectacle or contact lens dependence.  I put that in before I knew that -- I think Dr. Weiss asked that was the pre-op spectacle dependence known and since it's not known, I guess I retract No. 10.  I don't think you can make a comparison when it's not known pre-op.

                        DR. SUGAR:  If you take out the word "reduction" you can still ask for the data if they have it.

                        DR. GRIMMETT:  Yes, they know what the data is post-op.  They include it in Amendment 11.  I think it's a useful piece of information.  I just now don't know what to compare it to.

                        11 was regarding satisfaction data as has been mentioned regarding a 1 in 10 rate of dissatisfaction.

                        No. 12 is the manufacturer has already suggested to include a statement regarding a lack of retreatment data and therefore the suitability for future refractive procedures is unknown.  I think that's a crucial issue because of the decline in refractive effect with time.  It's critical that the patient know that future retreatments, it's really unknown what effect you're going to get.

                        No. 13, we just talked about the indications for statement, so 13 we've already discussed.

                        DR. SUGAR:  In there, there's not a statement about data beyond 12 months or whatever data is presented is not available at the present time, right?  Should that be in the labeling?

                        I don't know if there will be data put in including 24 months, but should there be a statement that data beyond a certain time period is not yet available?

                        DR. GRIMMETT:  Oh sure.  I would agree with that.

                        DR. ROSENTHAL:  Mr. Chairman, Rosenthal.  Certainly, the Panel, if they feel data beyond 12 months is required to be put in the labeling, you can request that be done or you can do it in a post-market arena where the labeling can then be altered afterwards.

                        DR. SUGAR:  Or we can do both.

                        DR. ROSENTHAL:  You can do both or you can do neither.

                        DR. SUGAR:  I'm sort of suggesting we do both.

                        Jose?

                        DR. PULIDO:  Jose Pulido.  I would also like to include what we talked about this morning, any implant of electrical devices in patients would be a contraindication for use in those cases.

                        I would like to ask the Panel their feeling about patients that have pre-existing narrow angles.  They were not included in the study.  Should there be something in the warnings and precautions about those patients?

                        DR. SUGAR:  Again, in the absence of data, it's worth at least stating that the effect on narrow angles is not yet known.

                        DR. PULIDO:  And also, I would like to know from the Panel what they feel about the part where it says onset of cataracts unrelated to age, systemic disease or trauma as a potential adverse effect of the device.  I guess they're alluding to the fact that this is microwave energy and microwaves can cause cataracts.

                        We don't know -- this was --

                        DR. ROSENTHAL:  This is not microwave.  This is radio frequency.

                        DR. PULIDO:  It's not microwave?  Okay.  So radio frequency, do we know the effects of these radio frequencies on cataracts?

                        DR. SUGAR:  Why doesn't the sponsor come to the table and answer so we can get it on the record.

                        You were reading from their proposed contraindications or proposed --

                        DR. PULIDO:  Yes, correct. 

                        DR. SUGAR:  This is just to answer a specific question.  You'll get your --

                        DR. DURRIE:  I think we're all familiar as ophthalmic surgeons to electro cautery that we use, bipolar cautery which is the same radio frequency waves and there's nothing I know of that has caused cataracts with the bipolar uses of cautery in the operating room.

                        So this i snot microwave.  It's radio frequency, like bipolar cautery.

                        DR. SUGAR:  Dr. Ho?

                        DR. HO:  I'm just trying to puzzle through what I think is an important point.  In Michael Grimmett's statement regarding reduction in spectacle or contact lens usage.  I think that's a very important point for a consumer to try and appreciate.  On the other hand, I think we're a little tight because we don't have the data from what the

pre-procedure usage was.  Can the sponsors comment to at least give me a sense for what the post-procedure dependence upon other correction was?

                        DR. SUGAR:  While they're coming up, I can make a comment that we have in other labelings asked them to supply data of what, how many proportion of patients still use spectacles after the procedure.

                        DR. HO:  It's a figure that will just hang out there in my mind as someone who is a trialist, but it's clearly and I'm a retina surgeon so I don't talk to patients too much about this, but that is clearly the driving force behind people even beginning to consider their options for refractive surgery.  It's a lessened dependence upon encumbering devices.

                        DR. SUGAR:  So you're supporting there being that data?

                        DR. HO:  I'd like to hear what the data is first.

                        DR. McDONALD:  Marguerite McDonald.  Fourteen percent of patients reported using distance spectacle correction at 6 months and at no time point at 3 months or later did more than 20 percent of patients use spectacle correction for distance.

                        DR. SUGAR:  So you're suggesting that there be some statement including that information?

                        DR. HO:  I'd like to puzzle through it with the committee, because I think in terms of language for labeling that is a very important point.  Perhaps something that will hang in a patient's mind more so than cylinder shifts and diopter shifts, etcetera.  So I'd like to hear other comments.

                        DR. SUGAR:  Jayne?

                        DR. WEISS:  Jayne Weiss, is there any way for the sponsor subsequently to get that information, how many patients had pre-op contacts or distance glasses?

                        DR. SUGAR:  Dan?

                        DR. DURRIE:  I think we need to remember, I think 100 percent of these people wore glasses

pre-op.  I mean that's why they came in.  On all of the patients I know of, we didn't ask that in the questionnaires, but these patients came in not because they were doing well and didn't need glasses.  They all came in and had this procedure because they were wearing glasses and having problems with it.  This was a distance only study, so this wasn't done to get rid of the reading glasses.  So these were 53-year-old hyperopes who were having problems, that's why they came in.  So I would say that 90 percent plus of them were wearing glasses pre-op for distance or they wouldn't have even thought about having this procedure.

                        DR. SUGAR:  Did you have an additional comment?

                        DR. WEISS:  I would assume there would be a certain number of the +.75s or the +1.00s or the +1.25s for vanity's sake, whatever, that might have been walking about blurred, so we would need the data if we're going to put it in there, the actual numbers.

 

                        DR. HO:  In Philadelphia, some of the +3.00s walk around.  They just can't see and they'd be very happy with this surgery, no matter what.  But seriously, I think that number is a very important number and Dr. Durrie's comments stand to reason, it would be more comfortable having that, perhaps making a disclaimer about not knowing exactly the number of patients that had used glasses for distance preoperatively would be fair and accurate and saying this is the results that we have after the procedure.

                        DR. SUGAR:  I personally think it doesn't matter what it was before.  What matters to the patients is what is after, but the sense of it is that we want information on -- and/or contact lens dependence following the procedure.

                        Jayne?

                        DR. WEISS:  Jayne Weiss.  I would like something in the labeling for the patients to sort of convey that initially they may expect an

over-correction and some myopia and that there is a gradual drop off and not to expect the semi-final result until 6 to 9 months so that patients understand this is going to be a long process.

                        DR. SUGAR:  Okay.  The sirens are not coming for us yet, I don't think.  I think we have dealt with adequately or inadequately all six questions.  Are there additional issues that the Panel would like to raise?  The process would be then to have open public hearing:  FDA posing statements, sponsor posing statements and then we'll go through the formal proposal, formal motion and discussion and voting options.

                        Tim?

                        DR. McMAHON:  Tim McMahon.  I didn't see this raised and if I missed it, I apologize, but there's been nothing mentioned about the immediate post-operative pain levels, duration and management issues.  I was wondering if any of the investigators or the sponsor wants to comment on that?

                        DR. SUGAR:  Dr. McDonald?

                        DR. McDONALD:  Marguerite McDonald.  The immediate post-op discomfort is minimal.  People either report no sensation whatsoever or a mild foreign body sensation for 2 to 4 hours.  Most report taking no pain killers or maybe a Tylenol, so it's very minimal.

                        DR. McMAHON:  Thank you.

                        DR. SUGAR:  Dr. Bradley?

                        DR. BRADLEY:  Just to remind us of something, I and a couple of other people mentioned earlier, I think it's important for the patients to have a good indication of what the actual procedure is and describing it as gently heating your cornea really is an inadequate description.  It might work for marketing, but it's not adequate for FDA patient information.

                        DR. SUGAR:  So that's suggesting changing the wording in the patient information booklet.

                        Okay.  Hearing no additional discussion, I'm sorry, I hear additional discussion.

                        DR. MATHERS:  You might say controlled heating rather than gentle.  Because on a relative scale it is controlled.

                        DR. BRADLEY:  I think if I hold a match to my cornea it's fairly well controlled, but --

                        (Laughter.)

                        I'm not sure I want to admit to that last comment.

                        DR. SUGAR:  Okay, we'll now move on to the open public hearing session.  Is there anyone from the public that would like to make a comment, a relevant comment?

                        (Pause.)

                        Hearing no such interest, the FDA now has five minutes for its closing comments and I will hold them to that five minutes.

                        DR. ROSENTHAL:  I'd like to thank the Panel for an excellent discussion of the issues and am particularly to the primary reviewers for very thoughtful reviews.

                        DR. SUGAR:  Would the sponsor like to comment?

                        DR. GORDON:  Judy Gordon.  We, too, would like to thank the Panel and FDA for some very good comments and I think we'll endeavor to communicate the gist of everything that's been discussed here as best we can in an articulate fashion in the labeling and particularly in the patient information brochure so that we convey the information accurately.  So thank you again for your input.

                        DR. SUGAR:  Next, Sally Thornton will read our voting options.

                        MS. THORNTON:  These are the options for the Panel recommendation on this pre-market approval application. 

                        The medical device amendments to the Federal Food, Drug, and Cosmetic Act is 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 or PMAs 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 probably 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 uses and conditions of use when labeled will provide clinically significant results.

                        Your recommendation options for the vote are as follows: 

                        Approval, if there are no conditions attached. 

                        Approvable with condition.  The Panel may recommend that the PMA be found approvable subject to specified conditions such as physician or patient education, labeling changes or further analysis of existing data. Prior to voting all of the conditions should be discussed by the Panel. 

                        Not approvable.  The Panel may recommend that the PMA is not approval if the data do not provide a reasonable assurance that this 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.

                        DR. SUGAR:  Thank you.  I would like to ask for a motion to be made from the floor concerning this PMA.

                        DR. GRIMMETT:  Mike Grimmett.  I'd like to make a motion that the Refractec PMA is approval with conditions.  I assume we're going to talk about the indications statement separately.  Is that right?  Vote on it separately?

                        DR. SUGAR:  No.  I think your motion should be -- the --

                        DR. GRIMMETT:  Let's leave it at approvable with conditions and we will discuss each condition and vote on them separately.

                        DR. SUGAR:  That's fine.

                        MS. THORNTON:  Each one has to be discussed and voted on separately.

                        DR. SUGAR:  But it could be also approval for the following indication and then with conditions.

                        A motion has been made.  Is there a second to the motion?

                        [Motion was seconded.]

                        DR. SUGAR:  Then we vote on this motion?  No.

                        MS. THORNTON:  You go through each condition, vote on each condition.

                        DR. SUGAR:  This is where I need help.

                        MS. THORNTON:  That's okay.

                        DR. SUGAR:  So a motion has been made and seconded that this be approvable with conditions.  We'd like to now flesh out the conditions, and I'd like to first ask that the indications be stated. 

                        Jane would like to do that.

                        DR. WEISS:  Jayne Weiss.  I would propose that the indications for the procedure be listed as follows:  CK treatment for the temporary reduction of spherical hyperopia in the range of +.75 to +3.25 diopters of cycloplegic spherical hyperopia, -0.75 diopters or less of refractive astigmatism, +0.75 to +3.00 diopters of cycloplegic spherical equivalent.

                        And would you like me to continue through this whole sheet or do you want to go through each thing and vote on it separately?

                        DR. SUGAR:  I'd like to, if you could state the indications and then we can vote on that as a single unit.

                        DR. WEISS:  Second point being in patients with less than or equal to 0.5 diopters difference between preoperative manifest and cycloplegic refractions in patients 40 years of age or older, refractive stability is unproven for the CK procedure.  The proportion of intended correction retained beyond 12 months is undetermined.

                        DR. SUGAR:  Is there a second to that?  Is there a different motion?

                        DR. McMAHON:  Jayne, would you accept an amendment to incorporate Dr. Ho's comment about that one bullet, about the magnitude of correction which read as "the magnitude of correction diminishes over time."

                        DR. SUGAR:  The period meaning that the last two clauses that Jayne had would not be in the statement?

                        DR. McMAHON:  The last part of the second to the last bullet would not be, but the very last bullet would.  So it would be "the magnitude of correction diminishes over time."  The next bullet:  "The proportion of intended correction retained beyond 12 months is undetermined."

                        DR. SUGAR:  Is there a second to that?

                        DR. GRIMMETT:  Did she accept the amendment?

                        DR. SUGAR:  Okay, I guess you can -- her motion was a not seconded --

                        DR. WEISS:  Jayne Weiss.  So just to clarify, you would agree with CK treatment for the temporary reduction of spherical hyperopia and then everything else that I mentioned stayed the same except for the last two bullets, the magnitude of correction diminishes over time and the proportion of intended correction retained beyond 12 months is undetermined.  I would second that.

                        DR. SUGAR:  Discussion?  Dr. Pulido?

                        DR. PULIDO:  Jose Pulido.  Again, my concern is the last two bullets have nothing to do with indications.  It's labeling.  And by putting "temporary" you already have taken care of the last two bullets and you can -- I would rather have that shifted -- those last two bullets some modification of the last two bullets shifted over to the labeling.

                        DR. SUGAR:  Other comments?

                        MR. McCARLEY:  Yes, may I suggest that we keep the first three bullets as they are and simply have a footnote at the word "reduction" and indicate the last two items with some wordsmithing to take out the percentage and so forth, so there's a clarification of what reduction of spherical hyperopia means and then again include this language in the labeling portion of it.

                        DR. SUGAR:  So you're not including the word "temporary" or are you including the word "temporary"?

                        MR. McCARLEY:  I am not.  I am defining it with the use of the last two paragraphs.  I would also -- yes, I would also include the word "temporary."

                        DR. SUGAR:  Okay.

                        MR. McCARLEY:  But I would do it as a footnote along with the last two points.

                        DR. SUGAR:  Okay.  Certainly that's gentler.  Further discussion of that?

                        I think that we need to have the motion -- I guess we're still discussing a motion that's been seconded and the discussion has suggested that the last two bullets be eliminated from the indications and that the word "temporary" be included, although a suggestion has been made that the "temporary" be footnoted and the other two things be footnoted.

                        I'd like to ask our expert on footnoting to discuss this.  Mike?  Dr. Grimmett, the footnote expert.  For those of you who didn't read his review, it was highly footnoted.

                        DR. GRIMMETT:  I would, if the word "temporary" is going to be used and the pro for the word "temporary" is that it's easily understandable by the consumer.  It's easily recognizable.  If the word "temporary" is going to be used, I would put it in the first sentence.  I wouldn't footnote it.  It's either there or not.  I wouldn't put it down, but the word "temporary", I agree with Dr. Pulido that the last two bullets, the word "temporary" replaces those.  You're saying the same thing in a different way.  I don't think you need to double say it.  You either say "temporary" or you say the last two bullets, one or the other.

                        DR. SUGAR:  Jayne?

                        DR. WEISS:  Jayne Weiss.  I think I could agree with that because it wold be easily understandable, succinct and the other two statements could be put in labeling, if necessary.  I would like the word "temporary" though, not to be footnoted because I think it makes it less clear, less obvious and less understandable.

                        DR. SUGAR:  Okay, this is Tim's motion?  Am I correct?  Whose motion is it?

                        DR. WEISS:  Actually, Tim's was an amendment to mine and Jose's was an amendment to Tim's, so I think we're at Dr. Pulido's at this point.

                        DR. SUGAR:  So you've restated your motion that it's the first three bullets with the word "temporary" added?

                        DR. WEISS:  Yes.

                        DR. SUGAR:  Is there any additional confusion?  Any additional discussion?

                        Please.

                        DR. MATHERS:  This is going to be seen as one way of handling this problem.  We might also consider a different motion, but we're going to vote on this motion now as it stands, is that right?

                        DR. SUGAR:  There's a motion on the floor that needs to be dealt with and then we could proceed with whatever other motions seem appropriate.

                        So we're going to vote on this, yes.  And I think it's now appropriate to vote.  All those in favor of the motion, signify by raising their hand?

                        MS. THORNTON:  Wait, could you just read

--

                        DR. SUGAR:  Yes, the motion is the indication for use is CK treatment for the temporary reduction of spherical hyperopia in the range of +.75 to +3.25 diopters of cycloplegic spherical hyperopia; -3.75 diopter or less of refractive astigmatism, +.75 to +3.00 diopters of cycloplegic spherical equivalent in patients with less than .50 diopter difference between preoperative manifest and cycloplegic refraction who are 40 years of age or older.

                        [Vote taken.]

                        All those in favor of motion?  Seven.

                        All those opposed?  Two.

                        The motion carries.

                        MS. THORNTON:  Wait.

                        DR. SUGAR:  Am I wrong?  We have 12.

                        MS. THORNTON:  We have 10 votes all together.  Could you raise your hands?

                        DR. SUGAR:  There are supposed to be 12 people and there were 7 and 3.

                        MS. THORNTON:  Okay, sorry.

                        DR. SUGAR:  Seven to three.  I abstained.

                        DR. ROSENTHAL:  What was the tally?

                        DR. SUGAR:  Seven to three.  We now move on to specifying the conditions because we now have the indication.  We've specified the conditions and I'd like a motion concerning -- I'm doing it wrong.

                        MS. THORNTON:  The condition that you just discussed was the change in indication.  The next condition that you're going to discuss is probably a labeling going on into your labeling.  But the change in indication is one of the conditions of the approval.  I just wanted to clarify that.

                        DR. SUGAR:  One of the problems we get into is wordsmithing the words, concerning the wordsmithing of the other words, but additional conditions.

                        DR. GRIMMETT:  Mike Grimmett.  There are some additions to the labeling list that I provided that will be a separate consideration because I don't have them written down.  Did you write them down, Dr. Weiss?

                        DR. WEISS:  I wrote them down as you were commenting.

                        DR. GRIMMETT:  Okay.  I make a motion to include the labeling issues as I've typed in my sheet dated November 30th with the following modification:  the No. 10, we were going to change the reduction of to include statement regarding the spectacle or contact lens dependence and No. 13 we just dealt with, so eliminate No. 13.

                        If I could make a motion that those following labeling suggestions be accepted.

                        DR. SUGAR:  Is there a second?

                        DR. ROSENTHAL:  Rosenthal.  Could you just -- I don't want you to go through all of the -- if you could just go through the category, you know --

                        DR. GRIMMETT:  Sure.

                        DR. ROSENTHAL:  Labeling issues relating to blah, blah, blah.

                        DR. GRIMMETT:  Sure.

                        DR. ROSENTHAL:  So we can have it on record.

                        MS. THORNTON:  Read the complete list as you have discussed and are adding on the complete list into the record, please.

                        DR. ROSENTHAL:  I'll just clarify with Nancy Pulowsky.  We don't need to go over every single one, but I think the general idea of --

                        MS. THORNTON:  Right, right.

                        DR. SUGAR:  He can't just say number 1, number 2, number 3?

                        DR. GRIMMETT:  Labeling issues, No. 1, best corrected visual acuity loss greater than or equal to two lines.

                        No. 2, issues related to subjective symptom data.

                        No. 3, issues related to inductive of cylinder data.

                        No. 4, data regarding loss of incorrect visual acuity with induced cylinder.

                        No. 5, data or statement regarding cylinder axis shifts.

                        No. 6, predictability data.

                        No. 7, statement regarding or data regarding post-operative standard deviations of the mean being wider than the pre-op standard deviation of the mean refraction.

                        No. 8, statement regarding decreased efficacy as the level of pre-op hyperopia increases.

                        No. 9, statement regarding that the procedure is refractively unstable.

                        No. 10, statement regarding the spectacle of contact lens dependence following the procedure.

                        No. 11, a statement regarding rates of dissatisfaction and quality of vision improvement.

                        No. 12, a statement regarding lack of retreatment data.

                        DR. SUGAR:  And that has been seconded?

                        DR. WEISS:  I'll second that.

                        DR. SUGAR:  Okay.  And are there amendments to the motion?

                        Jayne and then Jose.

                        DR. WEISS:  Jayne Weiss.  I would just add some amendment as I was scribing the suggestions that have been added to this point, one being I think Dr. Pulido's recommendation that implantable electrical devices are contraindications for this procedure.  I think Dr. Pulido also suggested that the effect in patients with narrow angles is not known.

                        Dr. Bradley had wanted labeling to include a better description of the procedure for the patient, including the fact that it involved needle placement in the cornea and the fact that data beyond 12 months is not available at this point.

                        DR. SUGAR:  Was there also something about over-correction and the word "gentle heating."

                        DR. WEISS:  Yes, Jayne Weiss.  I did leave out my suggestion which is that the patient be informed that initially there would be an overshoot or over correction and that it might take 6 to 9 months before most of the result is reached and also Dr. Bradley's suggestion that the word "gentle heating" be removed.

                        DR. SUGAR:  Is there a second to the amendment? 

                        Jose, do you have more to add?

                        DR. PULIDO:  No, I second her appended amendment.

                        DR. SUGAR:  Is there discussion of the motion with its 17 points?  All those in favor of the listed additional conditions, signify by raising their hand?

                        DR. HO:  There's a comment over there.

                        DR. SUGAR:  I'm sorry, please.

                        DR. MATOBA:  Yes, Alice Matoba.  My comment was simply that Dr. Weiss' last addition that the data, we do not have data after 12 months.  That should be placed in 9 so that when we say it's unstable, it's understood that we only have data up to 12 months and we don't know whether it's stable or unstable after that time period.

                        DR. SUGAR:  Do you accept that, Jayne?

                        DR. WEISS:  Yes, I do.

                        DR. SUGAR:  And Jose?

                        DR. PULIDO:  I would, yes.

                        DR. SUGAR:  So Ralph, has it been adequately stated?

                        DR. ROSENTHAL:  You've included all the labeling issues?

                        DR. SUGAR:  I believe so.  Are there additional labeling issues that anyone would like to add?

                        Yes?

                        DR. HUANG:  Andrew Huang.  I'd like to add.  I think we should probably clarify one of the labeling indications that the higher amount of hyperopia has less effect, but you probably included it in one of the points.

                        DR. GRIMMETT:  I believe that's No. 8.

                        DR. SUGAR:  Okay.

                        DR. GRIMMETT:  I included it by stating three pieces of information that support that tenet.

                        DR. SUGAR:  Okay, is there any confusion about the motion?

                        This condition with its numerous points is now up for vote.  All those in favor, signify by raising their hand.

                        [Vote taken.]

                        DR. SUGAR:  Those opposed?  Those abstaining?  So none opposed, one abstaining, nine in favor.

                        I believe that we have covered everything that's been presented thus far.  Is there anything that we have missed?  Are there any additional motions that anyone would like to make or any additional modifications?

                        Please?

                        DR. HUANG:  I would like to recommend to the sponsor to continue to monitor the patient beyond 24 months.

                        DR. SUGAR:  Okay, a suggestion has been made that we request additional follow-up data from the sponsor.

                        DR. ROSENTHAL:  Could you put that in as a motion?

                        DR. SUGAR:  As a condition of approval which is clarified to us as to what exactly you want.

                        DR. SUGAR:  So if we could form that up a little better, go ahead.

                        DR. GRIMMETT:  Well, I have a question first.  Mike Grimmett.  Isn't it tacitly assumed that since the study was designed for 24 months, they're at least going to go to 24 months and submit the data?

                        No? 

                        DR. SUGAR:  It doesn't hurt to ask for it anyway, I think.

                        DR. ROSENTHAL:  I don't think you can tacitly assume anything.

                        DR. GRIMMETT:  Okay. 

                        DR. ROSENTHAL:  We're asking for your recommendations.

                        DR. GRIMMETT:  I'd like to make the first motion that this study be completed to the 24-month interval with submission of the data for FDA review.

                        DR. SUGAR:  As a condition for approval or subsequent to approval?

                        DR. GRIMMETT:  Post-market evaluation that the study simply needs to be continued and not stopped at this time point.

                        DR. SUGAR:  Was that the sense of your motion?

                        DR. HUANG:  Yes.

                        DR. SUGAR:  So the motion has been made and effectively seconded, is that fair?

                        DR. GRIMMETT:  Yes.

                        DR. SUGAR:  Discussion?  All those in favor?

                        [Vote taken.]

                        DR. SUGAR:  Nine.  Opposed?  Abstaining?  One.

                        Any additional conditions or motions?

                        DR. McMAHON:  Would it be reasonable to ask the sponsor to supply data on retreatments,

post-market study?

                        DR. SUGAR:  I guess we can discuss that as an issue, not as a motion.  One of the conditions we had was the statement that there is lack of retreatment data.  Whether we -- and we can say what we want, but whether we want to make that a condition for the approval or not, I think is the issue at hand here.  Does anyone -- are you suggesting that as a motion, Tim, or not?

                        DR. McMAHON:  It's an issue that has me a little bit concerned and I guess I'd want this erred before we leave as to whether the rest of you feel the same way and want to make that a higher priority issue and a part of the approval process.

                        DR. SUGAR:  My question, if it's appropriate for me to comment is whether -- we would love to have that information.  I presume the sponsor would too.  Whether it's appropriate in approving what's been presented to us or not approving what's been presented to us to ask for that or not, I don't know.  I don't -- this process --

                        DR. McMAHON:  That's why I raised it as a question is I don't know if it's an appropriate question.

                        DR. SUGAR:  Ralph?

                        DR. ROSENTHAL:  We're asking for a Panel recommendation and I really don't want to comment what's appropriate or what's inappropriate.  I mean you have to consider least burdensome issues and you have to consider what is scientifically required and you have to consider what is necessary to label the PMA.

                        DR. SUGAR:  Dr. Ho, did you want to comment?

                        DR. HO:  In my view, I think that's a very important issue, but I think that I would not require it as a condition of approval of this particular PMA.  I think there are potentially incentives for the company and for the public, later on, as a separate study for that to be performed, but I would not view that as a condition for approval of this PMA.

                        DR. SUGAR:  Is there additional discussion of the nonmotion?  Are there any additional issues?  Please.

                        DR. GRIMMETT:  Mike Grimmett.  We just discussed and approved a motion for post-market evaluation to 24 months.  I think that assumes that stability will be at least established or reached during that time interval.  I just would like to raise the point what if stability is not reached by 24 months?  Would people be in favor of having the study continued longer or what's the sense about that?

                        DR. SUGAR:  Jose?

                        DR. PULIDO:  Jose Pulido.  I don't think so because the 2-year point we're doing just to see if it continues to be a temporary -- to leave it as a temporary situation.  If at two years the company sees that there still hasn't been any stability, then they can't come back to us and say well I want to change this.  So it's now on the company's side to determine whether they want to continue it past the 2-year point or not.

                        DR. SUGAR:  Please.

                        MR. McCARLEY:  I'd simply suggest that if you're going to ask for the 2-year data as a condition of approval, then the company be permitted or required, whichever way you want to look at this, to put that in the labeling when that information becomes available and it's been reviewed by FDA because then you're going to know what you want to know now and it may be in their favor.  It may be still a question.

                        DR. SUGAR:  The sense I have is that that's implied in our motion, is that correct?

                        MS. THORNTON:  Yes.

                        DR. MATOBA:  I think we're ready for voting on the main motion with its conditions, including the changes in indication, the labeling changes and the continuation of the study for 24 months.  Is there anything we have missed?

                        So that motion, I guess, was the original motion, so we need to vote on the package.  And no additional motion needs to be made, correct?

                        So can I say all in favor?

                        MS. THORNTON:  Yes.

                        DR. SUGAR:  Thank you.  All those in favor, signify by raising their hand?  All those opposed?  One opposed. 

                        [Vote taken.]

                        DR. SUGAR:  So the motion carries and we now poll the Panel for a comment on their vote.  We should be in with Dr. Pulido.

                        DR. PULIDO:  Jose Pulido.  I voted approvable with conditions.  And I believe that this is a device that can temporarily and unpredictably diminish hyperopia and with these conditions that shows that is the case.

                        DR. McMAHON:  Tim McMahon.  I voted for approval with conditions for essentially the same reasons.

                        DR. BRADLEY:  Arthur Bradley.  I voted against approval.  Basically, I think the CK procedure has been shown to be unreliable, inaccurate and unstable.  However, the accuracy and reliability did improve during the first year post-op and results from previous thermal keratoplasty procedures make it likely that the rate -- sorry, make it likely that the rate of change of regression will decline within the second year.  Therefore, I feel that it's premature at this time to approve this device and I would like to wait until evidence of stability before voting for approval.

                        DR. WEISS:  Jayne Weiss. I voted approvable with conditions because I think the sponsor has satisfactorily met the criteria set forth by FDA.  I have concerns about the shifting axis and amount of astigmatism, but that will be addressed in patient labeling.  I also have concerns about the fact that stability had not been reached at 12 months, but I think the consumer is protected by indicating at the present time this is a temporary correction of hyperopia.

                        DR. GRIMMETT:  Michael Grimmett.  I unenthusiastically voted approvable with conditions as I believe the procedure is reasonably safe, yet only marginally effective.  I'm uncomfortable with the lack of stability of the procedure, but with the conditions and labeling conditions that we approved, I feel the consumer should have an adequate chance of achieving the appropriate information in order to make an informed consent about this procedure.

                        DR. MATOBA:  Alice Matoba.  I voted for approval with conditions.  I think the procedure is reasonably safe and fairly effective and the sponsors did meet the criteria set by the FDA.

                        DR. HO:  Allen Ho, approvable with conditions.  I think that this a safe procedure.  Its efficacy seems to be marginal to fair in my view.  I think they've met the criteria set forth by the guidelines of the FDA a priori and with the conditions that are specified in the labeling, I'm comfortable with that.

                        DR. JURKUS:  Jan Jurkus.  I voted approvable with conditions since the conditions that we had so thoroughly discussed adequately reflected my concerns with this product.

                        DR. MATHERS:  Bill Mathers.  I voted approvable with conditions.  I believe that the device fulfills the FDA's requirements and is reasonably effective and reasonably safe and that the labeling will indicate to the public how it can understand the proper use of the device.

                        DR. HUANG:  Andrew Huang.  I voted for approval with conditions based on the fact that I think this is a relatively safe procedure, yet the effect is unsustained.  But I do believe that with the condition provided by the Panel that physicians, as well as the patient, now can make an informed decision on this procedure.

                        DR. SUGAR:  Thank you.  PMA P010018 then has been dealt with.

                        I'd like to just make a statement.  This is the end of my tenure on the Committee and as Chair of the Committee, even though it was brief, I went to the American Academy of Ophthalmology a couple of weeks ago and there was a videotape presented by Bobby Osher that was titled "FDA or DWB", something like that, FDA meaning you guys or DWB which is Doing What's Best and I having come into this a little bit skeptically have learned that the people here are doing what is best under the circumstances with which they have to work and I've been extremely impressed with people at all levels of the FDA involved with CDRH and have enjoyed working with them.  Thank you.

                        MS. THORNTON:  Thank you, Joel.  We have enjoyed very much working with you and we're sorry to have had to have you for Chair for such a short time.  It's been a pleasure working with all of you and I'd like to welcome again our new consultants to the table and our new industry rep and hopefully this hasn't been total shock treatment, but you'll be willing to come back and help us out in the future.

                        At this time I'd just like to reiterate that we will be having a meeting January 17th and 18th next year.  Until that time -- what?

                        DR. SUGAR:  Do you leave the papers?

                        MS. THORNTON:  Yes.  I'd like all the -- by the way, but I did want to say until that time I hope that you all have a happy and a safe holiday.

                        I'd like the Panel to leave all materials that were issued to them to review for this meeting at the table.  And please fill out for your benefit at future meetings, please fill out this evaluation form that I left at your table at the beginning of the meeting.

                        Thank you again.

                        (Whereupon, at 3:46 p.m. the meeting was adjourned.)