107TH MEETING



                 FEBRUARY 6, 2004


            The Panel met at 9:30 a.m. in Salons B-D of the Gaithersburg Marriott Washingtonian Center, 9751 Washingtonian Boulevard, Gaithersburg, Maryland, Jayne S. Weiss, M.D., Chair, presiding.




JAYNE S. WEISS, M.D.            Chair

ARTHUR BRADLEY, Ph.D.           Voting Member

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

MICHAEL R. GRIMMETT, M.D.       Voting Member

WILLIAM D. MATHERS, M.D.        Voting Member

TIMOTHY T. McMAHON, O.D., FAAO  Voting Member

KAREN BANDEEN-ROCHE, Ph.D.,     Consultant,

                                  deputized to vote

RICHARD CASEY, M.D.             Consultant,

                                  deputized to vote

ANDREW J. HUANG, M.D., MPH      Consultant,

                                  deputized to vote

MARIAN MACSAI-KAPLAN, M.D.      Consultant,

                                  deputized to vote

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

                                  deputized to vote

JANINE A. SMITH, M.D.           Consultant,

                                  deputized to vote

WOODFORD S. VAN METER, M.D.     Consultant,

                                  deputized to vote

GLENDA V. SUCH, M.Ed.       Consumer Representative

RONALD McCARLEY             Industry Representative

SARA M. THORNTON            Executive Secretary


PRESENT:  (continued)




















                     I N D E X




Call to Order, Jayne S. Weiss, M.D., Chair       4


Open Public Hearing                              4


Introductory Remarks                            26

  Sara M. Thornton, Executive Secretary


Open Committee Session, Jayne S. Weiss, M.D.    29


PMA PO10018/S005


SPONSOR PRESENTATION:                           29

  The ViewPoint CK System/Blended Vision


Panel Questions for the Sponsor                 62


FDA PRESENTATION                               114


COMMITTEE DELIBERATIONS:                         


Panel Questions for FDA                        132


Primary Panel Reviewers                        136


Panel Discussion of PMA PO10018/2005           161


30-Minute Open Public Hearing                  218


Closing Comments                               218


Panel Recommendation Taken by Vote             219


Comments from Consumer and Industry            243



Final Panel Comments                           243


Open Meeting Adjourned                         244

               P R O C E E D I N G S

                                  Time:  9:37 a.m.

            CHAIRMAN WEISS:  I would like to call this meeting of the Ophthalmic Devices Panel to order.  We have a quorum present, and we will have introductory remarks by Sally Thornton.

            MS. THORNTON:  Sorry for the delay.  Excuse me, please.  Is Sandy Berman in the room? 

            CHAIRMAN WEISS:  With a little bit of a delay for the usual introductory remarks Sally will make.  So in the interest of time, what I will do is read you a financial disclosure comment that is required by the agency, and this will be in preparation for those of you who will be participating in the Open Public Hearing.

            Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making.  To ensure such transparency at the Open Public Hearing session of the Advisory Committee meeting, FDA believes that it is important to understand the context of the individual's presentation.

            For this reason, FDA encourages you, the Open Public Hearing speaker, at the beginning of your written or oral statement to advise the Committee of any financial relationship that you may have with the sponsor, its product and, if known, is direct competitors.

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

            I will remind those of you who are speaking for sponsor, when you do come to the podium, aside from identifying yourself and giving your relationship with the sponsor, you also are required to disclose any financial relationships you may have.

            If you can just remain in your seats, we will sort of take an informal break for a few minutes until we have the necessary information here.  So you can talk among yourselves.

            We will go out of order.  As long as I have given the introductory statement for the Open Public Hearing, we will start with the Open Public Hearing.  In interest of the 30 minutes that we have for this section, on each of the speakers we will have no more than seven minutes.

            The first speaker is Mr. Glenn Hagele of the Council for Refractive Surgery Quality Assurance.

            MR. HAGELE:  Good morning, and thank you for the opportunity to address this Panel.  My name is Glenn Hagele.  I am the Executive Director and Founder of the Council for Refractive Surgery Quality Assurance which, from this point forward I will refer to by its acronym, CRSQA.

            I have no financial interest in Refractec.  My travel here is self-funded, and do not necessarily -- Sorry, I missed my notes.  The comments that I make here are my own and not necessarily those of anyone affiliated with the Council for Refractive Surgery Quality Assurance.

            CRSQA is a nonprofit consumer patient organization, and through its sister websites, and, receives over 800,000 visitors annually.  We provide objective information about refractive surgery issues and resources for those unfortunate few who have encountered poor refractive surgery outcomes.

            Additionally, CRSQA evaluates and certifies refractive surgeons based upon patient outcomes.  In addition to research of public studies and case reports, my interaction with patients provides me with a unique accumulation of anecdotal information and the perspective of a patient.

            The issues and concerns that I will raise today all relate to communications between physician and patient.

            I wish to commend the sponsor for investing the time and money in seeking FDA approval of conductive keratoplasty for monovision correction.  CK monovision is currently an appropriate off-label use of the approved device under scope of practice rules. 

            Seeking FDA approval for monovision correction is not a requirement.  Yet sponsor has decided to subject itself to the rigors of the approval process.  No matter what the final decision of this Panel regarding approval, the company should be recognized for this commitment.

            While it could be argued that the motivation for seeking approval of CK monovision is primarily for purposes of marketing, that opinion would overlook the important asset that will be afforded the public by sponsor's decision to seek approval, the safety and efficacy data that will be evaluated by this panel, which will, of course, help patients make an informed consent.

            Plano presbyopes seeking relief from the need for reading glasses inundate our organization with requests for information about techniques and technologies to rid themselves of what many consider a tolerable inconvenience.  As you can see, I am sliding my glasses down to be able to see these papers.

            Although we may be able to provide limited information about monovision correction with contacts, LASIK and other forms of refractive surgery, the information presented to this Panel by sponsor will provide prospective patients with hard data that they seek to be able to make an informed decision about CK monovision.

            Something about the terminology that will be used will be really important.  CK monovision is not a cure for presbyopia.  Accommodation will not be restored.  There will be no functional change to the crystalline lens. 

            For this reason, I am hopeful the language used in this labeling will reflect that CK monovision is a surgical process that attempts to compensate for the effects of presbyopia.  It is not a cure.

            It is very important that patients understand this difference, and I suggest that labeling reflect that presbyopia remains, even if CK monovision compensates for presbyopia's effects.

            Regarding the learning curve, today you are going to see results from what can only be described as some of the best surgeons in the world.  It is reasonable to assume that not every surgeon will be of the same caliber. 

            I have no reason to doubt that sponsor will provide significant training, and I am certain that this panel will insist on adequate training or proctoring.  I believe, however, that it is in the best interest of the patient to be informed of the practical experience of the prospective surgeon.

            From the results I have seen through direct patient interaction, it appears that the probability of successful outcome with CK for hyperopia is significantly dependent upon the surgeon's practical experience.  Although we have received relatively few patient complaints regarding CK for hyperopia, they have been primarily from patients whose surgeons had limited CK experience.

            I will quickly add that the sponsor was very responsive to our expressed concerns in these instances, but I will discuss that later.

            Our organization provides a list of 50 tough questions for your doctor for patients to use as a guide in selecting their refractive surgeon.  In our 50 tough questions we recommend that a patient seek a doctor who has performed at least 100 refractive surgeries of exact type intended to be used on the patient with the same equipment, the same refractive error, and significantly more practical experience with similar surgical techniques.

            While this panel may find our recommendation of 100 a bit conservative and even restrictive, it does seem reasonable to assume that the patient would like to know if he or she is the doctor's first unsupervised CK monovision patient.

            I respectfully request that this Panel include in the patient labeling an indication that training and practical experience of the surgeon may be an important factor in the probability of a desirable outcome.

            Determining which eye is dominant and, thereby, which eye would receive CK monovision is an important factor in the success of the monovision effect.  Surprisingly, I have found that a single best method for determination of dominant eye is not currently established in ophthalmology.

            If I ask 10 doctors how to determine which is the dominant eye, I will receive six different answers, from asking which hand the patient writes with to having the patient hold a camera up to see which eye the patient uses to look through the viewfinder, to tossing an object at a patient to see which hand they use to catch it.

            In researching the most appropriate technique to help advise patients on how to determine their dominant eye, I sought the counsel of those individuals who be very negatively affected if they did not use the correct eye as dominant, including SWAT team sharpshooters, hunters and, ultimately, members of the U.S. Olympic archery team.  I can assure you that the members of the U.S. Olympic archery team do not throw objects at each other to determine eye dominance. 

            I do not wish to be so presumptuous as to suggest to this Panel the technique for determination of eye dominance that is considered most accurate by these other groups, but I do respectfully request that the labeling for the physician include an appropriate technique and subsequent information.

            CK is currently approved as a temporary correction for hyperopia.  This decision to approve CK as a temporary correction was predicated on CK's rate of regression.  This is a very important consideration for a patient considering CK monovision, because it creates a unique situation after surgery.

            If the patient, for any reason, decides after CK monovision that he or she does not like the monovision effect, surgical corrective measures are probably not appropriate. 

            If a myope has LASIK in one eye and one eye undercorrected for the monovision effect, then decides that he or she does not like the effect, additional LASIK enhancement surgery would be appropriate, because both the primary and the secondary procedures are permanent.

            If the patient has CK monovision and--

            CHAIRMAN WEISS:  Excuse me, Mr. Hagele.  I think you have had your seven minutes, and your time is up.  I thank you for your comments.

            We are going to go on to Dr. Milne.  If I am mispronouncing your name, I apologize.  In interest of time and the agenda, we are sticking to the allotted time.  So just keep it in mind.

            DR. MILNE:  Thank you, and "Mill-ne" is correct.  The Scots say "Miln," but "Mill-ne" is the way we say it over here.

            CHAIRMAN WEISS:  Good.

            DR. MILNE:  My name is Rick Milne.  I am general ophthalmologist in Columbia, South Carolina.  I am not a paid consultant of Refractec, and I had to pay my way here today and was glad to get here last night through all the winter weather.

            I am here because I have a sincere desire to see CK approved for the correcting of -- or the recovery of near-vision in the presbyopic patient.

            I have performed over the last two years over 800 CK procedures in my practice.  I have a general ophthalmology practice that does more cataract surgery than refractive surgery.

            Interesting, over the last year over 80 percent of the patients I am doing CK on are having the procedure for the off-label use of regaining their near vision, and they are presbyopic.  That seems to be the true niche and the true great benefit this procedure is bringing to my patients.

            Now I am speaking not only as a provider of CK, but I am also speaking as a 47-year-old microsurgeon who has chosen to have CK to recover my near vision.  I had CK about two months ago.  Pre-CK I was a +.65 hyperope, and I was Jaeger 10 vision, and my life had become quite frustrating.

            As an ophthalmologist, we go from a slit lamp to chart work, speaking to patients.  Reading glasses were not a very good option for me there, and also contact lens wear -- I did try the monovision contact lens, and I have basically genetically dry eyes.  My father had dry eyes.  I have dry eyes, and really, contact lens wear was uncomfortable to me and something that was just really not very doable for me.

            So I chose CK.  It is interesting.  Maybe it is because I am now a 47-year-old presbyope or maybe it is because there's so many baby boomers who are becoming presbyopic, but over the last several years I have really noticed how frustrated our society and how intolerant our society is becoming over presbyopia.

            I will give you one example.  A few weeks ago I was traveling and was in a Hertz van in the late evening, and I was in a van full of a bunch of presbyopes, and we were heading out to get our cars, and everyone had their Gold Medallion car selections.  So the manifesto was passed around so people could see where their car was parked.

            Well, our driver was a presbyope.  All of our people in the van were presbyope, and person after person cannot read to find out where their car manifesto was.  To tell you the van was getting frustrated is a minor statement.  You know, it was a long travel, and there was a lot of anxiety going on there.

            Finally, there was one presbyopic myope that took his glasses off and read the manifesto for everyone.  Interestingly, I had had CK and I was just quietly waiting for my time to see the manifesto to help people.  I didn't want to be braggadocious or anything.  But anyway, of interest, my wife leaned forward.  She was sitting across from me, and she learned forward and she looked at me, and she said something very profound.  She said, "You could help these people."

            You know what?  She had it exactly right.  I had personally come to realize that presbyopia is really quite disabling in a lot of situations, and there really is a need to help people.

            Also just in general in our culture, I don't know if you have seen the movie, "Something's Got to Give," where Jack Nicholson and Diane Keaton play a great role.  But that movie identifies two things of becoming aged and infirm. 

            The one is Jack's need for Viagra, and the other is both he and Diane's need for reading glasses, over and over again throughout the movie.  It was portrayed in a way that most of us baby boomers don't like to be portrayed.  So it is something baby boomers -- we are definitely frustrated with our situation, and we are looking for good options. 

            It has been interesting.  I chose CK for a number of reasons, and I find my patients choose it for the same reasons.  Number one, the option of reading glasses, as I said, were not a good option.  Contact lens were not a good option for me, and a lot of patients over the age of 40-45 are beginning to have problems with their tear functioning.

            I found the procedure to be a very safe procedure after doing it on 800 people.  Even now, looking through the literature, and I will call John Hayashida from time to time to make sure I am correct about this, there has not been one serious complication from CK worldwide to this date.

            Now as a microsurgeon who makes my living needing to see things with fine detail, I wanted a very safe procedure.  I wanted one where I was not taking a risk, because I lose a few lines of vision and I don't get to do what I do and my family is very unhappy with me.  But I chose it, and I'm very glad I did.

            Also of interest, the stability of my patients, anecdotally -- I have not had one patient in two years have to return and say, you know, I'm beginning to lose the effect of this.  I'm hoping, if I get five to ten years from this procedure, I'll be thrilled.  At that time I may need something else down the road; maybe not.  We may find this to be quite stable.

            In fact, just as another anecdote, my hyperopic LASIK patients, I find that they seem to have more regression than this procedure does, just anecdotally.

            So I am thrilled with my CK procedure.  I am thrilled with what it has done for me.  I am very thrilled with what it has done for my patients.  I have a lot of happy people out there, and I would highly recommend you to approve CK for the recovery of near vision in the frustrated presbyopic patient.  Thank you very much.

            CHAIRMAN WEISS:  Thank you very much.  Barbara Jo Morley.

            MS. MORLEY:  Good morning.  My name is Barbara Morley, and I am from Overland Park, Kansas.  I am a teacher by education and a homemaker, and I have come here today as a recipient of the keratoplasty monovision procedure. 

            My mother once said to me that, be thankful you have long arms, because they will come in handy one day.  And they did, I found out, because the older I got, the further away I had to hold my piece of paper to read it.  But eventually my arms were not long enough. 

            So I resorted to other measures like buying glasses at WalMart, and I had them in every room in the house, bathroom, kitchen, bedroom and, then when I couldn't find mine, I would use my husband's, because he had the same problem. 

            As an educator, I tutor now out of my home, and I tutor on an individual basis.  So I was constantly having to put my glasses on to see the text of the students, and then take my glasses off to actually talk to the student.  I'm sure that was very distracting for the student, as it was for me.

            I also lead a Bible study with a group of 16 women, and the Bible that I have is very small print, and I would be doing the same thing, reading the verses in the Bible, taking my glasses off to speak to the ladies in the group, and putting them back on.  It came to be quite the joke.

            At a certain point when you can't find the glasses, when you are tired of doing that, you look to other options.  About the first time that I thought that I needed to have something done was -- Really, it wasn't a funny situation.  It was dangerous.

            I had been on Mapquest, and I needed to go to a place, and I didn't know how to get there.  So I printed the directions out, and as I was driving to the place, I don't drive with my glasses, but I actually needed my glasses to read what the Mapquest said. 

            So I thought this is dangerous.  So I had to pull over to the side of the road and read the directions and then get back on the road, and remember the directions, which is a whole 'nother problem, to get where I was going.  I thought that's just not good.

            I have never worn glasses before.  I have always had perfect vision.  So it was hard for me to identify people with glasses.  So what's the big deal.  But as I aged and I saw it was a big deal, especially when you only need them a portion of the time.

            So at that point, my husband had had eye surgery, but he had had not had this eye surgery.  So I was familiar with the clinic, the Hunkeler Eye Clinic in Overland Park, and was presented with the opportunity to have this done.

            I am not a person who takes risks at all, although you wouldn't believe that if you heard the story of how we got here.  But I decided that I wasn't liking my lifestyle as it was.  It was too much of a hassle and, if there was something that I could have done that would eliminate that, that I would be willing to do that. 

            I did a lot of reading that was presented to me by the clinic, and talked to several people and Dr. Durrie has an awesome reputation in our city.  So I decided that I would do that.

            The procedure itself takes such a minuscule amount of time.  I think I was in the chair and out of the chair in less than five minutes.  There was no pain at all associated with the procedure.  I was able to read immediately afterwards when they took me into the little recovery room there, and they gave me the after-procedures that I would need to do.  I could read the sheet right away.  So there was no time to adjust.

            The only inconvenience of the surgery itself was -- I think it was after the numbness, the anesthetic, wore off that your eye feels like it has sand in it or a little gritty for about a day.  Then after that, it's fine.

            I had the surgery -- it will be two years this August, and I can still read the phone book.  I have thrown all the glasses away in my house.  That's how confident I am.  It has been a huge blessing to me and my lifestyle for that.

            Just to end, Charlene, the other lady and I that came together to testify -- We feel so blessed that we had this that we were sitting in the Kansas City airport when the flight that we were supposed to take to come here ran off the runway.  So they came on and they say, Flight 5454 is no longer in existence.

            So Charlene and I sat there and, you know, what do we do now.  But we were determined to come and speak with you, because we are both so thankful for this procedure.

            My affiliation with the sponsor is none other than they did pay my travel expenses here.  However, I think they still owe me, because that was some harrowing trip.  Thank you very much.

            CHAIRMAN WEISS:  Well, you can do your negotiations with the sponsor.  Charlene Myers.  Thank you.

            MS. MYERS:  Hi.  I am Charlene Myers, and I am from Kansas City, Kansas.  I just want to say that -- I'm very nervous -- that I had the procedure done about -- It will be three years in August, and I have been absolutely thrilled with it.

            My job -- I work in the travel industry, and I have to read the computer a lot, and I have to read a lot of tickets and a lot of papers, and it is frustrating when you have to take your glasses off and on to be able to look at someone, that they are not blurred.  Then you have to tote them on to be able to read.  So that was an absolutely wonderful thing there.  I can also read to my grandchildren without my glasses, which is even better.

            How I got into it was two of my daughters had surgery, but for a different type of vision.  They made a comment, saying that it's too bad they didn't have something for you to be able to read better.  Well, they were speaking to someone there at the clinic, and they did say there was.

            So I went in and was, I guess you might say, a candidate.  So I did the procedure, which was very scary, but I did it, and I am so happy that I did. 

            I really don't know what else to say except it's just absolutely wonderful, and I would recommend it to anyone to have done if they cannot read without having glasses.  Thank you.

            CHAIRMAN WEISS:  Thank you very much.  Your sincerity overweighed your nervousness. 

            Are there any other speakers for the open public hearing?  If not, the open public hearing portion is closed.

            We will now have introductory remarks by -- or semi-introductory remarks by Sally Thornton before we go on to the open committee session.

            MS. THORNTON:  I would like to read at this time the conflict of interest statement for this date.

            The following announcement addresses conflict of interest issues associated with this meeting and is made part of the record to preclude even the appearance of an impropriety. To determine if any conflict existed, the agency reviewed the submitted agenda for this meeting and all financial interests reported by the committee participants.

            The conflict of interest statutes prohibit special government employees from participating in matters that could affect their or their employers' financial interests.  The agency has determined, however, that the 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, waivers have been granted for Doctors Michael Grimmett, Oliver Schein, and Woodford Van Meter for their interest in firms that could potentially be affected by the Panel's recommendations.

            Dr. Grimmett's waiver involves a past imputed interest, a grant to his institution for the sponsor's device, which is not the subject of this meeting.  He had no involvement and received no compensation.

            Dr. Oliver Schein's waiver involves two consulting arrangements, one pending for a competitor's unrelated device for which he had not received any compensation, and the second with a competitor's unrelated device for which he receives an annual fee between $10,000 and $50,000.

            Dr. Van Meter's waiver involves an imputed interest, a stockholding in the parent of a competing technology firm in which the value is greater than $100,000.

            The waivers allow these individuals to participate fully in today's deliberations.  Copies of these waivers may be obtained from the agency's Freedom of Information Office, Room 12A-15 of the Parklawn Building.

            We would like to note for the record that the agency took into consideration other matters regarding Doctors Anne Coleman, Arthur Bradley, Michael Grimmett, Andrew Huang, Marian Macsai-Kaplan, Oliver Schein, and Jayne Weiss.  Each of these panelists reported past or current interests involving firms at issue, but in matters that are not related to today's agenda.  The agency has determined, therefore, that the panelists may participate fully in all discussions. 

            In the event that the discussion involves any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participant should excuse him or herself from such involvement, and the exclusion will be noted for the record.

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

            Thank you, Jayne.

            CHAIRMAN WEISS:  Thank you.  With that, we will open the Open Committee Session for PMA P010018/S005.  The sponsor can come to the podium.  You have one hour for your presentation.  If you can please identify yourself when you speak into the microphone, what your relationship to the sponsor is, and any financial interests you have in the company or any other financial relationship you have with the sponsor.

            DR. HAYASHIDA:  Good morning.  My name is Dr. Jon Hayashida, Vice President of Clinical Affairs for Refractec. 

            I have the pleasure of introducing for consideration by this Panel our pre-market application, P010018 Supplement 5 for the ViewPoint CK System used for the improvement of near vision in presbyopes.

            I will be joined by Dr. Mark Bullimore who will present some background information on monovision, and Doctors Marguerite McDonald and Dan Durrie, clinical investigators in the PMA clinical trial.  Dr. Judy Gordon will facilitate our discussion in response to questions from the Panel.

            Please note that Doctors Bullimore, Durrie, Gordon and McDonald are paid consultants to Refractec.

            We appreciate the opportunity to present to this Panel and hope that our presentation elucidates the clinical data presented in this PMA.

            I will begin our presentation with a brief discussion of the indication for use.  The ViewPoint CK System indicated for the temporary treatment of hyperopia was approved by the FDA in April 2002.  Since that time, approximately 25,000 cases of conductive keratoplasty have been performed in the U.S., and to date the safety profile of the procedure has been excellent.

            The subject of the current PMA being considered by this Panel is the use of the ViewPoint CK System for the temporary induction of myopia, from -1.00 to -2.00 diopters, for improvement of near vision in the non-dominant eye of presbyopic hyperopes and presbyopic emmetropes with a successful preoperative trial of monovision or history of monovision wear.

            The improvement in near vision is provided by the clinical technique of monovision in which the non-dominant eye is targeted for a myopic endpoint, and the dominant eye provides distance vision.

            To present some pertinent background on monovision, I would now like to introduce Dr. Mark Bullimore.

            DR. BULLIMORE: Thank you, Jon.  Good morning, ladies and gentlemen.  My name is Dr. Mark Bullimore, and as previously mentioned, I am paid consultant to Refractec.

            Now the clinical technique of monovision is widely accepted and has a long history of use.  In their comprehensive 1966 review, Jain and colleagues concluded that monovision is an effective and reasonable therapeutic modality for correcting presbyopia.  They also noted that proper patient selection and clinical screening are essential for monovision success. 

            Currently, monovision may b achieved in our practices by means of contact lenses, intraocular lenses or refractive techniques such as PRK or LASIK.

            Nonetheless, monovision is not without its limitations.  Even in satisfied, successful monovision patients, it is common to find decreased contrast sensitivity and reduced stereopsis in selected patients, and this is, of course, due to the monocular blur.

            It has also been widely reported in the published literature that patients can experience glare and other night vision difficulties.  There are also a few case series and case reports of patients having more severe binocular vision anomalies associated with monovision.

            Now these monovision related issues serve to emphasize the need to balance good near visual acuity with maintenance of comfortable binocular vision.  In essence, the goal or the challenge is to provide or to attain some intraocular blur suppression.  It is well known that the quality of this suppression is associated with a number of factors, in particular, the magnitude of the reading addition.

            Now a number of factors contribute to a successful monovision patient.  Careful pre-screening of patients is important, along with a contact lens monovision trial or a history of successful monovision contact lens wear.

            As mentioned previously, it is important to maintain an appropriate level of binocularity, and this can be achieved by limiting the add power.  It has been documented that add powers higher than 1.5 to 2.0 diopters can result in a loss of binocular summation and associated problems.

            Finally, patient education is critical.  Patients need to understand, of course, that monovision is a compromise between distance vision and near vision.  There are potential for symptoms well documented and, most importantly, there may be a need for continued spectacle use, even though, hopefully, in a successful monovision patient, that dependence on spectacles would be substantially reduced.

            At this point, I would like to introduce Dr. Marguerite McDonald who will describe the technology and begin the presentation of our clinical trials results.

            DR. McDONALD:  Good morning.  I am Dr. Marguerite McDonald, and I am going to first present information on the ViewPoint CK System, then describe the study design and review the safety results.

            Monovision treatment performed with conductive keratoplasty or CK is the same procedure as was approved for hyperopia treatment, using the same device, same energy, same spot pattern and the same range of correction, but with a refractive target of -1.00 to -2.00 diopters.

            As shown in this photograph, the ViewPoint CK System consists of a portable console that generates the radiofrequency 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.

            CK involves the controlled intra-stromal delivery of radiofrequency energy to a depth of approximately 500 microns in the corneal periphery.  Radiofrequency energy passes from a generator to a probe tip into the corneal stroma, and returns via the lid speculum.  This provides a homogeneous and uniform cylinder of optimally constricted collagen to a depth of approximately 80 percent of the peripheral corneal thickness.

            The CK treatment applications are of constant 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.        Application of treatment spots in a circular pattern at fixed radii results in steepening of the central cornea with a range of correction from +0.75 to +3.00 diopters, since some patients required up to 3.00 diopters of intended change to reach a refractive target of -2.00 diopters.

            As shown, the optical zone marks of 6, 7 and 8 millimeters act as a template for the treatment application.  Once the optical zone marks are applied, the surgeon begins applying treatment spots until all of the rings of treatment are complete, resulting in steepening of the central cornea.

            I will now present the study design and the safety results for the prospective multi-center clinical trial of the ViewPoint CK System for improvement of near vision in presbyopes.

            The clinical trial that is the subject of our PMA was conducted at five clinical sites with investigators who are experienced refractive surgeons.  All but one of the study investigators participated in the hyperopia clinical trial of CK.

            The study protocol called for enrollment of 150 consecutive subjects who met all eligibility criteria.  To enroll in the study, prospective candidates were required to be presbyopes at least 40 years of age, requiring a near add of +1.00 to +2.00 diopters.

            Hyperopes with cycloplegic refraction spherical equivalence of up to +2.00 diopters and emmetropes were eligible for enrollment.  Patients were required to be successful monovision contact lens wears prior to enrollment or to successfully complete a contact lens monovision trial.

            To this end, a documented history of successful contact lens monovision or a successful contact lens monovision trial was required.  A contact lens monovision trial lasting an average of one week was conducted to carefully screen patients with no prior monovision experience.

            The treatment goal in this study was to improve near vision by targeting a myopic endpoint of -1.00 to -2.00 diopters in the non-dominant eye.  Distance vision was provided by the patient's dominant eye.  It should be noted that, because this study was initiated prior to approval of the CK procedure for hyperopia, dominant eyes of presbyopic hyperopes requiring distance correction were enrolled and treated under the study protocol. 

            The target correction for the non-dominant eye was determined by first performing a subjective refraction with add determination.  This was followed by addition of plus lenses until the best clarity was achieved at 14 inches.

            Patients had the option of selecting a partial near correction to meet individual preferences for near vision, such as reading or computer work, to ensure clinically acceptable anisometropia, the refractive target was limited to -2.00 diopters.

            Safety parameters included measurement of best correct visual acuity, induced cylinder, contrast sensitivity, patient symptoms, and as for any clinical trial, complications and adverse events.

            Following the CK procedure, all FDA limits for safety with regard to preservation of best corrected distance acuity were met in the study population.  No more than one percent of eyes lost more than two lines of best corrected distance acuity at anytime during the course of the study, and no eyes were worse than 20/40 post-operatively.

            The key effectiveness parameters in this clinical trial of CK for improvement in near vision are the same as those reported for all refractive surgery studies, but with a primary endpoint of improvement in uncorrected near acuity rather than uncorrected distance acuity.

            The data we will be presenting differ from the standard refractive surgery outcomes in that we will be presenting monocular and binocular, uncorrected near acuity, as well as combined uncorrected distance and near acuity.

            Please note that in this summary of effectiveness parameters 14 eyes treated for uncorrected near acuity at distances greater than 14 inches are excluded.  As you can see from this slide, FDA targets for predictability of the refractive outcome are approximated or exceeded at all follow-up intervals.

            The improvement in uncorrected near acuity from baseline is particularly impressive when considering that only five percent of eyes were J3 or better preoperatively, and this increased to approximately 80 percent after treatment with CK. 

            Clinical results:  A total of 188 eyes of 150 subjects were enrolled in this study, and demographic information for the study population is shown here.  Consistent with other clinical trials of refractive surgery procedures, a larger number of women than men were enrolled.  However, this is a slightly older population with a mean age of approximately 53 years.

            As mentioned earlier in our presentation, the study population included 38 hyperopic eyes treated for distance.  These eyes were included in the study protocol, since the study was initiated prior to approval of the hyperopia PMA.  However, since the results of these distance corrections were consistent with the approved PMA outcomes, they will not be discussed further.

            Accountability in the study was excellent, with 97 percent of all eyes enrolled available for analysis at six months.  This level of accountability and availability for analysis was discussed with FDA prior to submission of the PMA, and is consistent with the data presented in the approved hyperopia PMA.

            The safety cohort for this study consists of all 150 eyes treated for near, while the effectiveness cohorts are differentiated for the endpoint under consideration.

            Effectiveness with regard to accuracy of the refractive outcome to target was analyzed for all but three eyes with a target refraction above the protocol limit.  Uncorrected near visual acuity will be presented for the cohort of eyes treated with a full correction, such that 14 eyes treated for distance is greater than 14 inches, as well as the three eyes representing protocol deviations, were excluded.

            Safety:  As we move on to a discussion of safety parameters, please note that safety is reported for all 150 eyes treated for near. 

            The limits established in FDA guidance for preservation of best corrected acuity are:  Less than five percent loss of more than two lines of best corrected distance vision and less than one percent decrease, worse than 20/40, in eyes with preoperative best corrected distance vision of 20/20 or better.

            Following the CK procedure, all FDA limits for safety with regard to preservation of best corrected distance acuity were met in the study population.  No more than one percent of eyes lost more than two lines of best corrected distance acuity at anytime during the course of the study, and no eyes were worse than 2/40 postoperatively.

            Only five eyes in the total cohort of 150 eyes treated for near lost two or more lines of best corrected distance acuity at six months or later.  Four of the five eyes were 20/16 or better at the last reported visit, and the remaining eye was 20/25.

            Concerns were expressed by the primary Panel reviewers regarding the decrease of one line of best corrected distance acuity in 34 percent of eyes at one month.  In this cohort of eyes with a decrease of one line in BCVA, best corrected acuity in the majority of eyes was 20/20 or better, and all of these eyes were 20/25 or better.  At three months, all of these eyes were 20/20 or better.

            Beginning at three months, the proportion of eyes experiencing a gain of one line increased and then surpassed the proportion of eyes with a loss of one line.

            The next safety parameter to be discussed is the incidence of induced cylinder. 

            Preoperative cylinder of up to 0.75 diopters was allowed in the study population, and this is reflected in the baseline mean cylinder of approximately 0.3 diopters, and almost half of the study population had 0.5 diopters of preoperative cylinder. 

            Postoperatively, the mean increase in absolute refractive cylinder magnitude was relatively small, and decreased from 6 to 9 to 12 months.  No eyes experienced an increase of more than two diopters of refractive cylinder.  However, the effect of the lower levels of induced cylinder are of clinical interest, and we examined this more closely.

            To determine the clinical effect of induced cylinder on the key parameters of uncorrected and best corrected acuity, a comparison was performed of eyes with one diopter or more of induced cylinder versus eyes with less than one diopter of induced cylinder at six months.

            While there appears to be a numerical difference in the proportion of eyes achieving J3 or better, this difference was not statistically significant.  The number of eyes with higher levels of induced cylinder is relatively small, and precludes the ability to draw any definitive conclusions.  There was no difference between groups in change of best corrected near acuity.

            The same analysis was repeated using the more stringent criteria of the combination of axis shift of 30 degrees or more combined with induced cylinder greater than 0.75 diopters.  Consistent with the previous comparison, even this level of induced cylinder and axis shift had no significant effect on either uncorrected or best corrected near acuity when compared to the remaining study eyes.

            In summary, the incidence of induced cylinder is well below the FDA limit, with no cases of induced cylinder greater than two diopters.  Importantly, the frequency and magnitude of induced cylinder decreased over time, and no compromise in either best corrected or uncorrected near acuity was observed, even in the eyes with induced cylinder.

            Contrast sensitivity was evaluated more extensively in the study population than for other refractive surgery procedures, because of the possibility that contrast, particularly mesopic, might be reduced in subjects undergoing monovision treatment.

            Over half of the eyes treated for near, 83 eyes, underwent contrast testing, with and without glare, and non-treated fellow eyes were tested as well to serve as a control.

            Additionally, binocular contrast sensitivity testing was performed under both photopic and mesopic conditions.  Preoperative binocular  contrast sensitivity was compared to postoperative binocular contrast sensitivity with the near eye uncorrected.

            Mesopic monocular contrast sensitivity without glare was performed on eyes treated for near, and no change from baseline was observed over the course of the study.  The addition of a glare source had no effect on contrast sensitivity in the monovision eye, with no change from baseline over the course of the study.

            We will now present the results of the binocular contrast sensitivity testing. 

            As I just noted, this testing is not part of the standard battery of contrast testing performed in studies of refractive surgery procedures, since it was designed specifically to evaluate the potential effects of monovision. 

            As part of this testing, preoperative binocular contrast results were compared to postoperative binocular contrast results, with the near eye uncorrected to simulate actual visual performance with monovision.  There was no change in binocular photopic contrast sensitivity from preoperative across the 12 month study follow-up.

            The same binocular testing performed under mesopic conditions, without glare, similarly showed no change from baseline at three, six or 12 months.

            The addition of a glare source had no effect on the results of binocular contrast testing performed under mesopic conditions and, as before, there was no change in contrast sensitivity results from baseline following the CK procedure.

            In summary, there was no change in contrast sensitivity under any of the testing conditions, including uncorrected monovision under photopic and mesopic conditions, with and without glare.  These data establish the absence of any detrimental effect of CK on contrast sensitivity.

            Information on patient symptoms was obtained by means of subjective questionnaires administered to the study population preoperative and at follow-up examinations.  Patients were asked to rate symptoms as none, mild, moderate, marked, or very severe, with the same questionnaire administered at each visit.

            Visual symptoms were graded as significantly worse by a very small proportion of the study subjects, ranging from none to a maximum of four percent.  The proportion of subjects with visual symptoms graded as none or mild decreased slightly at one month, but then returned to close to preoperative levels at six and 12 months, suggesting that these symptoms largely resolved over time.

            The symptoms most consistently reported in the study population, blurred vision and variation of vision in dim light, are typical monovision symptoms.

            Since loss of depth perception is a common complaint with monovision contact lenses, study subjects were asked to grade the quality of depth perception preoperatively and following the CK procedure.  Depth perception was essentially unchanged from baseline throughout the follow-up period.

            In summary, the large majority of the study subjects were symptom-free or had very mild symptoms. Those symptoms that were reported were consistent with published studies of monovision contact lens wear and would be anticipated with any monovision correction.

            The final component of safety consists of reports of complications and adverse events.  FDA guidance limits the occurrence of adverse events to not more than five percent of eyes, with any single adverse event occurring in not more than one percent of eyes during the study.

            Only a very small number of complications were reported during the PMA clinical trial.  One patient reported foreign body sensation across all study visits.  There were four reports of double images and ghost images, and there were several other complications unrelated to the CK procedure.  These included one case of EKC, a case of viral conjunctivitis, and transient basement membrane thickening, not located in the vicinity of the CK spots.

            No serious, unanticipated or sight-threatening adverse events were reported at anytime during the course of the study.  Of the four adverse events that were reported, two were non-ophthalmic, a case of Type 2 diabetes and a case of multiple sclerosis.

            One subject experienced a decrease in best corrected distance acuity at six months, from 20/16 preoperatively to 20/32, returning to 20/16 at nine months.  Finally, there was a single case of mild iritis reported at one week, and this resolved uneventfully.

            In summary, the safety of CK for improvement in near vision has been well established in this PMA clinical study, with no significant safety concerns.

            I would like to now introduce Dr. Dan Durrie who will present the effectiveness outcomes.

            DR. DURRIE:  Thank you, Marguerite.  As  mentioned before, I am a paid consultant for Refractec, and they did pay my way here to the meeting.

            I'd like to now present the effectiveness outcomes following the CK procedure.  The areas we are covering in the effectiveness section in this presentation are standard measures of stability and predictability.  The main outcome we were looking at in the study is improvement in uncorrected near vision.

            We are looking at uncorrected near vision monocularly, binocularly, and combined with uncorrected distance vision.  We will also review patient satisfaction and the use of spectacles after the CK procedure.

            So that the N's in the slides don't confuse you, I would like to reemphasize the effectiveness cohorts.  For stability and predictability, we excluded three eyes with protocol deviations.  These eyes had a target of a -2.25 instead of the maximum of -2.00.

            The near cohort consists of only those eyes with full near correction, and excludes the 14 eyes corrected for distances greater than 14 inches, by patient request, as well as the three protocol deviations.

            The FDA criteria for assessing stability of refractive outcomes is shown on this slide. 

            The next two slides show stability of the manifest and then cycloplegic refractions.  All criteria for refractive stability were met except the confidence interval did not include zero.  This was true for the manifest refraction shown on this slide and the cycloplegic refraction on this slide, which the confidence level did include zero at the six to nine months, but not at the nine to 12 months.

            The current data meet all FDA targets for refractive stability with the exception of the confidence intervals.  These stability outcomes are consistent with the results reported in the approved hyperopia PMA, and the sponsor is suggesting the same labeling for temporary correction in the supplement for near vision improvement.

            The FDA targets for predictability of refractive outcome are:  Manifest refractions spherical equivalent of "0.50 diopter in 50 percent of eyes, and "1.00 diopter in 75 percent of eyes.

            This graph shows that both of these predictability targets were met from one month to 12 months postoperatively. 

            When we looked at the patients who were outside the target range, we observed undercorrection, with a maximum of 24 percent of eyes undercorrected at six months.  We were interested in understanding the factors that might be impacting the predictability of refractive outcome.

            We identified several factors that might be contributing to the undercorrections, including patient age, spot pattern used, and the preoperative refractive status, whether they were hyperopes or emmetropes.

            This slide displays two of the variables, age and spot pattern, with age shown along the top of the table and spot pattern on the left side of the table.  As you can see, there was a significant dropoff in the predictability within 1.00 diopter for eyes treated with 32 spots, and there was a slight decrease in predictability in older patients.

            This next slide also shows stratification by two variables, by spot pattern as well as baseline refractive status, whether they were hyperopes or emmetropes preoperatively. 

            There was no difference in the effectiveness for the hyperopes compared to emmetropes with the same spot pattern, but the 32-spot treatment pattern was less effective for both groups.  Even in the 32-spot treatment, there was still a very high proportion of eyes that achieved J3 or better for near.

            Statistical modeling using generalized estimating equation was performed to more definitively identify the predictors of both refractive accuracy and uncorrected near acuity of J3 or better.  When controlling for number of spots, neither age or baseline refractive status was a significant factor predictive of either refractive accuracy or uncorrected near visual acuity.

            Modeling only identified the 32-spot treatment pattern as a predictor of low refractive accuracy. 

            This is a summary of the 8, 16 and 24 spot patterns compared to the 32 spot pattern for effectiveness variables.  As we showed you in the GEE modeling, the 32 spot treatment is not as effective as the other treatment patterns and not as predictable.  But as a clinician, I think it is important to note that even the 32 spot pattern, 70 percent had uncorrected vision of J3 or better, and almost 50 percent were J2 or better.

            Also, this is the first time that we are showing you the entire group of eyes that received 8, 16 or 24 spots.  As you can see, the results are excellent, with 82 percent of eyes achieving J3 or  better.  In 72 percent of eyes, they were J2 or better at six months.

            I will now discuss the improvement in uncorrected near visual acuity, which was a main goal within this study.

            We have clear targets for improvement in uncorrected distance acuity from the FDA and ANSI guidelines, but there are no guidelines or standards to define what can constitute a successful outcome for uncorrected near acuity.

            In the absence of established target, a target for uncorrected near acuity of J3 or better in at least 75 percent of the treated eyes was defined at the start of the study protocol. 

            To put these Jaeger values into perspective, we can now look at something familiar to all of us, the front page of USA Today.  Font sizes for this front page were measured on an optical comparator and converted to Jaeger values.  J16 is headlines.  J10 is smaller headlines, and the print in the body of these articles is J5.  J3, which is the target of our study, is even smaller print, and J1 is really footnote size print.

            If we had tried to make every patient J1, it is very likely they would have more symptoms of anisometropia. 

            This is an example of the type of reading material that you see routinely, and you may be surprised to see that the font size is actually J5.  This suggests that functional vision is achieved at print size larger than J3.

            What we really hear from our patients, and as a presbyope who has been successfully treated with monovision LASIK myself, and especially for you who have not gotten to presbyopia yet, I can certainly tell you that functional vision at J5 and J7 are really important for cell phones, menus and reading your watch.  Nearly every patient in the study achieved J5 uncorrected near vision.

            Monocular uncorrected near vision improved significantly from baseline at all levels from J1 through J5, with approximately 80 percent of eyes achieving J3 or better.  Additionally, nearly 85 percent of subjects achieved binocular uncorrected near vision of J3 or better.

            On this slide, you will note there was a small improvement in binocular uncorrected distance acuity, with the 20/20 rate improving from approximately 75 percent pre-op to 95 percent post-op, likely attributed to CK treatment of the 38 hyperopic fellow eyes for distance correction that were included in the study.

            Perhaps the most important indicator of a successful monovision procedure is the combined binocular uncorrected distance vision and uncorrected near vision.  Over 80 percent of subjects achieved uncorrected distance acuity of 20/20 or better, and J3 or better at near.

            Again, if we look at the group of eyes with 8, 16 and 24 spots, excluding all 32 spot treatments, the number improves to almost 90 percent of subjects with combined binocular uncorrected distance visual acuity of 20/20 and J3 or better, and 75 percent of patients achieving 20/20 at distance and J2 or better at near.

            Subjective questionnaires regarding patient satisfaction and spectacle use were administered to all subjects in this study.  Two different questionnaires were used to ask patients about spectacle use for near tasks.

            Questionnaire number one administered from the beginning of the study had only three categories of near task identified.  This leaves us realizing that we need a better definition of near task.  So we introduced a second questionnaire later in the study.

            Because it was introduced late in the study, the second questionnaire has been administered to only a small number of study subjects.

            In the first questionnaire, we only asked the subjects about their use of spectacles for computer work, reading and whether they were used for all near activities.  Reading was not defined with regard to print size or how long their spectacles were used.

            You can see that approximately 85 percent of study subjects did not require correction for all near activities, and 81 percent of study subjects did not require correction for working on a computer.

            In the second questionnaire we asked the question:  What can you see without your glasses? and gave them different topics to fill in.  Because the second questionnaire was introduced during the course of the study, we did not have the preoperative information and answers to these questions.

            As a result, the subjects were asked to recall what they could see before the CK treatment.  As expected, very few subjects could read menus and newspaper print preoperatively.  After CK, not only did 65 percent of subjects read fine print, they also have significant improvement in mid-range targets, such as menus and computers.

            A more global index of success of the procedure is to ask the study subjects whether they were satisfied.  Patient satisfaction levels were high, with 84 percent of patients reporting satisfied or very satisfied at 12 months, and only four percent dissatisfied or very dissatisfied.  At 12 months over 90 percent of the subjects said that they would have the procedure again. 

            The goal of monovision is to decrease, not eliminate, the spectacle use, and we saw a clear reduction in reported spectacle use in the study population.  Since we had a refractive limit of -1.00 to -2.00 diopters to minimize anisometropia, we anticipated that reading fine print would require spectacles. 

            The high patient satisfaction reported in the study population reflects the clinical benefit that patients associated with improvement in near visual acuity. 

            I would now like to summarize the body of data presented for this PMA.

            The ViewPoint CK System is indicated for the temporary induction of myopia, -1.00 diopter to -2.00 diopters, to improve near vision in the non-dominant eye of presbyopic hyperopes and presbyopic emmetropes with successful preoperative trial of monovision or a history of monovision wear.

            All safety limits established by the FDA and the study protocol were achieved in the study population, including all criteria related to preservation of best corrected vision and induced cylinder.

            Induced cylinder decreased in frequency and magnitude over time and had no effect on the best corrected distance acuity or uncorrected near acuity.  There was no effect of CK monovision treatment on contrast sensitivity.  Finally, the incidence of adverse events was very low, and all resolved without sequelae.

            In summarizing the effectiveness of CK procedure, we can see that we achieved the target of improvement of near vision monocularly, binocularly, while preserving excellent distance vision.  As noted before, results for the eyes treated with 8, 16 and 24 spots are even better in all three analyses of effectiveness, monocular, binocular, and when combined with uncorrected distance and near vision.

            We believe these excellent outcomes for the 8, 16 and 24 spot treatment patterns support a recommendation for approval of these treatment patterns, since safety and effectiveness have been clearly established.

            We understand the agency and the Panel reviewers concern related to the lower levels of effectiveness associated with the 32 spot treatment, and look forward to the Panel's discussion of the risk to benefit ratio of these treatment patterns, and whether adequate labeling can be developed to address these concerns.

            In closing, this PMA represents an additional indication for an approved device and a procedure that is a widely used clinical technique known as monovision for the improvement of near vision. 

            The safety profile was excellent.  The ViewPoint CK System provides a significant and clinically meaningful improvement in uncorrected near vision, resulting in very high satisfaction to the patients.

            This ends the formal portion of our presentation.  The presenters and the sponsor would like to thank the FDA and the reviewers for their careful review of this study.  Thank you.

            CHAIRMAN WEISS:  Thank you very much.  We will now move into -- I will ask any members of the sponsor of they could sit at the table here, because we are going to entertain questions from the Panel.

            I just wanted to start out with one question addressing stability.  We had received Table 4-1 from a Panel review packet dated January 19th.  I would appreciate some help in understanding the following.

            It talks about, for those patients who -- excluding 32 spots -- uncorrected visual acuity was 59 percent, so at J1 at month one, which went down to 51 percent at month six and went down to 39 percent at month 12, basically decreasing from a 59 percent rate at month one to a 39 percent rate at month 12.

            That seems to me like that is not stable.  So I could use your explanation of how that would confirm your stability.

            DR. BULLIMORE:  This is Mark Bullimore.  A couple of points.  Firstly, the sponsor has previously discussed with the FDA the use of the word temporary in the labeling, in the indication, to address some of these issues.

            With reference to the data you quote, and  that is for J1, yes, there are some changes and reductions and the apparent effectiveness, going from -- I forget the time points you quoted, six months and 12 months?

            CHAIRMAN WEISS:  From one month to 12 months, it consistently decreases.

            DR. BULLIMORE:  If we look at other effectiveness outcomes, things appear to be much more stable, particularly when you compare, for example, the six month and the 12 month outcome where we believe that stability is much more tolerable.

            Eighty-two percent of patients are able to read J3 or better at six months, 81 percent at 12 months.  Actually, if you use a consistent cohort, which would be a more correct thing to do, the numbers are identical at six months and 12 months for J3.

            If you look at J1, the data do seem to change a little bit more, but we believe that J3 perhaps gives you a better idea of the functionality.

            CHAIRMAN WEISS:  But wouldn't J1 be more accurate because, of course, if your correction at near was decreasing, you would be able to see J3 consistently, but if your near vision was decreasing, then what would fade would be a J1.

            DR. DURRIE:  Dr. Weiss, one thing -- and I tried to allude a little later on there -- is at the same time those patients have a higher percentage of J1, they have more symptoms at that point in time, too; and as they move, as you saw, into more the stable J3, which seems to be consistent across that, the patients are actually happier when they have less anisometropia. 

            So I think that this is actually part of the thing that clinically I like about this procedure, that although they may be J1 at the one month, as they get to J2 and J3, they are actually happier, because eyes are working together better.  You have to remember, this is a monovision procedure.  So we have to keep in mind both eyes.

            CHAIRMAN WEISS:  I guess my question is really targeting the question of stability.  If it is temporary, I assume it's temporary because it is not stable.

            DR. DURRIE:  Well, and I think that maybe I wasn't quite clear there.  I want to make a point.  We agree with the temporary indication.  So we don't mislead patients that this is stable.  I think it is very important this patient group understand that this procedure -- They may need reading glasses more and may have to put them on for more tasks as time goes on.

            CHAIRMAN WEISS:  So sponsor would agree that stability has not been proven in this procedure?

            DR. GORDON-MEYER:  That is correct, and on that basis the sponsor proposed labeling including the word temporary.  But I'd like to add to that.

            This data, the set of data were very interesting in that we did compare it back to the original hyperopia PMA because it is the same treatment.  In that population, I think there was a little bit more early overcorrection.  There was some overshoot. 

            Here, it is less noticeable, but I think that is what you see happening when you have these early J1s, and that does -- you know, you see a decrease there.  But we think that there is reasonably good stability in terms of uncorrected vision, particularly at J3, over time from six to 12 months, but we do not claim anything other than temporary.

            I think the early data is a small overcorrection, less than we saw in the previous study, but very consistent with that set of data.

            CHAIRMAN WEISS:  But if it is a temporary, you would have to indicate to the patient at two years or three years, then your "stability" of day three might not be so stable.  Then we might have to look at stability of day five.

            DR. GORDON-MEYER:  Well, I think Dr. McDonald will speak to that. 

            DR. McDONALD:  I started doing CK in April of '99, and I have done several hundred cases since then, somewhere between five and six hundred, I think.  The cases that I did in April of '99 were part of the hyperopia PMA, but I did quite a few of them.  Five years out, none of them have come back and asked to be enhanced or to have further treatment.

            So using that as my experience, when I speak to patients, I say this is temporary, but you will probably need further correction of some kind of five, seven or ten years, based on my experience.  Not one of those people has come back for a touch-up.

            CHAIRMAN WEISS:  I had two other questions, and then we are going to go around to the panel.

            Why doesn't induction of cylinder more than a diopter decrease your vision in this study?

            DR. GORDON-MEYER:  We think that it is regular rather than irregular astigmatism, and also the number of eyes -- If you look at the number of eyes in both of those cohorts where there's either one or more diopter or the combined axis shift and induced cyl, it's a fairly small number of cases.  So we are not really sure how robust that observation is.

            I think the more important observation or what we were looking for is was there any effect on the patient's ability to be corrected, and there wasn't.

            CHAIRMAN WEISS:  And just my last question in reference to a comment made at the open public hearing, that there have never been any serious complications.  I recall at the first PMA there was a case where there was a perforation of the cornea, and subsequently I think the company changed the device.  But I also vaguely recollect a report, I think in the literature, of a perforation for someone who had prior refractive surgery.

            So what serious complications are you aware of with the device?  Those are the ones I'm aware of.

            DR. GORDON-MEYER:  Right.  And certainly, we were aware of the report in the initial study, but that was the only report during that period.  Since the product has been in commercial distribution, and the company has a very active product surveillance activity going on, and also because of training and being in very frequent contact with their user base, you know, there is kind of a plethora of questions.

            There has not been a serious adverse event.  I am not personally aware of this perforation that you noted in the --

            CHAIRMAN WEISS:  Perhaps I misspoke.  Maybe it was --

            DR. GORDON-MEYER:  I think we are not aware of it.  The sponsor is not aware of it.

            CHAIRMAN WEISS:  Maybe it was in a publication, but it was a cautionary note in someone who had prior LASIK.  Are you aware of that one, Dr. Durrie?

            DR. DURRIE:  Yes.  I get calls on that.  There was no sequelae to it, but certainly it is something that is a significant potential problem.  We recommend that people with previous refractive surgery, especially incisional refractive surgery -- and that was a post-RK patient -- that this is not a good treatment for that, and I think it is important in labeling to have this be pointed out.

            CHAIRMAN WEISS:  Thank you. 

            DR. GORDON-MEYER:  I just wanted to confirm with the company, but at the time of the first study when there was the perforation -- and you know, we, of course, were acutely aware of that -- the tip has a stop on it so that it controls the depth.  That stop had come off, and the design of that was changed immediately, and the design was verified through the design control process.

            We felt that that had been addressed, because there's been no additional reports of the stop coming off.

            DR. McDONALD:  If I may add just one more thing:  We also -- Since the development of the new improved stop, we also teach doctors to do peripheral pachymetry.  Anyone with a corneal thickness less than 560 in the periphery should not have CK, and it is an absolute contraindication to do this procedure on post-RK patients.

            CHAIRMAN WEISS:  Thank you.  We are going to go around among the Panel members and ask you if you have any questions.  Dr. Huang, I believe you had a question for sponsor.

            DR. HUANG:  Yes, for the sponsor.  You know, there are a significant number of patients who are undercorrected greater than one diopters.  Does sponsor have any kind of recommendation regarding the subsequent management options?

            DR. DURRIE:  If I could, if I could talk about some of my -- This procedure is approved for hyperopia.  So if I can talk about my clinical experience, patients who are under-responders or undercorrected for this procedure, if they have had less than 32 spots, I rotate a 8-spot additional treatment and put them in between the previous spots.

            If someone did not respond to that or already had 32 spots, I have done laser procedures on patients who have been successful both with LASIK procedures and PRK procedures and have not had any difficulty doing that.

            I think one of the things about this study is we wanted to keep the database as pure as possible.  So we didn't encourage people to do re-treatments, but then you don't have re-treatment data to report at this time.  So I think we have to use the -- The advantage of this procedure is it is approved, and 25,000 of these have been done.  So if you talk to surgeons, that is what we hear from surgeons that they would do.

            There is a chance if you are adding more CK, and I think laser procedures can be performed successfully, if necessary.

            DR. GORDON-MEYER:  I'll just add that the sponsor feels that a re-treatment study to evaluate whether additional correction could be induced would be an appropriate thing to do, and there is a lot of interest in doing that.  But in this study, it was well controlled to look at the effect of an initial treatment.

            CHAIRMAN WEISS:  Dr. Huang?

            DR. HUANG:  I have an additional point.  You mentioned that you can potentially do a re-treatment with the CK.  You had mentioned you can do an additional laser procedure.  How about the LASIK procedure?

            DR. DURRIE:  I have performed LASIK, and other doctors have.  Personally, I prefer PRK, just because you are not having a flap -- you are not adding a flap through the CK spots, and I like surface ablation anyway.  So there's a lot of doctors who don't like surface lasers as much as I do.  But LASIK has been performed successfully as well as surface PRK.

            DR. HUANG:  I have a comment to my fellow members.  In this past Academy there is a report regarding the subsequent LASIK after the conductive keratoplasty and with the perforation.  So I think there should be a precautionary statement.

            DR. GORDON-MEYER:  Right.  In the absence of data on re-treatment generated in a clinical study and in this PMA, the labeling that has been proposed indicates that the safety and effectiveness of re-treatment has not been established.  So we put that in right up front.  We understand that concern.

            CHAIRMAN WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  Yes.  I have two questions.  But first I would say I am just having the first signs of presbyopia.  I am not a clinician.  I am not a psychophysicist.  So I am probably the closest thing to a relatively uninformed patient on the panel.

            So if I were to come to you -- I'm getting at this word temporary.  Dr. McDonald, you partially answered my question.  But I would say something like, I'd like to be able to read Times New Roman font 11 comfortably.  Suppose that my initial procedure works, and I am able to do that.  How long will it be before I need to start wearing reading glasses again, and you know, more than just sort of clinical opinion, what data can you show me to inform how long I can expect to go without glasses?

            DR. GORDON-MEYER:  Yes.  FDA actually asked us to look at kind of the percent retention.  It was something we did in the hyperopia database, because there was the same question.  We have done it here, and that information also will go into the product labeling.

            So I think it will give patients a sense.  I am going to turn around to my colleague, Dr. Hayashida, to see if he remembers the number, because I don't have it at hand.  Ninety percent retention of the initial effect at one year.

            DR. BANDEEN-ROCHE:  So that's just through one year that you could tell me?

            DR. DURRIE:  If you wouldn't mind, I'd like to answer that question, because I have to answer it every day.  Every patient who is thinking about this procedure asks me that particular question.

            I think it is important, because if this procedure -- this supplement is approved, it will provide some information that we will provide in the teaching for the doctors on what to say. 

            I think it is very important to not over-promise how long this procedure is going to last, because we know statistically patients get a little more hyperopic as they age.  They get a little more presbyopic as they age. They lose their ability to read.

            So I tell patients that it is going -- The study data shows that it looks for at least a couple of years, because we have the hyperopia data that it is going to be stable, but I like to not over-promise, and I would like to see within the labeling, if we get to that stage, that this temporary is a very good thing to tell patients, because we do not want to let them think they are actually going to get younger or that we are actually correcting presbyopia.  We are just improving near vision in a presbyopic population.

            When I give patients that kind of ambiguous answer that I just gave you, it makes them think, do I want to have an elective procedure that could be temporary?  I think it is a very good thing for the patients to jump through, and good communication between doctors and patients is important.

            DR. BANDEEN-ROCHE:  Thank you very much.  Then my second question is just for a very simple data analysis that maybe someone can do.

            It goes to the question:  Do you wear spectacles or contact lenses?  Dr. Bullimore already referred to the consistent cohort issue.  So what I'd like to see is a cross-tabulation, month six to month twelve, of that question:  Do you wear spectacles or contact lenses?  Just yes/no, yes/no, going from month six to 12.  You know, whenever that is ready, that would be fine.

            DR. DURRIE:  Would you like to see that -- because there's different spectacle tasks that were asked.

            DR. BANDEEN-ROCHE:  If we could see it for all of them, that would be fine, but I'd like to see it for the overall question as well.

            DR. GORDON-MEYER:  We will start trying to generate that, if we can get to it quickly.

            CHAIRMAN WEISS:  Dr. Smith?

            DR. SMITH:  Since monovision is a key aspect of this study, and I know you did ask about the quality of depth perception in a subjective way, can you tell me why there was no objective testing for stereopsis included in the study design?  Was that discussed?

            DR. DURRIE: There was not, and one of the problems -- and I have done other studies on this procedure and other monovision procedures.  We have a real problem with stereopsis testing with plain old presbyopes, because they can't see the chart.  So you give them the fly, and they go, what fly?  You put them on the reading glasses, and now you are not testing their near vision.

            We have worked with distance stereo testing in other studies on this, and we are still trying to adapt that.  So we have this unique set of patients who it's hard to test with our classic test, because you give them a stereo test, and they can't see it. 

            So it's an interesting dilemma.  So we weren't able to really do our regular tests that we normally do, and I'm still interested in that.  So we've been trying to figure out ways to evaluate that more. 

            It is interesting, though, because I think all of us expect with this -- Since it is a monovision procedure, we expected to have problems with depth perception, which did not show up.  We expected to have problems with contrast sensitivity, and it did not show up either.

            So I think that these are good things for this particular procedure.  But I think it shows that our testing that we traditionally use we need to continue to look at as we are developing these new procedures.

            DR. GORDON-MEYER:  Dr. Bullimore would like to add.

            DR. BULLIMORE:  Just to follow up, most of our clinical tests required really almost pinpoint visual acuity at near to perform these stereo tests.  As Dr. Durrie suggests, it is a problem for clinical testing. 

            There have been a number of studies that have looked at sort of functional real world stereo tests like card sorting, putting pointers into straws and things, and you do see the kind of decrement that you would expect in somebody who has some monocular blur associated with monovision.  But the performance deficit is relatively modest.  It's sort of in the three to five percent range rather than being equivalent to covering one eye.

            So people have tried to quantify that, but it is something that is very difficult to do in the consulting room.

            CHAIRMAN WEISS:  Dr. McMahon.

            DR. McMAHON:  I have three questions.  Is that all right?  My first one is, I think, the gist of my concern, and you addressed it peripherally.  That is:  If 32 spots really doesn't demonstrate any meaningful effectiveness, why are you asking for it?

            CHAIRMAN WEISS:  Can you repeat that question?  I didn't hear the rest of it.

            DR. McMAHON:  I said, if 32 spots or the application of 32 spots clearly is not demonstrating any meaningful effectiveness -- and I will say that equivocally -- why are you asking for that indication?

            DR. DURRIE:  Well, I think it certainly shows a significant improvement in near vision in the 32 spot treatments.  I mean, we had 75 percent of people that could read J3, and it was actually 50 percent of people could read J2.

            So they did have very good improvement in their uncorrected vision.  They didn't look very good on the refractive accuracy within plus or minus a diopter.

            Now one of the things with this is the study was almost a small, medium and large study.  They either got 8 or -- or most of them got 16, 24 or 32 spots, and that is -- There is a gap in between there.  So we had to kind of choose one or the other.

            So some of that refractive accuracy may be because of the nominals of what we were kind of shooting at.  But I think that, from the standpoint of vision improvement, there definitely was significant improvement with the 32 spot patients. 

            Their satisfaction was good.  There wasn't any difference in their satisfaction from the other patients', but I think when we look at it in the refractive surgery world, we are always looking at plus or minus a half, plus -- and it didn't do very well in those categories. 

            So I think that is why a discussion of the Panel on the 32 spots, I think, is very appropriate, as we kind of have this -- It helped the patients, but it didn't look very good on our criteria.  So I think that's why we are asking for discussion on that. 

            DR. McMAHON:  I will posit a potential theorem here, and that is that there isn't much more effect going from 24 to 32, and what you are seeing is the effect of the initial 24 in that particular population.  In fact, 32 actually may be a decrement in response.  But again, that is up for discussion.

            The second question is:  Presbyopia is a continuum up to a certain point.  You start off, as Dr. Bandeen-Roche is, at the nexus of presbyopia, and then where Dr. Bullimore is heading, near the bottom of presbyopia.

            As you said, this is sort of a small, medium and large procedure.  The question comes into play then, when is this indicated in the presbyopic scenario, in view of the fact that there is no information that is available at this point on the efficacy of secondary treatments?

            So is somebody who needs a 1.00 diopter correction the appropriate patient to do or do you wait until they are 2.00?

            DR. GORDON-MEYER:  I think this is really a clinical question.  So I'll allow my colleagues here to answer, but the mean age in this population was 53 years.  So I think that really speaks to -- You know, patients are going to self-select, to some extent, as to when they feel they need it, but I think again that is the -- we'll get an answer from the clinical perspective.

            DR. McDONALD:  Not to beat a dead horse, but as I said, the people who were treated for distance five years ago have not come back for an enhancement, but that is something that is decided on a case to case basis, and we are not asking for any claims about enhancement in labeling, for sure.

            If I could very quickly just say one thing.  We are getting together the table for Dr. Bandeen-Roche very quickly, but it's the sort of thing where you have to make an individual decision based on a conversation with the patient as to exactly what their near point is.  We will return to that as soon as we get the table for you.

            DR. DURRIE:  I think that it is interesting, because my average age for this procedure -- and since it has been performed a lot off-label -- is 55.  So it's even higher than the study, because I looked at my data quite carefully.

            So the patients -- you're right.  When they need 1.00 diopter in their early forties, they don't come in for this procedure.  So there is a lot of self-selecting.

            I have had some patients now -- There's just two of them.  They are both dentists -- who came in and never wore reading glasses and had CK, because with their occupation, they didn't want to wear them.  They heard this was available.  So I think that might change over a period of time, but I think that right now the patient selection for this is when they are having enough trouble -- You know, I had my monovision when I was 50.  So before then it wasn't bad enough.

            So I think there is some self-selection.  I don't know how we really handle that in labeling as much other than telling them that the average age of this population was 53, and I think that is important to know.

            DR. McMAHON:  That's a good point.  You know, with the mean age of the group being 53 and in your experience 55, that's close to the bottom, in which case that's not much of an issue, because your accommodative amplitudes have sort of hit bottom anyway, and then that's not a worry.

            It's the 46-year-old that comes in who is starting to have early presbyopic symptoms and, if you have a shot at them then with 8 spots of 16 spots, then what do you do when they are now 50?  And an issue is whether we should deal with that in labeling or just --

            CHAIRMAN WEISS:  The problem is we don't have the answer.  But it's an excellent point, but we don't have the answer.

            DR. McMAHON:  One minor quick question.  That is:  In the list of complications you list, you mention a few cases of "viral infection."  Was this viral conjunctivitis or was it corneal?

            DR. McDONALD:  One was viral conjunctivitis, and one was EKC.

            DR. McMAHON:  Okay, thank you.

            CHAIRMAN WEISS:  Dr. >Coleman?

            DR. COLEMAN;  No questions.

            CHAIRMAN WEISS:  Thank you.  Dr. Van Meter?

            DR. VAN METER:  Early in your presentation -- I don't know if this was Dr. Bullimore or Dr. Durrie -- the mention was made that depth perception was tested by subjective means and was not a problem.  There are a number of ways to accurately test depth perception objectively and, given the obvious imperfections in judging depth perception subjectively, why did you not test depth perception objectively in these patients?

            DR. BULLIMORE:  Which test are you exactly thinking of?

            DR. VAN METER:  Anything.  You know, even a fly test will give you something.

            DR. BULLIMORE:  As I probably did a poor attempt of explaining earlier, you really do need good acuity in both eyes for those tests to work.  They require probably J3, J2 acuity to test that kind of fine stereopsis. 

            So it would have been a self-fulfilling prophecy that the patients probably wouldn't have been able to see very much on those tests, had we used them.  I think the bigger issue is it will be nice to have a test of distance stereopsis, some clinical metric of how well people judge distances, particularly from the point of view of driving and things like that.

            That's what we were trying to get at with the questionnaire.  Whether we did a good job of that or not --

            DR. VAN METER:  I just didn't understand what the questionnaire was supposed to show.

            Second question:  Dr. Durrie, you mentioned in Slide 83 that there were -- I'm sorry, Slide 12, that there were three patients eliminated for treatment deviations, because they required +2.25 diopters of change rather than 2.00 diopters of change.

            Yet it looks like the treatment on Slide 12 is the same.  It is --  The same number of spots would be for 2.00 as 2.25.  Are these considered treatment deviations or is this a --

            DR. DURRIE:  This was just in our discussion with the agency in filing it, because the protocol said you were not supposed to attempt any correction greater than 2.00 diopters, and the investigator included somebody and wrote down on the form that their target was a -2.25.  So it was classified as a protocol deviation. 

            The patient had no safety issues.  The performance was exactly the same as the other group, but it's just -- It's kind of just fallen between the cracks, because it was something the investigator was not supposed to write down, and they did.  But the treatment was exactly the same.

            DR. VAN METER:  Slide 83 showed a graph of people who could see what their tasks were before and after the procedure.  I notice that there were nine people who could sew without glasses, another nine people who could read a gold score card. 

            Given the fact that in Slide 85 you say these people will need glasses for fine print anyway, help me see what would be gained for these nine people by having the procedure under the given indications.

            DR. DURRIE:  Those are percentages.  I mean, just for clarification, those are percentage of patients, not really patients.

            DR. VAN METER:  Oh, I'm sorry.

            DR. DURRIE:  But the situation here is this overall improvement is kind of what we see from patients as functional vision improvement is very hard to define.  So we are trying to define it with both these questionnaires, neither of which were adequate.

            The one thing is, certainly with some of the expertise we have on this Panel in near visual acuity questionnaires, I'd love to get more questions.  Dr. Schein's questionnaire was not available at the start of this study, but I think we will be using more addressing this.

            So there's weakness in both these questionnaires.  We did the best we could, and we are reporting the information we have, but I think we all need to continue to address that more as more near procedures are being looked at.

            CHAIRMAN WEISS:  Than you.  Dr. Van Meter, do you have any other questions?

            DR. VAN METER:  I have one question about what do we tell patients when surgical re-treatment is indicated, since we don't really know where that goes?  We can discuss that later.

            CHAIRMAN WEISS:  I think we don't know where that goes.  I am also going to ask sponsor, in order to limit the amount of time for the question session, if you could just have one person answer the question, so it just doesn't go around the panel.

            Dr. Bradley.

            DR. BRADLEY:  I have questions about Slide 68.  Again, it is a confusion about the use of the 32 spot treatment.  You have emmetropes receiving -- emmetropes grouped in the 8, 16 and 24 spot group, and emmetropes included in the 32 spot treatment. 

            I just wondered if you could clarify under what circumstances the 32 spot treatment was used.  The particular reason we would like to know that is that didn't work as well.

            DR. DURRIE:  Great question.  We asked the same question when I saw this data.  Emmetropes are defined up to plus a half a diopter of hyperopia.  So they were patients that, when we went through the steps as established in this on deciding how much treatment was done, and that was done on a very controlled basis, they fell into that nominal group that required 32 spots because they were plus half a diopter of hyperopia and the way that we set the near card at 14 inches and did an add, that is what they were assigned to.

            So I think that most emmetropes under the real world criteria will probably not receive 32 spots, but it was just the way the study was designed.  When we did the testing, because they were hyperopic plus one-half, they required 32 spots under the protocol, just because the range in 32 spots was from 2.37 to 3.00 diopters of attempted correction.  So those were our buckets.

            So if you wanted to get a -2.00 and you were plus one-half, you had to do 32 spots.

            CHAIRMAN WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  Dr. Grimmett.  Pardon me while I put on my very first pair of readers here for my question, a gift from my wife this Christmas.

            The first question for Dr. Durrie.  On slide 32, a chart regarding the change in best corrected vision shows at one month there was a decrease in one line of best corrected vision by 34 percent, and this decreased to eight percent by month twelve.

            I am inferring that the early decrease in best corrected vision is secondary to corneal irregular astigmatism.  Do you agree that that is true or is there another reason that there is a decreased vision that subsequently improves with time?

            DR. DURRIE:  That is my clinical impression also, because when you are doing these spots around, I have clinically noticed that you can get a little edema in the superior spots more than the inferior spots during that first month of healing, and I think there is some irregular astigmatism.

            It really doesn't show up even on wavefront testing or topography testing, and I have looked at it pretty carefully, but clinically that is what I think it is, and it decreases with time.

            DR. GRIMMETT:  You anticipated my second question, topography and wavefront.  In any of those patients, were contact lens over-refraction performed to rule in the diagnosis of corneal irregular astigmatism at early time points?

            DR. DURRIE:  We did not do it in the study, because it wasn't in the protocol, but that is something I am really interested in looking at now.

            DR. GRIMMETT:  Has anybody done it clinically, just as a clinician or anything that you know of?

            DR. DURRIE:  Not that I know of

            DR. GRIMMETT:  Okay.  Second question directed to Dr. Bullimore regarding monovision status.  How is the sponsor recommending to the physician to determine which eye is the dominant or non-dominant eye?  Clearly, that is probably an important issue.

            You mentioned that 70 percent or so of patients tolerate monovision in studies that have been published, with the non-dominant eye as the near eye.  So my first question is how do you recommend they determine, and if the choice is wrong, if it is done the other way, how many percent tolerate it when the wrong eye is chosen for which task, or does that data exist?  

      DR. BULLIMORE:  Let me take the last question first.  Those data do exist in the literature.  Jain, et al. who did the comprehensive review, a more recently published case series where they went back to the records and looked at monovision patients and determined tolerance of surgically induced monovision and tested very carefully, at least in their terms, ocular dominance.

            What they found was that -- I can't remember the exact proportions, but there was a significant number of people who had what they called crossed monovision.  That is to say the distance eye or  distance corrected eye was actually the non-dominant eye.  The dominant eye, for whatever reason, had been corrected for near.

            They found no difference in the outcomes in terms of satisfaction with monovision in the cross-monovision patients and the conventional.

            DR. GRIMMETT:  So it's still two-thirds tolerate it, or so.

            DR. BULLIMORE:  I can't remember their exact data.  I think it was eight out of ten of the cross-monovision patients were still tolerant of that.

            As far as their technique that they describe in the literature, it's a sort of holding the hands technique.  Make the hand smaller, and see which eye is sighting through the small hand.  That seems to be the most or among the most prevalent technique for assessing dominance.

            I mean, there are certain rules that, you know, if you were going to test dominance, eye dominance, you should use both hands so you are not biased by the hand that the patient uses to point with.  So if you are making other gestures with your hands, you should use both hands rather than just one hand or finger.

            As far as what the sponsor plans to put in the labeling, that is very much sort of still on the table, and we would appreciate -- It's not on the table?  It's off the table now. 

            DR. GORDON-MEYER:  I apologize for interjecting as the second speaker on this question, but it is important that -- I don't remember what year, but FDA provided to manufacturers of contact lenses information on labeling for monovision.  We have adopted that information, and it included a determination of dominance, how to determine dominance, and we have included that language as just a basis and a precedent and certainly a body of experience in our labeling.

            Again, we are open to discussion, but we did feel that we adopted at least that standard.

            DR. GRIMMETT:  Excellent.  I am glad to hear that.  I have another quick issue.

            Does the sponsor recommend any kind of contact lens monovision trial prior to actually performing this surgery?  It's included?

            DR. GORDON-MEYER:  It is also in the labeling.  It was included in the protocol --

            DR. GRIMMETT:  Thank you.  Sorry for the oversight.

            DR. GORDON-MEYER: -- and absolutely vital.

            DR. GRIMMETT:  Sorry.

            CHAIRMAN WEISS:  Dr. Casey.

            DR. CASEY:  My question relates to trying to appreciate what the functional duration of temporary is.  Looking at patient satisfaction information, particularly the questionnaire number two that was provided, I guess Table 13A, what patients can see without glasses.

            The first question is:  Is this group that is listed with questions asked at six months, nine months and 12 months a consistent cohort; and if so, what do we know about those patients in terms of what their preoperative refractions were, what spot number they received in terms of the treatment?

            Then the third question would be:  How come all the patients just haven't been given this questionnaire, regardless of where they are, so that we an get a sense of what their functional capabilities are?

            DR. DURRIE:  Well, as far as the questionnaires are concerned, as the second questionnaire which you alluded to, that did give us more information.  Unfortunately, we didn't do it at the beginning of the study.  So that we had to ask them to recall and from their memory, which is not a great way to come up with some defined data.

            We reported it with that caveat and telling you that up front.  But I'll come back to the point where I think that in hindsight I would have loved to have that questionnaire pre-op.

            Now there is a lot of work going on in this where people are looking at these satisfaction tests going forward, and I think that, as the agency and this Panel, I think it is something we truly need.  Unfortunately, it just wasn't available, and we did the best we could.  So I can't go on and state about that, as it is not here.

            DR. GORDON-MEYER:  I'd like to add by responding to the specific question on data.

            CHAIRMAN WEISS:  Do we have to?  I mean, at this point we are going to end up having to limit the questions from some of our Panel members.  So if the additional stuff is very important, then please add it, but if it's not, please don't.

            DR. GORDON-MEYER:  I think we have Dr. Bandeen's -- a response to Dr. Bandeen on the consistent cohort, and I think it tires in as well with this question. 

            Part of your question was do we know what patients were treated with 32 spots.  As we analyzed the data by excluding the 32 spots and looking at the rest of the population, there really weren't differences in satisfaction and spectacle dependence types of things.  But again, you are cutting the data, and so now you have a smaller group.

            If you look at -- The largest number of cases  was in the first questionnaire and, while very imperfect, I think, gives us an idea when we look at a consistent cohort.  Again, it does not take into account frequency of use, but just use, yes/no.

            In a 12-month cohort, the percentage of patients who used correction for all near activities was 13 percent at six months, 14 percent at 9 months, and 15 percent at 12 months.  So I'd say it's fairly level.

            CHAIRMAN WEISS:  Dr. Mathers, and I would just let the members of the Panel know, we have about 10 more minutes.  So if you could -- as well as the sponsor, if you could limit the length of your answers, I would greatly appreciate it.  Dr. Mathers?

            DR. MATHERS:  Did you correlate or stratify them by the number of spots for stability or for patient satisfaction?

            DR. GORDON-MEYER:  Yes, we did.  In our January submission we provided -- and Dr. McMahon had suggested it, and we ourselves come to the conclusion to separate by spots.  We pulled the 8, 16 and 24 versus the 32, and we did not perform statistical testing, but we commented that we had done a review comparing those, and there were no differences in any of the safety or stability findings or patient satisfaction.

            The difference really seemed limited  particularly or most accentuated in the refractive accuracy and, of course, lower levels of uncorrected, J3 or better.

            DR. MATHERS:  I am also interested in who gets induced cylinder.  I wondered if you looked at this in terms of the number of spots or age or their pre-op cylinder to give us some indication as to who you could predict would get cylinder.

            DR. GORDON-MEYER:  Surprisingly, there was no relationship between number of spots and induced cylinder, but I don't think I know or recall whether there was a relationship between preoperative cylinder and induced cylinder.

            There was not in the hyperopia population, and there was less cylinder induced here,  So I can find out, but other factors did not have any effect.

            DR. MATHERS:  Thank you.

            CHAIRMAN WEISS:  Dr. Schein.

            DR. SCHEIN:  Thank you.  First, my compliments to the sponsor for a very clear presentation.  I have a question that relates to a difference between temporary and reversible, reversibility.

            So imagine if monovision is successful in the contact lens trials in the 60 or 70 percent range, and everyone gets a contact lens trial.  If they fail it, they don't get this procedure.  It's not going to be 100 percent, that everyone is going to be happy with the more permanent monovision, and you have just divulged to the patient that it's not temporary, but what information do you think is appropriate for indicating potential reversibility of the procedure?

            It may be a good thing that it is temporary for some patients.

            DR. DURRIE:  One thing that was interesting is when you get the chance to really look at this data, what was interesting is in this study we didn't have anybody in the study who was intolerant of their monovision and had any -- We had no requests for reversal.  We didn't have anybody who wanted to go back.  We had undercorrections.

            So I thought that was an interesting fact, because the screening that we did, which we are suggesting in the label and the same that was done with the monovision trial within future labeling, did a good job; because we didn't have that happen.

            I think that reversibility of the procedure goes back to what I said before about re-treatment.  You certainly wouldn't add more CK spots, but doing a laser treatment is an option, and I have done that, not in this procedure but I have done that procedure with overcorrected LTKs way in the past, which should have some similarity, where somebody  is very overcorrected, that I did do a PRK procedure for myopia, and it worked fine with no haze or problems.  But certainly, we have to label that we don't know anything about that, but it is one of those things where, theoretically, correcting a little bit of myopia shouldn't be that hard.

            DR. SCHEIN:  Right.  The other question I had has to do with:  Did you measure uncorrected distance acuity in the treated eye?

            DR. GORDON-MEYER:  We haven't looked at that data, and we did not do that consistently, because it was not making a lot of sense.

            DR. SCHEIN:  The concern I have as an emmetropic presbyope is that, if I am only correctable distance now with the spectacle that I didn't have to wear before or there is some induction of irregular astigmatism which is potentially correctable, that would be a downside for an emmetrope.

            CHAIRMAN WEISS:  Thank you.  Dr. Macsai.

            DR. SCHEIN:  No response

            DR. BULLIMORE:  We have a response.

            CHAIRMAN WEISS:  A short one, I anticipate.

            DR. BULLIMORE:  It should be handled in the labeling, and it is not unusual for a monovision contact lens patient to have a pair of occasional distance glasses that they put on, say, if they were driving home in bad weather conditions.

            Just to point out that the combined binocular distance acuity was excellent in these patients.  They did have the benefit of two eyes, were not blurred in one eye and not allowing them to use the other eye.

            DR. SCHEIN:  Somehow in the survey the distance vision improved dramatically in your survey.

            DR. GORDON-MEYER:  I think that had to do with the correction, that we are actually very successful in the 38 hyperopic eyes.

            DR. SCHEIN:  Oh, hyperopic eye?

            DR. GORDON-MEYER:  Right.  So they had an average planned refractive change of about two diopters.

            CHAIRMAN WEISS:  Dr. Macsai?

            DR. MACSAI:  Can you give us some information on the patients that are on slide 75 and 76 who preoperatively seem to have J5 or better?  There's even some patients who are J2 or J1 or better, J3 or better.

            I am curious on a number of issues.  One, why did they have this done?  Two, what happened to them?  Three, what was their specific regression rate?  That's question number one.

            Question number two is:  If we are saying that this is not stable and it is temporary, and we are treating an average of 55-year-olds -- I guess maybe this question goes to Dr. Durrie -- how do you do IOL calcs in these patients, should they develop cataracts within five years after their treatment or how do you predict your PRK treatment, if they are not stable?

            DR. DURRIE:  Well, in general, the "not stable" is something that we are agreeing with in the label, but these patients are quite stable, because when we looked at the data, all of the patients who were J3 or better at six months -- all of them in the cohort were still J3 or better at 12 months.

            I just think that I like the fact that we are saying temporary, but I don't want to overemphasize.  It's not like these people go up and down all over the place.  You know, they have a tendency to maybe drift slightly over a long period of time.

            I IOL calculation, I think, is a very important issue, because these patients are older.  So we have been looking at this with the technology of a topography refraction, K readings.  I have yet to have a patient who has had cataract surgery, but I've been looking at it, and it doesn't appear that there is a difficulty like we see in the myopic flattening that really throws our tests off with the hyperopic steepening.

            I have had hyperopic LASIK steepened corneas that have gone on to cataract surgery and have not had any difficulty at all choosing the IOLs in those patients compared to myopes.  So I am not as worried about the steepening as our past history is, but again we are going to have to label for that one, too, because we don't know.

            DR. MACSAI:  Can you get the data from the first question?

            DR. DURRIE:  Yes.  The first question, I think we will have to dig for the data a little bit, but why would somebody who is J3 preoperatively have this procedure?

            This was a very defined entrance criteria into the study.  They had to be of this age and have this problem and everything else, and there were people that fit.  They were candidates, and they fit within the criteria.  So we did do them.

            The interesting thing is they did extremely well.  Matter of fact, those patients who had a little bit more near vision did even better than the patients who didn't.  I think it gets back to Woody's comment a little, or somebody's comment about -- I think it was Tim's -- about when can you do this.

            I don't really know, but I think that my feeling is some of the patients that do it younger, earlier in the future, that have still more residual accommodation may do even better.  But I think that's wait to be seen.

            CHAIRMAN WEISS:  If Mr. McCarley or Ms. Such has any brief questions -- If they are just comments, I would respectfully --

            MR. McCARLEY:  This is Rick McCarley, the industry rep.  Sorry I have a cold.  I hope you can hear me okay.  Just one question.

            I don't have access to the clinical data.  So I'll ask a more general question.  Since this procedure can be done with available equipment on the market now, what percent or number of patients do you think out of the 25,000 procedures that have been done -- do you think people have actually done this outside your study?  In other words, is it a common thing, once it became available, that people just started recognizing that it was something that was a potential?

            DR. DURRIE:  I would say that from the doctors I have talked to, greater than 50 percent of them that do CK on a regular basis use it for monovision in one eye.

            CHAIRMAN WEISS:  Ms. Such, did you have any questions?

            MS. SUCH:  Let's see if I can do this and bend at the same time.

            Given that -- I was going to mention a computer screen, since I am a technology  person.  Given that computer screens, the -- as we call them, the font sizes, as you call them the J factors -- range from J1 to J4, depending on the size of the screen, the contrast and resolution, I'm wondering:  When you talk about that patients were asked about do they have problems with the computer screen, whether they were done in center and, at the same time, on their patient reporting form were they asked that same question while they were in front of the same computer screen?

            Your difference between the laptop and an 18 inch monitor could be the difference between J1 and J3 to J4.

            DR. DURRIE:  I think that it is a great point, and no, we did not ask them whether they -- When we asked the subjective question, can you read the computer, we did not control for can you read the same computer you could read before surgery.  I think it is a very important point.

            These questionnaires really need to look at these issues in the future, because near vision tasks can certainly change with the type of print that you are looking at.  But we did not control for that.

            CHAIRMAN WEISS:  Okay.  We have about three more minutes.  We have three more questions.  So what I would ask the sponsor is, if you could answer these questions in two sentences, not paragraphs, I would really appreciate that; and if the people asking the questions could ask them in one sentence, not paragraphs.

            So with that introduction of mine, Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  This is just a follow-up to the data that I requested.  I regret if I was unclear.  What I'd like is a cross-tabulation, six months to 12 months of the overall do you wear glasses or spectacles question, please.  I would be happy to receive that during the break.  I can read it into the record.

            CHAIRMAN WEISS:  Thank you so much.

            DR. GORDON-MEYER:  That is what we provided.

            CHAIRMAN WEISS:  Okay, you'll provide it.  That's a good sentence.

            DR. GORDON-MEYER:  That is what I just provided.

            DR. BANDEEN-ROCHE:  No, it's not quite, because you gave for all tasks, not the overall question.  You gave "do you have difficulty" -- "do you wear glasses for all tasks, 13, 14, 15 percent?"  I also want a cross-tabulation, not just the consistent cohort, six to 12 months.  Thank you.

            CHAIRMAN WEISS:  Okay.  That's elucidated.  Dr. Grimmett had two questions which I think were important.  I'll read, and these actually probably could be done in a sentence or two.

            I think, Dr. Durrie, you had mentioned 90 percent retention at what year.  Dr. Grimmett and I also would like to know retention of what?  Are you talking about retention of uncorrected vision?  Okay, you got out of that one.  What was that?

            DR. GORDON-MEYER:  It was a calculation that was requested by FDA for initially labeling for the hyperopia PMA and now for this.  So the calculation is of the refractive effect. 

            CHAIRMAN WEISS:  So 90 percent -- So if you intended to correct a +2.00, at 12 months down the line you would have 90 percent of that 2.00 corrected?

            DR. GORDON-MEYER:  I am looking here to my colleagues from Refractec just to confirm. 

            DR. GRIMMETT:  Does that take into account the original overshoot?  You're talking about what your target was.

            DR. GORDON-MEYER:  No.  From six to 12 months.

            DR. GRIMMETT:  That's from six to 12 months?  You only lose 10 percent more from six to 12 months?

            DR. GORDON-MEYER:  Correct.

            DR. GRIMMETT:  What do you lose overall from the start? 

            CHAIRMAN WEISS:  From zero to 12 months?

            DR. GRIMMETT:  Do you lose a third? 

            DR. GORDON-MEYER:  I don't have the answer to that.  We can get it.  Mark has the answer.

            DR. BULLIMORE:  It's tough, because there's initial overshoot.  There is initial overcorrection.  So it would be like hindsight, you know, what is the change initially to whatever.  So it's difficult.  I think it is more prudent to think about what goes on from three to six, six to 12, 12 to twenty-four.

            CHAIRMAN WEISS:  What would you lose from three to six?

            DR. BULLIMORE:  Three to six -- The change in effects, which are presented in the tables for you, is about actually all the way from three months out to 12 months is about .03 to .04 diopters per month.  Those are the numbers that are in the tables.

            CHAIRMAN WEISS:  We'll calculate out.

            DR. GRIMMETT:  If at some point later somewhere after lunch you could tell me, of the total surgical effect you get, how much you actually lose at the longest time period that you have.  I did the original review of the PMA a couple of years ago, and I would like to know if you have longer data or give me a sense of what you are losing.

            DR. DURRIE:  We would be happy to provide you with what you want.

            CHAIRMAN WEISS:  And I thank you for staying on track.  So with that, I am going to thank the sponsor, and they can move back from the table, and we will now go on to the FDA presentation.

            We digress.  My apologies. 

            MS. CALLAWAY:  Dr. Beers was going to defer in the interest of time. 

            Good morning.  I am Jan Callaway, the FDA Team Leader for this application.  Since the company has already introduced the device, I have just a few brief comments.

            First, I want to thank the Panel for reviewing and discussing this application today, as well as the primary reviewers, Dr. Andrew Huang and Dr. Timothy McMahon, for their expertise.

            I want to commend the sponsor for being so responsive to all FDA and Panel review questions and concerns.

            The FDA team responsible for Supplement 5 included Dr. Sheryl Berman, medical officer and clinician; Mr. T.C. Lu, statistician; Ms. Carol Clayton for review of patient labeling; and Ms. Pam Reynolds for bioresearch monitoring.  I would like to thank them for their diligent work, and I would like to introduce Dr. Sherri Berman who will present the areas for which your input is being requested today.

            DR. BERMAN:  Good morning.  Today the Panel members are being asked for their clinical judgment as to whether the PMA study outcomes provide reasonable assurance of safety and effectiveness for the indication that is being requested.

            In my presentation this morning, I would like to highlight a few issues which I think warrant Panel discussion to make their determination.

            Refractec is currently requesting approval for the following indication:  Temporary induction of myopia, -1.00 to -2.00 diopters, to improve near vision in the non-dominant eye of presbyopic hyperopes or presbyopic emmetropes, via spherical hyperopic treatment of up to 3.00 diopters in patients 40 years of age or greater with a documented stability of refraction for the prior 12 months as demonstrated by a change of less than a half diopter in spherical and cylindrical components of the manifest refraction, and with less than or equal to .75 diopters of cycloplegic refractive cylinder and with a successful preoperative trial of monovision or history of monovision wear -- that is, the dominant eye corrected for distance vision and the non-dominant eye corrected for near vision.

            In April of 2002, Refractec received FDA approval for conductive keratoplasty for .75 to 3.00 diopters of spherical hyperopia.  The approved surgical procedure, treatment patterns, and magnitude of refractive correction are the same in the requested indication today.  However, the patient population and refractive target differ.

            The proposed treatment is for presbyopic emmetropes and hyperopes targeted to myopia rather than spherical hyperopes targeted to emmetropia, as in the original PMA. 

            The creation of monovision is a widely accepted method for the management of presbyopia.  This PMA supplement is the first time a monovision indication has been requested for an ophthalmic surgical device.

            Accountability is summarized in these tables, and is identical to the accountability that was acceptable in the original PMA for the treatment of hyperopia.  For the record, I'd just like to indicate that the sponsor has updated the original PMA labeling with 24 month study outcomes and has indicated their willingness to do so for this PMA supplement for monovision.

            I have also provided the distribution of eyes for the various spot patterns as performed in this PMA study.  Only four eyes were treated with the 8-spot pattern, and a relatively similar number for the other three spot patterns.  Just keep the small number for the 8-spot pattern in mind when you are looking at the rest of the data tables.

            For the PMA cohort, given the relatively small magnitude of the intended correction, accuracy of MRSE is less than ideal.  As you can see from the first table, at six months 24 percent of subjects were undercorrected by more than 1.00 diopter.  This was 16 percent at 12 months.

            A significant proportion of undercorrection can be attributed to the 32-spot treatment pattern, as indicated on the second table where 59 percent of those eyes treated with 32 spots were undercorrected by more than a diopter at six months, and 63 percent at 12 months.  The numbers for the other three spot patterns are significantly lower.

            The sponsor, I just want to indicate, in a very recent submission reanalyzed the data, excluding those eyes treated with 32 spots, and the reanalysis indicates a significant reduction in the proportion undercorrected. 

            Whereas, 24 percent were undercorrected by more than a diopter at six months for the overall cohort, this dropped to eight percent when you exclude eyes with the 32-spot treatment.  It drops to nine percent at nine months and six percent at 12 months.  Similarly, zero percent of eyes were undercorrected by more than 2.00 diopters with the exclusion of the 32-spot treatment.

            Protocol predetermined target endpoints that were set by the sponsor were met or approximated for the overall cohort for accuracy.  However, Refractec performed statistical modeling to address the impact of age, baseline refractive status of emmetropia or hyperopia and spot pattern on their effectiveness outcomes.

            While age was not found to be predictive of outcome, the 32-spot pattern was associated with lower accuracy.  This was most clearly manifested in older patients and in hyperopic ones.  The effective of age was concluded to be confounded by spot pattern, in that older subjects would require larger near add, and these had the largest relative proportion treated with 32 spots.

            As you can see in the second table, there is a significant dropoff in accuracy observed for the 32-spot treatment group. 

            Again, the sponsor recently submitted data excluding those eyes treated with 32 spots and, as predicted, there was a significant improvement in the study outcome for accuracy.  They have provided all those slides in their presentation.  So I won't repeat them here, but I will just point out some of the differences.

            At six months this 49 percent increased to 64 percent within a half diopter, and at 12 months the improvement was not as significant, 61 percent improved to 66 percent.

            Within 1,00 diopter the 76 percent at six months improved to 92 percent, right here, and the 84 percent at 12 months improved to 94 percent within 1.00 diopter, excluding the eyes treated with 32 spots.

            I did a similar analysis here, just pointing out the differences when you stratify by age.  Relatively similar number of patients in the three bins, and you can see that there is a significant dropoff in the accuracy in the older patients, again attributed to the proportion that required the 32-spot treatment.

            I do want to point out that, of the 45 subjects treated in that age group, 41 of them did receive full correction for near.

            The sponsor indicates their believe that near uncorrected acuity that is achieved in the study is reasonable.  However, I do want to point out that 22 percent of subjects had final uncorrected vision of J5 or worse, both at 12 months and at six months.

            Of note, I also want to point out that there appears to be a trend of decreasing proportion of eyes with an outcome of J1 over time, 45 percent at six months, 34 percent at 12 months.

            Also here, you can see a significant dropoff in the uncorrected acuity for the 32-spot treatment pattern, 59 percent for the 24 spot and 32 percent for the 32 spot treatment, J1 or better.

            Since the 32-spot monovision can currently be done as an off-label procedure, and the sponsor indicates that that is very commonly done at this time, the sponsor has indicated their wish to provide labeling information to patients and physicians.

            Again, in their most recent submission they reanalyzed data excluding eyes treated with 32 spots, and the results indicate a moderate improvement in near uncorrected acuity outcomes, not as significant as the improvement in the accuracy outcomes.

            The number of eyes J1 or better improved at six months from 45 percent to 51 percent, and at 12 months from 34 percent to 39 percent.  The J3 or better outcome improved from 78 percent at six months to 82 percent, and improved from 78 percent at 12 months to 81 percent.

            Again, I provided a similar table here stratifying the outcome by age.  Again you can see a dropoff in the uncorrected near outcome with the older age group.

            The sponsor indicates their belief that, despite its limited effectiveness, the 32-spot treatment, quote, "still provides adequate levels of J3 or better."  Here you can see that that level is 66 percent at month six.

            FDA also looked at a comparison of effectiveness for the hyperopes and emmetropes, since this is the first time that this procedure would be used to treat emmetropic patients.  This stratification reveals that effectiveness endpoints are clearly dissimilar between the two cohorts.

            The sponsor attributes this difference to the disproportionate number of eyes in the hyperopic cohort that received a 32-spot treatment.  I indicated down here that 65 percent of hyperopes received 32 spots versus only eight percent of emmetropes, and that the remainder of the hyperopes all received 24-spot treatment.

            As you can see, there is a significantly lower accuracy for the hyperopes as compared to the emmetropes, and a somewhat lower J3 uncorrected near outcome, though not as significantly lower than the accuracy outcome.

            Regarding the need for spectacle use after the procedure, a large proportion of subjects who underwent the procedure are unable to read without glasses.  The study initial questionnaire that was given to all patients treated indicates, when asked the question "Do you wear spectacles of contact lenses for near in the treated eye for reading?" 40 percent of patients indicated yes at month six and 55 percent did so at month 12.

            The sponsor -- I just want to clarify -- also partway through the study, as they have indicated,  initiated a second questionnaire to more clearly elucidate the near tasks that patients required spectacles for.

            FDA noted several issues that raised question about the validity of drawing conclusions from this questionnaire.  Firstly, the small number of patients:  There were only 22 patients at month six and 16 at month 12.  Secondly, it is unclear.  One of the questions asked patients about whether they could see fine print, and it is not defined what fine print is, how this is different from a magazine print or a newspaper print.

            Also, it asks patients what can you see without glasses.  Again, "see" is not defined, and it is unclear to me whether this means see clearly, see blurry or what.  I think the potential for different interpretations is there.

            Finally, there were several concerns about recall bias, since the patients were not given the questionnaire preoperatively and had to recall what they were able to see before they had the procedure.  So I'll ask you to take those concerns into your deliberations regarding labeling.

            In their most recent response, again the sponsor stated that the goal of monovision is to improve functional near uncorrected vision at a patient's habitual near point demand, and that complete independence from spectacles is not a goal of this procedure and is unrealistic.

            It is important to note that excluding the 32 eye treatment cohort, the outcomes for this questionnaire did not change in a clinically significant fashion; whereas, 40 percent indicated that they wore spectacles for reading at six months and 55 percent at 12 months, excluding the eyes treated for 32 spots, 38 percent indicated that they wore spectacles for reading at month six and, similarly, 55 percent indicated that they wore spectacles for reading at month 12.

            I'll provide some brief information for cylinder outcomes, just for your information.  Induced cylinder at least 1.00 diopter, 11 percent at month six and nine percent at month 12.  Whereas, none of the eyes had an absolute magnitude of cylinder more than .75 diopter at baseline, 29 percent did so at month six, and 21 percent did have this level of cylinder at month 12.

            The sponsor was asked to perform comparative analyses to assess the clinical impact of induced cylinder, and these analyses appear to demonstrate no clinically significant compromise in near uncorrected acuity.

            I'll summarize here the FDA questions for the Panel deliberation today. The first question is:  Is the length of follow-up sufficient to demonstrate reasonable assurance of safety and effectiveness for the proposed indication?

            Number two:  Is the magnitude of induced cylinder and the associated effect on uncorrected acuity clinically acceptable for the proposed indication?

            Number three:  Is the rate of undercorrection more, more than a diopter, clinically acceptable?  Are there any subgroups of the PMA cohort for which this outcome is not acceptable.

            Number four:  Are the reduced accuracy to target refraction and poorer near uncorrected acuity outcomes, both monocular and binocular, reasonable to justify the risk of elective surgery with "temporary" results; and is the near uncorrected correction achieved clinically useful in the following groups:

            (a) Eyes treated with 32 spots?

            (b) Subjects greater than 55 years of age?

            (c)  Hyperopic patients?

            (d)  Any other populations or any other magnitude of refractive correction?

            If the answer to any of these is no, how do you suggest the indication and/or labeling be modified?

            Number five:  Do the spectacle dependence rates for near activities support approval for the requested indication in a presbyopic population?

            Number six:  Do the safety and effectiveness data support approval for the requested indication?  If not, what indication does the data support?

            Finally, I'd like to say that adequate physician and patient labeling are critically important to prevent unrealistic expectations.  Do you have any additional labeling recommendations, either descriptive text or data?  Should additional data tables be added to the physician and/or patient labeling?

            Finally, I just wish to point out three other short points regarding things that came up in the sponsor's presentation.

            The first is that reduced stereopsis is known to be an effect of monovision correction.  The sponsor claims from their study data that depth perception is unchanged from baseline.

            I just want you to note that this determination is based on a comparison to preoperative depth perception with contact lens monovision wear, not with non-monovision spectacles.

            The second comment I would like to make is that the sponsor was asked to perform a calculation to indicate in the labeling what percent of eyes retained their initial correction at one year.

            They performed it similarly to how they calculated it for their initial original PMA, and they concluded 90 percent retention at one year.  I just want to clarify that this calculation was defined as maintaining effect by comparing the six month's outcome to the 12 month outcome and calling any eye that retained within .50 diopter of the six-month outcome as maintaining initial effect.

            Finally -- sorry for this long winded presentation here -- I just want to indicate regarding subjective questionnaire that there were many subjective symptoms reported as, quote, "none" pre-op that significantly increased in the percentage of "none" post-op.  I hope I made that clear.

            A few of them were transient, such as gritty feeling, but many of them had long term changes in the reports of "none."  I will just briefly run through them.

            Light sensitivity, 81 percent of people reported no light sensitivity pre-op, whereas only 75 percent did at month 12.

            Dryness:  85 percent to 76 percent.

            Glare:  93 percent to 71 percent.

            Halos:  95 percent to 75 percent.

            Blurred vision:  79 to 68 percent.

            Double vision:  97 percent had none pre-op, whereas only 80 percent had none at month 12.

            Fluctuation in vision:  93 percent none pre-op, 68 percent none at month 12.

            Several different iterations of variation in vision, all with similar decreases and, interestingly, night vision driving problems, 84 percent had none pre-op, 81 percent had none at month twelve. 

            That concludes my presentation.

            CHAIRMAN WEISS:  Thank you very much.  If that concludes the FDA presentation, what we will do is break for lunch for exactly one hour.  Please be seated so we can be ready to begin at that moment.

            (Whereupon, the foregoing matter went off the record at 12:07 p.m.)

                       - - -

















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

                                  Time:  1:12 p.m.

            CHAIRMAN WEISS:  I'll let members of the panel now that there is a sheet going around that you might want to sign concerning various times you would like to leave here for planes.  We are going to be starting with FDA questions, if you want to be seated there, and if you need to hook up your computer for anything, it's ready to roll.  So we have countdown and blastoff in three minutes.

            I think we will open the afternoon session and start with Committee deliberations and Panel questions for the FDA.  I would ask the members of the Panel to keep their questions directed to things that are specifically relevant to the review process as opposed to questions that are not relevant.

            I know Dr. Grimmett had some questions.  So we can -- No?  Well, I can state it.  This is sort of like inquiring minds want to know.  I mean, inquiring minds of the Panel would like to know what the dropoff rate of the treatment is at various time points in order to have an idea of what the effectivity of this treatment is, especially in view of the fact that, talking about plus and minus one is fairly irrelevant when you are treating a +1.00.

            Some of us might even have an effective treatment while we are sitting here, because we are within "1.00, although we actually don't even have to have the treatment done.

            So in any case, would you be able to address that?

            DR. BERMAN:  I'll try.  Basically, as I had pointed out in my short presentation, you know, based on the limited magnitude of treatment, FDA felt that the accuracy of the correction was less than idea. 

            One of the deficiencies that was communicated to the sponsor was a request to perform an analysis to indicate in the labeling or to provide in the labeling a patient information about how much correction can be anticipated at the one-year time point, since that is the extent to which this PMA has data submitted at this time.

            Only about a week or two ago, we received a response.  If the Panel feels the response is adequate as I presented at the very end of my presentation when I described how they did the six-month to the 12-month comparison with the definition of maintaining effect being plus or minus a half-diopter -- If you feel that is acceptable, then there is nothing more to say.  However, if the Panel -- and, you know, FDA will have their own issues that we will take up with the sponsor as well afterwards, but today we are here to hear the Panel's clinical judgment.

            So if the Panel decides that that is not acceptable and they want additional description or an additional analysis or type of calculation to be performed, that can be made a condition of approval or a labeling recommendation or however you would like to word that.

            CHAIRMAN WEISS:  They had submitted two-year data as well, 24-month data.  I don't recall seeing that?  Did I see that?

            DR. BERMAN:  They don't have 24-month data.

            DR. BEERS:  The 24-month data -- Wasn't it referring to the original PMA that they recently submitted?

            DR. BERMAN:  Correct.  Right.  The original PMA.  The only reason I brought that up was to indicate that they have indicated to us their willingness -- Although they only have six and 12 month data, that they have indicated their willingness to update this labeling with 24-month data when it becomes available, just as they did for the original PMA.  And they did do that.

            DR. GRIMMETT:  I am strongly in favor of that, because that is a relevant issue, even though it comes from a different PMA.  I would be specifically interested in the graph of, on the X axis, time and, on the Y axis, MRSE and diopters at every time point.  That way, the reader can interpret what he wants to know, not only six months to 12, but you can analyze anything you want, Day One to three months.  You can see how it levels off and see how it asymptotes. 

            DR. BERMAN:  And would you want just one line or -- You might want to discuss this, whether you would want it differentiated between emmetropes and hyperopes or different cohorts or what have you.

            CHAIRMAN WEISS:  Any other -- Are you satisfied?  Any other questions from Panel to FDA?  Thank you.

            We will then move on to the primary panel reviewers.  Dr. Huang is first, followed by Dr. McMahon.

            DR. HUANG:  Good afternoon.  Dr. Weiss and fellow Panel members, I would like to present my review regarding this PMA P010018/Supplement 5.

            First, I would like to thank my fellow reviewers, Dr. Berman and Dr. McMahon, for their detailed review.  That made my job much easier.

            As we all know that this device has previously received approval for hyperopic indications in April 2002.  However, the off-label use of the conductive keratoplasty for astigmatism as well as the monovision has been prevalent.  Yet prior to submission, the efficacy and safety of this device for monovision remains unclear.

            I would like to commend sponsor for their willingness to subject their data for our scrutiny.

            First, I would like to present the safety issue.  As we heard this morning, a cohort of 150 patients with 188 eyes were presented, of which 150 eyes were treated for near and 38 eyes previously had been treated for distance.

            The safety profile is similar to the hyperopic study and raised no additional concern.  However, the patients were treated with 24 or less spots.  Greater than 90 percent of them were within 1.00 diopter.  Conversely, when the patient was treated with 32 spots, only 45 percent or less than 45 percent of the patients -- they were only within 1.00 diopter.

            In this group of grossly undercorrected patients, there is a lack of information regarding future re-treatment or management options for undercorrection.  Of note, 34 percent of the patients with loss of one line best spectacle corrected visual acuity at distance at one month -- This is an alarming portion of the patients that with initial post-operative visual compromise.

            The question related to their depth perception and quality of life remain unanswered in this submission.

            There is a significant number of protocol deviations, and some of it will be addressed.  Dr. Mathers' question earlier today might be able to get some insight from here.

            One site had 16 patients with additional intraoperative spots to decrease the CK-induced astigmatism, of which 11 were used for near vision.  As shown in this stratification, one patients in the 24-spot treatment group out of 51 had additional enhancement or treatment to reduce astigmatism.  Ten of these patients in the -- In 52 of the patients treated with 32 spots had to use this -- ten patients had intraoperative spots to decrease the astigmatism.

            It is very perplexing to this reviewer that ten of these patients were originally excluded in the initial analysis.  However, in their amendment submitted in January, they were included in the efficacy study.  Furthermore, there were only four patients treated with eight spots.

            When we look at the safety issue, we also like to look at the clinical efficacy.  First, there are two parameters for this reviewer to rely upon.  One is the accuracy to the refractive targets.

            As we all know, FDA has provided predictability guidance for myopic refractive lasers in which 75 percent of the patients is expected to be within 1 diopter of target.  Fifty percent of the patients is expected to be within .5 diopter of target, and I think this is used by the reviewer, used by the sponsor.

            Second, uncorrected near visual acuity should be our gold standard, since this is the treatment for monovision.  Unfortunately, there is no established FDA guidance for this parameter.  However, the sponsor willingly submitted a criterion.

            They indicated 75 percent of the patients with uncorrected visual acuity at distance should be J3 or better.  As a reviewer, as a potential consumer, I would like to propose that 75 percent of the patients need to have a near uncorrected visual acuity of J3 or better.

            I also would like to -- This is for their functional vision.  I will also like to propose 50 percent of the patients ideally should have an uncorrected visual acuity at near at J1 or better -- that is a 20/25 equivalent -- for their reading.

            Upon stratification of their initial submitted data, there were 24 percent of the patients was grossly undercorrected by greater than 1 diopter at six months.  Sixteen percent of them were undercorrected by 12 months.

            When we stratified them by spot sites, the amount of treatment, 59 percent of the patients probably was grossly undercorrected at six months in the 32-spot treatment group, and this incidence increased to 63 percent in 12 months.

            Looking at those ten patients excluded and then later included in the study, potentially those were the patients -- they had a higher amount of induced astigmatism and, therefore, that they were excluded from the study.  So if we were including those patients to review the entire aspect of the treatment parameters, the 32-spot certainly has a significant amount of induced astigmatism as well as reduced efficacy.

            Again, you know, if we stratify this data by the sponsor as well as by Dr. Berman, we can see that patients, when treated with 24 spots or less at any given point, that they had less than -- within 5 diopters -- half a diopter of target is about 66 percent, and the patients within 1 diopter of treatment target is about 90 percent in the 24 spots or less.  Both of these findings met FDA guidance.  However, if you look at the 32-spot treatment, only about 25 percent of the patients are within 1 diopter of treatment at six months, nine months and 12 month spots.

            The incidence further decreased to 45 percent of the patients that were only within 1 diopter of target, and that incidence further decreased toward 12 months.

            So if we would look at the -- stratified within 1 diopter of target at six months by the age group, you can see the patients with 16 and 24 spot treatment, that regardless of the age group, they were always in FDA guidelines.  Greater than 75 percent of the patients met the criteria.  However, 32-spot treatment is not the case.

            Thirty percent to 50 percent of the patients actually is only within 1 diopter.  So the majority of the patients, greater than half of the patients, were outside the 1 diopter range with 32 spots.  So this did not meet the FDA criteria.

            So if we -- Finally, using the near vision as our gold standard for the treatment, if the patient can see J3 or better vision, 80 to 85 percent of the patients with 24 spots or less treatment can achieve that goal, which meets the FDA guidance.  However, if you use the 32 spots -- I'm sorry, which meets the sponsor's guidance.  If you use the 32-spot treatment, none of it exceeds 70 percent.  So it did not even meet the sponsor's criterion.

            For the consumer or for the reviewer's criteria, only 24 spots at six months reached 51 percent.  So that is the only treatment, to me, that is satisfactory.

            In summary, I think the reviewer's data has met FDA guidance regarding the safety, with no patient loss of best spectacle corrected visual acuity greater than two lines.  The efficacy, however, is only temporary, and this monovision is not reversible.

            The data has indicated that 40 percent of the patients resume full time reading aids at six months, and 55 percent of the patients resume full time reading aids at 12 months, and the 32-spot treatment failed to meet FDA guidance and sponsor's goal.

            I took a look at the risk/benefit ratio.  As a consumer, as a reviewer, I certainly would like to look at cost versus benefit ratio.  For emmetropic hyperope -- I'm sorry, for emmetropic presbyope, I would like to think that I can use the over-the-counter readers which cost about $15 per pair. 

            If I have to buy three pairs a year, it is going to cost me about $45, and that would probably last me for a year, because my presbyopic change may shift.  However, with the monovision by conductive keratoplasty, no spectacle correction for one year -- that will cost me at least $1500. 

            For me, the best analogy for this kind of expanded indication is probably to eyeliner versus eyelid tattooing. 

            This reviewer also has a great reservation and concern regarding the premature advertisement of yet unapproved indications that I just received in my office, that there is a training course for people to sign up since January 17 to this kind of procedure for their patients.

            Granted, this has been indicated -- The procedure has been used for off-label, but I think it is somewhat disrespectful to the FDA to have this premature advertisement.

            So the recommendation by this reviewer, based upon the limited efficacy and the safety, I would like to urge the Panel members to consider restriction of this indication to induction of monovision via spherical hyperopic treatment up to 2.25 diopters using 24 spot sites.  This is in contrast to the previous approved indication, up to 3.00 diopters and 32 spots in the non-dominant eye.

            Also, sufficient labels should be provided regarding a warning against 8-spot treatment.  Thank you very much for your attention.

            CHAIRMAN WEISS:  Thank you very much, Dr. Huang.  I guess I'll stick to my eyeliner.

            Dr. McMahon.

            DR. McMAHON:  Thank you.  I am going to sound like a broken record from the previous presentation.

            First of all, I would like to thank the sponsor for presenting a nice, clean study presented in clear, understandable and organized format.  IT makes it so much easier to review and get to the heart of the issue in terms of safety and efficacy when these PMAs are presented in this format, and I want to thank them personally for that, and particularly since it was over the holidays that we had to read this.  The fact that I didn't have to agonize over the PMA like the folks from yesterday, I had an easier job. 

            A few comments:  Accountability was excellent.  This has been commented on.  One issue is enrollment was highly skewed toward one site.  Even  though GEE modeling indicate this is not statistically biasing, the numbers at the other sites were low enough that I have some questionable faith in that statistical modeling.

            As you know, there are lies and lies and bigger lies where there are statistics.  So I am wondering if this might be an issue.  However, I have no evidence to go beyond that.

            The subjects were almost exclusively white.  This is a trend in refractive surgery, and mostly female.  These numbers are almost identical to other studies.

            The protocol deviations were minor and small in number, and of not great importance to me.

            From a safety perspective, let's deal with this first.  The key issue has to do with induced cylinder.  As you will recall, the target amount of induced cylinder is less than or equal to five percent of the cohort, would be 2.00 diopters or greater, and none of the cases in this particular PMA demonstrated that.

            Of some concern is the fact that there are, at months one, six, and 12 months, 28 percent, 11 percent and 9 percent had greater than 1 diopter of induced astigmatism.  However, the mean cylinder at baseline was a third of a diopter. 

            It increased a little bit to a little over half-diopter at six months, and dropped another small percentage at 12 months, but this is relatively small compared to the mean baseline cylinder.  Collectively, this does not appear to be overly worrisome, to me.  However, for those with greater than 1 diopter of induced cylinder, 12 to 14 percent of those lost one line of best corrected spectacle acuity at six months and 12 months respectively. 

            The number of absolute patients who had this type of loss is relatively small, but I do believe this is worth putting in the labeling, and the sponsor agrees to this.

            Best corrected acuity or distance acuity:  The target was less than one percent of the cohort having acuity worse than 20/40, and no eyes exceeded this criteria.  Very few eyes had a loss of greater or equal to 2 diopters of best corrected acuity at either far or near, indicating that this, from an acuity perspective, is a safe procedure.

            No eyes had greater than 25 millimeters of mercury of increase in IOP.  Corneal haze and adverse events were not impressive.  Complication rate at eight percent seems high, but the type of complications that they had actually were quite small and, in fact, if you take out the viral conjunctivitis, the number almost drops in half.

            Therefore, from a safety perspective, I believe that CK for the inducement of near correction appears to be reasonably safe.  Two-year follow-up data on induced cylinder and its effect on best corrected acuity seems warranted and, as I understand it, the sponsor is willing to provide that.

            Efficacy is a little different story, as you have been hearing thus far.  You will recall, the FDA guidance for refractive surgery procedures in October of 1996 specified the target rates for end results, since this is for distance correction of the design, 75 percent within plus or minus one diopter and half of those cases being within plus or minus a half.

            Sponsor and FDA agree that this should be employed toward intended corrections.  An important review in intended corrections is the total amount of correction; whereas, the sponsor's indication is toward achieving between up to one to two diopters of resultant myopia.

            So patients who are hyperopic by one diopter who you want to achieve a two diopter presbyopic correction needs three diopters of intended correction. 

            For treated eyes for near, for all eyes treated completely for near, the number of patients within plus or minus one diopters can be displayed on the screen as a function of the number of the spots applied.  The bold areas stipulate those individuals that don't meet this criteria.

            As has been mentioned, the criteria for plus or minus one diopter for a total intended correction of three diopters is wide enough to drive a truck through, and in this circumstance with the 32-spot circumstance the treatment does not meet that for any time course.

            For those to have a tighter criteria, which I think is a much more reasonable benchmark to look at a plus or minus a half-diopter -- For those between .75 diopters of correction and 2.25, all those eyes met that except for the very low correction numbers at nine and 12 months, and all of the 32-spot corrections.  It is important to realize, though, that there were less than a handful of individuals who had eight spots. 

            Plotted otherwise, if you put both of these guys for emmetropic eyes and exclude the hyperopic eyes, all of the individuals in this cohort met the benchmark of plus and minus 1 for all time periods, as did all those for plus and minus 1/2 for emmetropic eyes.

            It is important to realize, however, though, that the number of spots that are applied is directly related to the native emmetropic or hyperopic correction.  In fact, the vast majority of the patients who were emmetropes were treated with 16 and 24 spots.

            If you moved up to the 32-spot character, 6, 4 and emmetrope, you had actually only a third of individuals within plus or minus 1, again a very wide benchmark to shoot for.

            If you look at the half-diopter, plus or minus 1/2 intended correction, again you have individuals between 8 spots and 24 spots, all meeting this benchmark, but again only a third of those individuals who were treated with 32 spots, but again the number here is quite small.

            The story is a little different for hyperopic eyes.  If you look at the plus and minus 1/2 and plus and minus 1, virtually none of these eyes met either one of these benchmarks, if you are a hyperope to start with.

            All the hyperopic eyes were treated with either 24 spots or 32 spots, and the reason that the hyperopes don't make it is because the 32 spots have a very poor outcome.   For those individuals who were hyperopic who had 24 spots, 94 percent were within the plus or minus 1 characteristic, and 67 percent within the plus or minus 1/2.  Again, the 32 spot group performed poorly in terms of accuracy.

            The near visual acuity is an important adjunct and is sort of the baseline of the benchmark that we are eventually going to have to come to deal with here, because this is what the procedure is for.  Sponsor and FDA converged on 75 percent seeing J3 or better at near, and with all eyes included you can see that individuals met this characteristic as an aggregate, though the number of those individuals as you move to smaller font sizes drops off relatively remarkably.

            Now if you take out the 32 spot group, that number improves about nine percentage points.  So that now you get into the upper 80s and low 90s for individuals seeing J3 or better if you take out the 32-spot group, and even at the J1 level improve significantly except at the 12 month interval.

            It is quite evident that there is a decay in response as you deal with finer and finer vision, and that is most likely because at the J1 level you are much closer to threshold.  So you are failing off a threshold; whereas, when you are dealing with a patient who has J3 or better who might have a post-operative best acuity of J2, you've got a little slot to be able to withstand decay in treatment.

            So actually looking at the finer vision acuity measures, I think, is a better indicator of what is actually happening relative to stability of effect.

            A few comments:  There are very few eyes treated with 8 spots, and sponsor acknowledges this and it is actually small enough that you can't analyze this in amy meaningful manner.  Therefore, it raises the question of should the application of 8 spots then be removed from the indication for treatment.

            The intended treatment range, as I mentioned, is between .75 and 3.00 diopters, but the target ranges were virtually almost as large as the treatment range itself.  Is this a reasonable target range for this or procedures similar in the future seeking relatively small corrections?  I submit to you that it is not.

            CK for near is not very effective, in my view, when 32-spot treatment regimen is used.  The near vision procedure is more effective, therefore, in emmetropes, because the intended correction range is more suitable for emmetropes than hyperopes, and at no interval did hyperopics meet the plus and minus 75 target criteria that was agreed upon.

            Patient satisfaction:  The frequency of change in symptoms -- and I am going to look at those for the worst rather than those for the better, because from our point of view of safety and efficacy, we are looking for the worst side rather than the better side. 

            Symptoms do appear to persist and, in some cases, increase over time.  I reference you to my page 6 of my report toward that side.  However, patients have asked about the terms in terms of quality of improvement, not given the opportunity to say that things are worse, by the way -- it's basically same to better.  Thirty-seven percent demonstrated extreme improvement down to moderate improvement of 16 percent. 

            If you exclude the 32-spot group, actually, these numbers change very little, which I found quite remarkable.  Seventy-nine to 84 percent, depending on the time interval, report being satisfied or very satisfied, and this actually happens to trend very nicely with those percentage of patients who see J3 or better.  Whether that is a statistically significant correlation, I can't say, but it visually is.

            The sponsor in their latest comments and review -- which, by the way, thank you very much for providing data relative to those with 8, 16 and 24 spots, because I think that is where the real story is for this procedure.  But the sponsor commented in their response of January indicating that hyperopes and, to a lesser extent, I'll posit, presbyopes will appreciate virtually any improvement in their uncorrected vision. 

            I think that this is important to recognize, in that the more desperate the group, the more likely it is to satisfy them, and I don't think we should overweight the patient satisfaction results because of that.  So in that circumstance you could have a procedure that has a relatively modest treatment effect, and you could generate a fairly high satisfaction rate.

            Spectacle dependence:  Now this is the one that diverges the greatest, and I have not been able to come to resolution on this.  Keep in mind, these are individuals that passed a trial of monovision for suitability and tolerance, and that the number of individuals who use spectacles, whether they have all treatment spots included or those excluded where the 32-spot treatment is excluded, are virtually identical, and virtually half the patients end up using glasses for reading.  I don't have an answer as to why that would be the case.

            One comment that I think is important for all of us to realize is that threshold acuities near the target size that you want to look at is a very poor benchmark to use to measure near vision performance.  We don't read at threshold.

            You need to have the target that you are looking at to read comfortably and for long periods of time at least two steps larger than your threshold levels.  That is well understood in the clinical domain.

            Now just like you don't want to use all of your accommodation to be able to read comfortably, you don't want to be operating at a threshold level.  So we need to be very careful about establishing what is a reasonable level for near vision for reading performance, and Dr. Huang's notion of adapting some of the distance correction things to multiple steps, I think, actually is a very valid one.  The notion of having 50 percent of the group at J2 or better, I think, is actually a very good idea.

            Conclusions:  CK for near appears to be reasonably safe, though I think longer term follow-up concerning loss of best corrected spectral acuity from induced cylinders and the symptoms that have been demonstrated to increase over time seems warranted.  I understand that the sponsor is willing to do this.

            CK as a procedure for near is modestly effective at best.  In my view, the 32-spot treatment is not effective and should be excluded from approval for the near indication.

            The treatment has not been shown to be effective for less than 1.00 diopter of intended effect or 8 spots either, because there is not enough data here to make that judgment.  Therefore, the effective range that potentially could be considered, in my view, is between 2.00 diopter and 2.25 diopter of intended effect. 

            This will have the result of basically eliminating many myopes from the group -- or my hyperopes, excuse me, from the applicable pool of subjects.

            There also is no data that supports efficacy for re-treatment or intraoperative placement of additional spots, and the sponsor acknowledges that.  That is important to make sure that is clearly labeled in patient labeling -- in physician labeling.

            One additional comment, and Dr. Huang has addressed this to some degree.  It doesn't apply to this particular sponsor, but I think for future applications -- there are more of these near things coming.  For future device applications, I would suggest that FDA should consider dropping the plus or minus 1.00 target for accuracy procedures in those that are seeking less than 4.00 to 5.00 diopters of treatment effect, and increase the target rate for plus and minus .50 to .70 percent of intended treatments, and potentially adding numbers similar to the ones that Dr. Huang specified.

            Thank you for your attention.

            CHAIRMAN WEISS:  Thank you very much.  I want to thank both of the Panel reviewers.  I would like the sponsor perhaps, if they have the information, to answer the questions that Dr. Mathers and Dr. Bandeen-Roche had posed in the morning, if they could just come forward. 

            I will let the Panel know that this is not the time for any other questions.  This is just to answer the two that we had to get further data on before we go to discussion of the FDA questions to the Panel.

            DR. GORDON-MEYER:  Yes.  Just briefly, we have provided the cross-tabulation or a cross-tabulation to Dr. Bandeen-Roche.  I was not sure if that is what she is looking for but, if not, we can revise.

            We also looked at uncorrected visual acuity over time for the eyes that had pre-operative J5 and J3.  This was in response to Dr. Macsai's question, the question being how did they do, and did they experience improvement.

            At three months, six months, nine months and 12 months, they were generally 90, 95 percent, 91 percent, J2 or J1.  So there was improvement to a higher level of visual acuity than they started with.  In fact, all of them did have that level of improvement.  So we hadn't looked at that before.  That was a good question.

            I'm thinking what else.  Was there another question?

            CHAIRMAN WEISS:  I think those were the only two.  Your set, Dr. Smith.  Dr. Mathers, are you set as well?

            DR. GORDON-MEYER:  Dr. Mathers, I think, we had responded to before, that we didn't see.  And I think Dr. McMahon spoke to no difference or no effect of 32 spots on some of the other parameters.

            CHAIRMAN WEISS:  Great.  Thank you so much.

            DR. GORDON-MEYER:  Thank you.

            CHAIRMAN WEISS:  I would ask the FDA to be so kind as to show us their individual questions to allow us to begin the Panel discussion.

            The first question that I am going to pose to the Panel is:  Is the length of follow-up sufficient to demonstrate reasonable assurance of safety and efficacy for the requested indication?

            Why don't we go around, and you can tell us yes or no or if you have anything else you want to say that is applicable and brief.  Dr. Macsai:  Question Number 1:  Is the length of follow-up sufficient to demonstrate reasonable assurance of safety and efficacy for the requested indication?

            We are specifically talking about the length of follow-up, not necessarily how you might want to change the indication.  Am I correct on that, because otherwise we could get involved in -- and I am just posing this to the agency.

            The first question, you just want us to talk about the length of follow-up as opposed to if we wanted to change how the requested indication was phrased?  Yes.  So number 1 is only talking about the length of follow-up?

            DR. BERMAN:  Yes, but if you have anything you want to add, that's great.  I just wanted basically the -- get a sense that the panel was satisfied with the length of follow-up.

            CHAIRMAN WEISS:  We are just going to talk about length of follow-up, because Sally has pointed out to me question number 6 talks about the indication and, if you don't agree with the indication, what indication would you prefer.  So we are just going to talk about length of follow-up.  Are you satisfied with the length of follow-up?  Yes or no, or what would you like?

            DR. MACSAI:  It appears safe, but I can't tell if it is effective yet.

            CHAIRMAN WEISS:  Fine.  So but the length of follow-up is not an issue for you?  That's a good enough answer for me.

            DR. MACSAI:  No.  I don't know.

            DR. McMAHON:  Could I ask a pointed question?

            CHAIRMAN WEISS:  I don't know is an answer as well.  We'll increase it to three:  Yes, no or I don't know.

            DR. McMAHON:  Jayne, question about your question.

            CHAIRMAN WEISS:  Yes?

            DR. McMAHON:  Length of follow-up with the current data or the willingness to provide two-year data?

            CHAIRMAN WEISS:  You can ask for the willingness.  I think what this question is really trying to address:  Do you want two-year data?  Do you want three-year data?  Are you happy with one-year data to make any assessments that you want to make? 

            Of course, you can always, when we get to question 6, voice the opinion that you want a different indication.  So I'd like to sort of stay focused on a time period for this question. 

            Dr. Schein?

            DR. SCHEIN:  Yes.

            CHAIRMAN WEISS:  Yes.  Thank you.  Dr. Mathers?

            DR. MATHERS:  Safety is fine.  We can't tell about longer duration. So I would like to know more about longer duration, but I think there are ways we can do it.

            CHAIRMAN WEISS:  So that sounds like a maybe.

            DR. MATHERS:  Maybe.

            CHAIRMAN WEISS:  Maybe.  Dr. Casey.

            DR. CASEY:  I don't know.

            CHAIRMAN WEISS:  I don't know.  Dr. Grimmett.

            DR. GRIMMETT:  Dr. Grimmett.  The sponsor, I believe, has agreed to provide 24-month data on the original PMA in the treatment of hyperopes.  That would factor into my decision about how much regression actually takes place, and my probable answer is yes, there is sufficient follow-up.  But it sounds like the sponsor is willing to provide longer term data to help us as well.

            CHAIRMAN WEISS:  So, basically, if you want two-year data, you can get it from one of the other PMAs rather than this one, and that would provide you with more information and perhaps enough information.

            DR. GRIMMETT:  Yes.  And even though it is a different PMA, I believe it is relevant.

            CHAIRMAN WEISS:  Thank you.  Dr. Bradley.

            DR. BRADLEY:  Simple answer, yes.  Basically, since the indication is for temporary treatment, I think one-year data is sufficient.  I think it is in the sponsor's interest to provide longer term data rather than rely on anecdotal reports of the surgeons regarding the stability and longevity of the treatment.

            CHAIRMAN WEISS:  Dr. Van Meter.

            DR. VAN METER:  Yes.

            CHAIRMAN WEISS:  Dr. Coleman.

            DR. COLEMAN:  Yes.

            CHAIRMAN WEISS:  Dr. McMahon.

            DR. McMAHON:  I echo Dr. Bradley's comment.

            CHAIRMAN WEISS:  Dr. >Smith.

            DR. SMITH:  Yes.

            CHAIRMAN WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  I echo Dr. Grimmett's comment, I guess, with the qualifier that I would really sort of like to see the complete one-year data to feed into the labeling.

            CHAIRMAN WEISS:  The complete one-year data is data that the sponsor has that they have not given to FDA or more data?

            DR. BANDEEN-ROCHE:  Well, my understanding is it doesn't yet exist.  I mean that it is still accruing.  Correct me if I am wrong.

            CHAIRMAN WEISS:  Dr. Huang.

            DR. HUANG:  There is a very limited number of the patients at 12 months.  So I would like to -- The answer to your question is yes, but I would like to see post-market surveillance for up to another year.

            CHAIRMAN WEISS:  Dr. Rosenthal.

            DR. ROSENTHAL:  Just a comment, that the sponsor is obliged every three months, I think, to update the PMA with data that comes in.  I mean, I don't know how much of the one-year data will be available over the next few months.  I'm not sure when they --

            DR. GORDON-MEYER:  Can I speak to that?

            DR. ROSENTHAL:  Yes.

            CHAIRMAN WEISS:  Yes.

            DR. GORDON-MEYER:  Okay.  Because of the relatively short time we have to respond between getting questions and the Panel, we focused on that, and we will provide a 90-day update with considerably additional 12-month data. 

            We also are organizing, and we will show you as we close, the very high level of consistency.  We have an n of 320 from the original PMA hyperopia population where there is still excellent accountability at 24 months. 

            That data is in the public domain in the physician labeling for hyperopia, and the stability to date in the current population is exactly the same as the stability in that population.  But we, of course, don't have the 12 to 24, but the pattern is extremely consistent between the populations, as you would expect with the same procedure.

            We will provide ongoing data.  The study is a 24-month study.  It will be completed, and the information submitted to FDA over time.

            CHAIRMAN WEISS:  So from what I hear from members of the Panel on question number 1, you will be able to address perhaps all of the concerns in that there will be further data coming from this PMA, that there will be two-year data coming from a prior PMA, if desired, and rather than doing a post-market, there will two years data coming from this PMA.

            So I would think -- and if anyone disagrees, please interrupt me, but that would address all the concerns from question 1.  Dr. Bradley?

            DR. BRADLEY:  Yes.  I think the sponsor wishes to argue equivalence with the earlier PMA data for stability and longevity of the effect.  A general equivalence analysis should be done and provided to the FDA to substantiate those comparisons.

            DR. GORDON-MEYER:  We would be glad to do that.  To date, the data look similar.

            CHAIRMAN WEISS:  And at this point, I would prefer not to have any dialogue, ongoing dialogue.  I appreciate your answering those questions, though.  Thank you.

            Question number 2:  Is the magnitude of induced cylinder and axis shift, and the associated effect on uncorrected visual acuity, clinically acceptable for the requested indication?

            Well, I guess, we will be doing this verbally as opposed to slide-wise, but -- Okay.

            Question 2 -- We just did question 1.  Question 2.  Okay.  So we are talking about the cylinder and basically, are you concerned about this issue?  Dr. Macsai?

            DR. MACSAI:  I'm confused why it doesn't interfere with the vision more, but the answer is yes.

            CHAIRMAN WEISS:  Dr. Schein.

            DR. SCHEIN:  Yes.

            CHAIRMAN WEISS:  Dr. Mathers.

            DR. MATHERS:  Yes.

            CHAIRMAN WEISS:  Dr. Casey.

            DR. CASEY:  Yes.

            DR. GRIMMETT:  Yes.

            CHAIRMAN WEISS:  Dr. Grimmett.  That was Dr. Grimmett.  Dr. Bradley.

            DR. BRADLEY:  Since my read of the table showed that the presence of uncorrected astigmatism improved near acuity, I would have to say yes.

            CHAIRMAN WEISS:  So then you should ask your doctor for some of that.  Dr. Van Meter.

            DR. VAN METER:  Yes.  I think the induction of irregular astigmatism is probably due to centration on the cornea, and this is a physician issue that we can discuss in labeling.

            CHAIRMAN WEISS:  Okay.  Dr. Coleman.

            DR. COLEMAN:  Yes.

            CHAIRMAN WEISS:  Dr. McMahon.

            DR. McMAHON:  Since two-year data is going to be provided, yes.

            CHAIRMAN WEISS:  Dr. Smith?

            DR. SMITH:  Yes.

            CHAIRMAN WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  I defer to my clinical colleagues.

            CHAIRMAN WEISS:  Dr. Huang.

            DR. HUANG:  Yes.

            CHAIRMAN WEISS:  So agency, there do not appear to be any concerns about the magnitude of induced cylinder and axis shift.

            Question 3:  Is the rate of undercorrection, greater than 1 diopter, clinically acceptable?  Why don't we just answer that one. 

            Dr. Huang, is the rate of undercorrection of greater than a diopter clinically acceptable?

            DR. HUANG:  No.

            CHAIRMAN WEISS:  No?  Dr. Bandeen-Roche?

            DR. BANDEEN-ROCHE:  Same.  Defer to my clinical colleagues.

            CHAIRMAN WEISS:  Dr. Smith.

            DR. SMITH:  No.

            CHAIRMAN WEISS:  Dr. McMahon.

            DR. McMAHON: No.

            CHAIRMAN WEISS:  Dr. Coleman.

            DR. COLEMAN:  No.

            CHAIRMAN WEISS:  Dr. Van Meter.

            DR. VAN METER:  No.

            CHAIRMAN WEISS:  Dr. Bradley.

            DR. BRADLEY:  No.

            CHAIRMAN WEISS:  Dr.  Grimmett.

            DR. GRIMMETT:  No.

            CHAIRMAN WEISS:  Dr. Casey.

            DR. CASEY:  No.

            CHAIRMAN WEISS:  Dr. Mathers.

            DR. MATHERS:  Yes, I think it is.

            CHAIRMAN WEISS:  It is?  Okay.  Dr. Schein.

            DR. SCHEIN:  Yes.

            CHAIRMAN WEISS:  Dr. Macsai.

            DR. MACSAI:  No.

            CHAIRMAN WEISS:  So as a poll, the majority feel that it is clinically --

            DR. BRADLEY:  I would like to change my poll to yes.

            CHAIRMAN WEISS:  So the majority feel that it is not acceptable.  Most feel that it is not acceptable.  So we will go on to question, Part B.

            Are there subgroups of the PMA cohort for which this outcome is not acceptable?

            So in other words, if we are talking about the 8, the 16, the 32, etcetera, are there some subgroups that are not acceptable, making the rest of the subgroups acceptable?  Dr. Macsai?

            DR. MACSAI:  Thirty-two spots hyperopes.

            CHAIRMAN WEISS:  Is unacceptable?

            DR. MACSAI:  Right.  Correct.

            CHAIRMAN WEISS:  Dr. Mathers.  Dr. Schein

            DR. SCHEIN:  No.

            CHAIRMAN WEISS:  So you feel that all of the subgroups are clinically acceptable?

            DR. SCHEIN:  Yes.

            CHAIRMAN WEISS:  Dr. Mathers.

            DR. MATHERS:  Yes, they are all acceptable, including the 32.

            CHAIRMAN WEISS:  Dr. Casey.

            DR. CASEY:  I feel that the 32 is not acceptable.

            CHAIRMAN WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  I feel that 32-spot is not acceptable.

            CHAIRMAN WEISS:  Dr. Bradley.

            DR. BRADLEY:  I also agree that 32-spot is not acceptable.

            CHAIRMAN WEISS:  For someone who is name challenged, this is really taxing.  Dr. Van Meter.

            DR. VAN METER:  Thirty-two spots is not acceptable.

            CHAIRMAN WEISS:  Dr. Coleman.

            DR. COLEMAN:  The same.

            CHAIRMAN WEISS:  And Dr. McMahon.

            DR. McMAHON:  Thirty-two spot is not acceptable.  Eight spot, but not enough data to analyze.

            CHAIRMAN WEISS:  Dr. Smith. 

            DR. SMITH:  I agree with Dr. McMahon.

            CHAIRMAN WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  Also agree with Dr. McMahon.

            CHAIRMAN WEISS:  Dr. Huang.

            DR. HUANG:  I agree with Dr. McMahon.

            CHAIRMAN WEISS:  So the consensus that I hear is the majority do not feel the efficacy for the 32-spot is acceptable, and would like more data in order to make a determination about the 8-spot, but the other two spot sizes are clinically acceptable.

            Okay, moving on to Number 4:  Are the reduced accuracy to target refraction and poorer near uncorrected visual acuity outcomes, monocular and binocular, reasonable to justify the risk of elective surgery with "temporary" results? 

            Should we break this up, FDA, into two questions? 

            DR. MATHERS:  There are four questions.

            CHAIRMAN WEISS:  Well, no, but the preface is -- We will keep it how you have that.

            And is the near uncorrected visual acuity correction achieved clinically useful in the following groups? 

            DR. GRIMMETT:  I don't understand the question.

            CHAIRMAN WEISS:  Can you clarify for the simple minded among us?

            DR. BERMAN:  Yes, I will clarify.  I'm not looking for answers to every bullet there.  I am looking for your overall clinical judgment as to the approvability for each of these cohorts, basically, and I am bringing up some of the things that you may want to take into consideration in making your decision about A, B, C and D.

            CHAIRMAN WEISS:  Well, I think the Panel has already answered that in the majority, they do not think that it is justifiable because of clinical efficacy for the 32-spot pattern.  I think that is what I just heard.

            I think what I just heard, at least for a good proportion -- and I don't know if it is the majority, and that could be coming up in a labeling unless, Ralph, you feel we should go around and poll -- for 8 spots, there is data that is requested by a significant minority of, if not majority, of the Panel.

            For subjects greater than 55 years of age and for hyperopic patients, I believe you have already showed us that that has less clinical efficacy, but that is associated with the fact that they had more people with 32-spot pattern.  So I'm not sure that we need to discuss that unless there is anyone on Panel who wants to comment on the age or the fact that people had hyperopia.

            Dr. Bandeen-Roche and then Dr. Bradley.

            DR. BANDEEN-ROCHE:  I would just say that, with respect to age, there is very little power to distinguish there not being an age effect.  So I would just be careful about saying that, while we have shown that there is, you know, not really an effect with respect to age, we don't know this.

            CHAIRMAN WEISS:  We don't know about age, and hyperopia, would you say -- What would you say about hyperopia?

            DR. BANDEEN-ROCHE:  Hyperopia -- I mean, to me, I felt less confident about the 32 versus -- I feel less confident commenting about that.

            CHAIRMAN WEISS:  Dr. Bradley, and then Dr. McMahon.

            DR. BRADLEY:  Of course, the 32-spot pattern, the subject age, the initial subject refraction all interact, and it would be -- Rather than making a decision based upon our clinical judgment, seems to me, this is an opportunity to employ multivariate statistics and find out which of these really is the key problem. 

            DR. BANDEEN-ROCHE:  It's not enough data.  I mean, there is a -- If you look at the data, it sure looks like there is an interaction, but there is not nearly enough statistical power to document it.  I agree, it would be nice to, as maybe more -- Well, I guess there isn't going to be fuller data accruing.  Maybe we should think about future data.

            CHAIRMAN WEISS:  Okay.  Dr. McMahon and then Dr. Mathers, and then Dr. Schein.

            DR. McMAHON:  The age of the patient in the pre-operative distance ametropia and the resultant near acuity are unalienably intertwined here, and the issue is, does the intended effect meet the pre-operative requirements.

            Age and bifocal power add are linearly aligned.  So age is going to be related to how much add effect you are going to have.  So this is an issue not specifically of age but of intended correction amount that you want to achieve.

            CHAIRMAN WEISS:  Dr. Mathers.

            DR. MATHERS:  I think that there are two properties here.  There is the objective measurement of accuracy as acuity J3 or whatever, and there is the quality of vision satisfaction issue.

            Quality of vision and satisfaction issue does fine for the whole group.  In fact, for 32-spot it is at least as good as the less than 32, and same with satisfaction.  But it doesn't achieve a measurable improvement. 

            That may be a good thing, because these patients may not actually tolerate three diopters of anisometropia, but in terms of efficacy, if we are talking about patients being happy, they're happy, and they are satisfied.

            CHAIRMAN WEISS:  Dr. Schein.

            DR. SCHEIN:  I plan to magnify on that.  It is my understanding, the indications for this device is to reduce spectacle dependence for near activities in emmetropes and hyperopes, and that reduction in dependence and the patient outcomes are equivalent for the hyperopes in the lower, and I see no justification to parse an approval based on a refractive outcome.

            CHAIRMAN WEISS:  Dr. McMahon.

            DR. McMAHON:  Just a point, and that is, even with Dr. Mathers' comment, for those who are hyperopic to start with, the majority of those patients had their other eye treated for distance.  So their anisometropic correction at the end was very similar to that of the emmetropes.  So you're dealing with really two diopters of anisometropia rather than three.

            CHAIRMAN WEISS:  Is the FDA satisfied with that discussion on that particular issue?

            DR. VAN METER:  Dr. Weiss, can I make one comment?

            CHAIRMAN WEISS:  Dr. Van Meter.

            DR. VAN METER:  One issue that was raised earlier is the older hyperopes that had the 32-spot size would still get some improvement from the 24-spot size.  We just don't know how much improvement they would get.  There is some reason to think that in an older cornea, you might get more effect from the same treatment.  We learned that from the old RK data.

            So this is not to say that an older patient that got 24 spots would not necessarily be unhappy.

            CHAIRMAN WEISS:  Dr. McMahon.

            DR. McMAHON:  Along those lines, and I brought this up before, there actually may be no different in effect between 24 spots and 32 spots, and actually that would be something the sponsor would want to look at.

            CHAIRMAN WEISS:  I think, really, what I would like to see is for each of the spot sizes how much hyperopia was treated at different time points, so you know what a 24 and what a 32 and what an 8 on the average treats and how it degenerates with time.  That would, I think, answer the question that you are asking, is does it do any different than the 24-spot.

            DR. McMAHON:  You would have to decouple it from the binning that they are using down individual data, and it might be there under those circumstances.

            CHAIRMAN WEISS:  So on those particular issues, does the FDA -- We will go on in a moment to other subgroups or the last section of Question 4, but on the sections that we just covered, are you satisfied?  Okay.

            So the last section is:  "Are the reduced accuracy to target refraction and poorer," etcetera.  "How do you suggest the indication and/or labeling be modified for any other subgroups or refractive correction?"

            So aside from what we have already discussed, are there any other stipulations that you would want, aside from talking about the actual spot patterns, because that is the only thing that I have heard that people sort of want to have either more information on or maybe say some of them don't show any efficacy.  Anything besides what we have mentioned?  Dr.  Macsai?

            DR. MACSAI:  Dr. Weiss, is this for any labeling or only in regard to these things?

            CHAIRMAN WEISS:  Only in regard to these things.  Question 7 will address labeling recommendations, additional ones.  Dr. Bradley?

            DR. BRADLEY:  I don't want us to get too focused on the number of dots.  I mean, with this procedure the number of dots is correlated with the intended refractive change, and it may be more sensible to analyze the data. 

            If we are concerned about a particular dataset, it may be better to describe it as we are not satisfied with data when the intended correction exceeds 2.25 diopters as opposed to 32 dots, because they are one and the same, and in the end that may be the better way to define the limited range of this procedure, not in terms of number of dots, because again, as Dr. McMahon has explained, we are not quite sure if it is a dot problem, and it may just be a limit to the procedure.  You can't do more than two-plus diopters.

            CHAIRMAN WEISS:  Dr. McMahon.

            DR. McMAHON:  Actually, I would argue just the opposite, in that because they are related, it may be that the spots is the key issue, not the intended correction, within certain bounds.

            CHAIRMAN WEISS:  Well, I would assume that the agency could request to look at it both ways in terms of what is the maximal correction that you can get from this procedure, and in addition, is there any difference in terms of the average correction -- and  those statisticians at the table can phrase this much better than I can, but between a 32 versus a 24, how much additional correction are you going to get from that, if you are going to get any additional correction. 

            I see a nod.  So that is comforting, from Dr. Bandeen-Roche.  So we are going to go on to question number 5.  I'm told she was drifting off.  Thank you. 

            DR. BANDEEN-ROCHE:  False advertising.

            CHAIRMAN WEISS:  Okay.  Question 5 :  Do the spectacle dependence rates for near activities support approval for the requested indication in a presbyopic population? 

            So I think what FDA is referring to is there's a lot of folks here who have to wear reading glasses.  But given that, does this show reasonable efficacy?  Dr. Huang.

            DR. HUANG:  I don't know.

            CHAIRMAN WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  My concern would be that people very clearly understand what the rates are, what their chances are.

            CHAIRMAN WEISS:  So you can address this.  I would assume your answer is yes, as long as you address it in labeling?

            DR. BANDEEN-ROCHE:  Yes.

            CHAIRMAN WEISS:  Dr. Smith.

            DR. SMITH:  I agree with Dr. Bandeen-Roche.

            CHAIRMAN WEISS:  Dr. McMahon.

            DR. McMAHON:  I agree, same.

            CHAIRMAN WEISS:  Dr. Coleman.

            DR. COLEMAN:  I agree.

            CHAIRMAN WEISS:  Dr. Van Meter.

            DR. VAN METER:  I don't know, because I think spectacle dependence rates are so nebulous, to start with, that I have no idea how to answer this.

            CHAIRMAN WEISS:  Dr. Bradley.

            DR. BRADLEY:  I also don't really know.  It seems to me they did two surveys.  One survey biased the data to say, yes, I need spectacles.  The second survey biased the data to say, well, I can do without them.  In the end, I'm not really sure what was going on with the patients. 

            CHAIRMAN WEISS:  How many "I don't knows" do we have at this point?

            DR. McMAHON:  A lot of them.  Everyone so far. 

            CHAIRMAN WEISS:  We can't even know how many "I don't knows" we have.  Okay.  Dr. Grimmett.

            DR. GRIMMETT:  Yes, with proper informed consent.

            CHAIRMAN WEISS:  Dr. Casey.

            DR. CASEY:  I agree with Dr. Van Meter.  I don't know.

            CHAIRMAN WEISS:  Dr. Mathers.

            DR. MATHERS:  Yes, with informed consent or addressed in labeling.

            CHAIRMAN WEISS:  Dr. Schein.

            DR. SCHEIN:  Yes.

            CHAIRMAN WEISS:  Dr. Macsai.

            DR. MACSAI:  Yes, with a disclaimer.

            CHAIRMAN WEISS:  For labeling.

            DR. MACSAI:  Labeling.

            CHAIRMAN WEISS:  Dr. McMahon.

            DR. McMAHON:  I want to make it clear that I was voting I don't know, but it could be addressed in the labeling.

            CHAIRMAN WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  Yes.  I mean, certainly the concern about the quality of this questionnaire measurement is very valid.  I mean, maybe this is a good time to just very briefly cite something off of this table, and I will cite more of it later.

            Going no to yes, 33 percent, 34 percent from six month to 12 month -- I guess that would be incidence of using glasses, but there was 15 percent remission of using glasses.  So I don't know what that means, whether it speaks to the quality of measurement or what.

            CHAIRMAN WEISS:  So from the agency's standpoint, there may be a slight majority on one side or another, but basically it's either it does support it or there's uncertainty whether it supports it.

            DR. VAN METER:  Dr. Van Meter.  I believe all the "I don't knows" would agree that labeling can solve the issue.

            DR. McMAHON:  I concur.

            CHAIRMAN WEISS:  Dr. Bandeen-Roche?  Agency satisfied? 

            Question Number 6:  Do the safety and efficacy data support approval for the requested indication?  If not, what indication does the data support?

            So this was the question that I promised you we would get to.  I think we have answered some of it, but perhaps not enough.  Dr. Macsai?

            DR. MACSAI:  I thought we answered it with the 32 spots.

            CHAIRMAN WEISS:  So that you feel that the safety and efficacy data support the indication for treatment for all the spot sizes except for the 32-spot?

            DR. MACSAI:  Yes, with the disclaimer that we don't have enough patients on the 8, and we have no idea how long the temporary lasts for.

            CHAIRMAN WEISS:  Dr. Schein.

            DR. SCHEIN:  The answer is yes to the question.

            CHAIRMAN WEISS:  Dr. Mathers.

            DR. MATHERS:  Yes.

            CHAIRMAN WEISS:  Dr. Casey.

            DR. CASEY:  I agree with Dr. Macsai.

            CHAIRMAN WEISS:  Okay.  Dr. Grimmett.

            DR. GRIMMETT:  Yes.  And I would like to offer an explanation.  I look at it differently in terms of whether the product is already in the marketplace versus whether it is not.  If this procedure were not in the marketplace, I would do as Dr. Macsai suggested, that the 32-spot size be eliminated due to effectiveness issues.  However, this is a procedure that is in the marketplace. 

            It is my believe that physicians will use it off-label anyway, because the 32-spot indication is already out there, and I would rather have as much information available to physicians and patients as possible so that in that circumstance they have something to rely upon.

            I also would want FDA to have access to wordsmith it.  So I answer the question yes.

            CHAIRMAN WEISS:  You probably, though, could change the indication but still put the data in the labeling.

            DR. GRIMMETT:  As long as the data is in the labeling, I'm happy, no matter what happens.

            CHAIRMAN WEISS:  Okay.  So we have a two and a half on one side and a two and a half on the other.  Dr. Bradley.

            DR. BRADLEY:  Safety, yes.  Regarding efficacy, somehow we need to either put it in labeling.  I'm thinking that the procedure is efficacious for creating a near reading add for emmetropes.  It is efficacious for correcting distance vision for the hyperopes, but it is going to produce only a limited aid for reading in the hyperopes.

            So it is efficacious for reading add for the emmetropes, but for the hyperopes it has limited efficacy, because of the limited range of the procedure. 

            CHAIRMAN WEISS:  So what would your indications be?  So this is safe and effective for -- fill in the blank.

            DR. BRADLEY:  Safe and effective for emmetropes.  For the hyperopes, it has limited efficacy.

            CHAIRMAN WEISS:  Safe and effective for increasing near vision --

            DR. BRADLEY:  Yes.  Providing a reading add.

            CHAIRMAN WEISS:  For emmetropes.  Up to?

            DR. BRADLEY:  Just emmetropes.

            CHAIRMAN WEISS:  Oh, just emmetropes.

            DR. BRADLEY:  Yes.  As soon as we get into hyperopia, we run into the limit of the procedure.  It  produces less than desirable effects.  That is what we have been talking about.

            CHAIRMAN WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  Dr. Rosenthal, I have a question.  Is it possible to limit the range of approval, exclude the 32-spot, yet still include all that data in the labeling?

            DR. ROSENTHAL:  Absolutely.

            DR. GRIMMETT:  Fabulous.  That would be my vote.

            CHAIRMAN WEISS:  We're not voting now.  We are voicing opinions. 

            DR. ROSENTHAL:  We do it with the excimer lasers all the time.

            DR. BRADLEY:  We are all agreeing.  It's just a matter of how that gets presented.  As the FDA gets a sense of what our concerns are, and I think that the concerns are very self-evident in the data.  Sponsor is aware of them.  Sponsor raises the concerns, too, in their analysis.  It's just a matter of how that gets packaged in the final product, it seems to me, whether it's an issue of restricting it for hyperopes or number of dots or whatever.

            CHAIRMAN WEISS:  Dr. Berman.

            DR. BERMAN:  I just want to remind you that my first slide had the proposed indication as the sponsor currently has it proposed, and in there in the second line they are proposing presbyopic hyperopes or presbyopic emmetropes.

            So I just wanted to clarify.  Are all of you in agreement that you are recommending that you would delete the words "presbyopic hyperopes" from the indication?

            CHAIRMAN WEISS:  I think we have to go around again, because that, I think, was really just brought up this moment.  So why don't we -- The requested indication, of course, doesn't distinguish between presbyopic hyperopes and presbyopic emmetropes.

            Dr. Bradley has proposed that presbyopic emmetropes be the only ones included in the efficacy and in the indication.

            DR. BRADLEY:  No, that's not what I said.  I said it has limited efficacy for the hyperopes.  IT does provide them with some extra add power.  They end up being slightly myopic, but not as much myopia in that eye as the emmetropes can achieve, and maybe not quite enough for the reading that they may request.  But it does give them some add power.  So it is going to help them a little bit.

            CHAIRMAN WEISS:  So is that something that we can put an indications, that it is indicated to improve near vision in one group but is limited -- I mean, help me on this.

            DR. ROSENTHAL:  No, I don't think --

            DR. BERMAN;  I think you would indicate who it is indicated for, and then in the labeling you would provide the various outcomes.

            CHAIRMAN WEISS:  Dr. McMahon has a comment.

            DR. McMAHON:  Let me suggest some wordsmithing, and it comes actually from my recommendation in the presentation, that this is a safe and efficacious procedure for intended near corrections of 1.00 to 2.25 diopters of effect.

            DR. MACSAI:  Temporary.

            DR. McMAHON:  Right.  Temporary.  The issue then is you have a range of 1.00 to 2.25 worth of effect, and it's what is your end goal.  So if your end goal is to have a 1.00 diopter worth of effect, you can actually do 1.00 diopter of hyperopia, too.

            So this has been proven to be reasonably efficacious, in my view, for that particular region, and I think that's enough.

            CHAIRMAN WEISS:  Would you be in agreement with that, Dr. Bradley?

            DR. BRADLEY:  Yes. 

            CHAIRMAN WEISS:  And then you could always address your concerns about any of the subgroups in labeling, if you wanted to.

            DR. BRADLEY:  Yes.  I think it may be need some labeling because, given the fact that we have struggled with this issue, it would be worth laying it out in clear language for both the physician and the patient.

            CHAIRMAN WEISS:  So, actually, can you refresh my memory?  What is the present -- Dr. McMahon suggests saying specifically 1.00 to 2.25 of effect.  What is it presently listed as, the present indication?

            DR. BERMAN:  The current one says temporary induction of myopia to improve near vision in the non-dominant eye presbyopic hyperopes or presbyopic emmetropes, blah, blah, blah.

            It currently says up to 3 diopters but, of course, FDA has indicated to the sponsor in previous communication that it would be not up to, but it would be .75 -- you know, it would be the amount treated in the PMA, which didn't include zero to 1 or zero to .75.

            CHAIRMAN WEISS:  So if we basically let you do whatever you wanted but gave you the guidance that -- with some of these words here, because it is fairly lengthy -- but gave you the guidance that -- and after we get consensus, if we get consensus on this proposal, 1.00 to 2.25 effect -- that would answer your question? 

            Okay.  So Dr. McMahon has proposed using that.  I would like to sort of have the rest of the Panel members address that, and then we are just going to go back over that for those who haven't addressed that.  Dr. Van Meter.

            DR. VAN METER;  I agree with Dr. McMahon.

            CHAIRMAN WEISS:  Dr. Coleman.

            DR. COLEMAN:  I do, too.

            CHAIRMAN WEISS:  Dr. McMahon, I assume you agree with yourself on most days.

            DR. McMAHON:  Fairly likely.

            CHAIRMAN WEISS:  Okay.  Good.  Dr. Smith.

            DR. SMITH:  That's fine.

            CHAIRMAN WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  Ditto, plus I second Dr. Grimmett's comments about the data.

            CHAIRMAN WEISS:  Dr. Huang.

            DR. HUANG:  I agree with Dr. McMahon.

            CHAIRMAN WEISS:  And starting it back again, Dr. Macsai, would you be in agreement with that?

            DR. MACSAI:  Yes.

            CHAIRMAN WEISS:  Dr. Schein.

            DR. SCHEIN:  Yes.

            CHAIRMAN WEISS:  Dr. Mathers.

            DR. MATHERS:  Yes.

            CHAIRMAN WEISS:  Dr. Casey.

            DR. CASEY:  Yes.

            CHAIRMAN WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  Yes.

            CHAIRMAN WEISS:  Okay.  I have not meant to exclude industry and consumer reps here.  If you have any comments on any of these things, including this one in particular, please let us know.  You would?  Then give us your comment.

            MR. McCARLEY:  I would let you know.

            CHAIRMAN WEISS:  Oh, you would let me know.  Okay.  Question Number 7:  Do you have additional labeling recommendations, explanatory text or data?  Are there data tables that should be added to the labeling for physicians and/or patients? 

            So why don't we start with the primary reviewers, and then we can go on from there.  Dr. McMahon.

            DR. McMAHON:  Do you want me to read out the number of labeling suggestions I put in my report or can we --

            CHAIRMAN WEISS:  Yes, if you can just -- You don't have to belabor them, but if you can just state them, and then I can give you this so you don't have to write it out, and we can just check them off.  This is the review from Dr. McMahon.

            DR. McMAHON:  It starts on page 11.  The first one, which had to do with blended vision -- The sponsor has already acknowledged that they will drop that.  So it is not an issue.

            On page 11 of 31 of the patient information booklet, the first bullet, I suggest that adding "keloids" in parentheses.  Since they talk about scars, the real issue is keloid formers, I believe.

            Page 11 of 13, the sixth bullet:  I have some concerns about concluding nystagmus as a precaution.  This is done under topical anesthesia, and I can't understand why it is not a contraindication unless surgeons are good enough to move their hands at the same rate as the nystagmus.

            Page 14 of 31, the first bullet address re-treatment, and I would remove this item, as the effectiveness and safety of re-treatments have not been determined.

            On page 13 and 14 of 31, when they go over about important things for consideration, there is really no mention about the monovision trial.  It is later on, on page 19.  I think it should be up here, because this is an important part for the patient to understand, and the sponsor, I believe, agrees that a monovision trial is needed.

            Page 12 of 31 -- Am I going too fast, Michael?  The last two paragraphs of the first days seems to better fit in the first paragraph of the weeks after surgery.  That is sort of wordsmithing.

            On page 23 of 31, Table 8, if there is any data relative to response to worse -- you know, because it is same -- you know, little improvement, marked improvement.  If there is any data relative to worse, that should be added.  If there was none available -- in other words, it wasn't questioned which I think is the case -- then ignore that.

            Page 24 of 31 in the section of questions to ask your doctor, omit the first bullet pertaining to nystagmus, if we are going to make it contraindicated. 

            Add a table to finding the frequency of induced cylinder and effect this has on near and distance visual acuity in the trial.

            A cautionary statement should be added after Table 1, which is on page 8 of 31, indicating that equivalent outcomes in non-Caucasians have not been determined.  This is an issue, I think, for Asians in particular, since their corneal architecture is a bit different than others.  This may pertain to other ethnic groups as well.

            Under physician labeling, remove nystagmus from warning and place it into contraindications.

            In the section on how long contact lenses should be removed prior to the procedure, I have a little bugaboo about this in refractive surgery in general, and I don't have real solid wording, but in particular with rigid lens wears the notion of some fixed time period, to me, is not realistic. 

            It needs to be that there's corneal stability in terms of its shape or the equivalent refractive error before this is done rather than some fixed time frame.  I know that that is an awkward situation for refractive surgeons, but it is reality.

            Add a statement:  "The effectiveness of this procedure device has not been determined for patients with less than 20/25 best spectacle corrected visual acuity pre-operatively," as all these patients had normal acuity.

            That's all I have at the moment.

            CHAIRMAN WEISS:  Dr. Huang.

            DR. GRIMMETT:  There is a re-treatment comment in there that has not been determined?

            DR. McMAHON:  Yes, I mentioned that.

            DR. GRIMMETT:  It's in there? 

            DR. McMAHON:  Re-treatment and as well as the effectiveness of intraoperative spots beyond the standardized treatment has not -- The effectiveness of that has not been determined as well.

            DR. GRIMMETT:  Thank you.

            CHAIRMAN WEISS:  Dr. Huang.

            DR. HUANG:  I would suggest to add additional data tables to the physician labeling, if there is any information regarding the re-treatment, as well as those ten excluded patients that had additional intraoperative additional spots to reduce the CK induced astigmatism, if those data were available; because this device has been already approved for hyperopic indications.

            So the physician may not read the label carefully.  I think, you know, they can treat with the 32 spots easily, and then there is induced increase amount of astigmatism induced.  So I think the warning or label should adequately reflect these kind of precautions.

            CHAIRMAN WEISS:  Just to clarify, I think they have tables already in the physician's and perhaps the patient labeling as well.

            DR. HUANG:  Not the ten excluded patients.  There are additional ten patients in the 32 spots treated with additional intraoperative spots, in addition to the 32 spots.  They have additional spots.  They treat additional spots in the area of the cylinder induced.

            CHAIRMAN WEISS:  I see.  Well, that's totally off-label.

            DR. HUANG:  Yes, that is totally off-label.  Yes, but you know, given this device is likely to be used off-label anyway, so I think they should warn the physician, if you want to treat with 32 spots, be prepared, you may have to deal with astigmatism.

            CHAIRMAN WEISS:  There was more induced astigmatism in the 32-spot?

            DR. HUANG:  Well, the data is not submitted for analysis.

            DR. MACSAI:  It is the 11 patients that were excluded, right?  Ten of them had 32 spots, and they got treated with more spots for induced astigmatism?

            DR. HUANG:  Yes.

            DR. MACSAI:  They are the ten out of 52.

            DR. HUANG:  Yes, exactly. 

            DR. MACSAI:  Those ten need to be in the warning to doctors.

            DR. HUANG:  Yes.

            CHAIRMAN WEISS:  What do you want to say about them?  Well, what do you say about these people.

            DR. McMAHON:  They just need to present the data.

            DR. HUANG:  Yes, just show additional physician warning table, say, well, ten patients in the 32 spots were treated with additional intraoperative spots, and these were the outcomes; because there was no data that I could find.

            CHAIRMAN WEISS:  I see.  So, basically, you would like data in the physician's booklet on the 10 excluded patients?

            DR. HUANG:  Exactly.

            CHAIRMAN WEISS:  Okay. 

            DR. HUANG:  Because that is the question:  Should additional data table be added?

            CHAIRMAN WEISS:  We understand that.  Thank you.  Any other comments, Dr. Huang?

            Dr. Van Meter.

            DR. VAN METER:  If you are going in order about labeling, that's fine.

            CHAIRMAN WEISS:  We are just going to go to those who have relevant comments.  Dr. Van Meter?

            DR. VAN METER:  I have two questions in  the patient labeling under "Be Sure to Talk to Your Doctor If," and I will go with Dr. McMahon's pagination, because I think mine is different.

            It says "Be sure to talk to your doctor if you have a cornea that is too think for the procedure to be completed safely."  That is beyond the scope of most patients, I think.  That probably ought to go in physician labeling.

            Also, I would like in physician labeling the importance of accurate centration on a properly identified visual axis of the cornea.

            CHAIRMAN WEISS:  And basically along the same line, it indicates that if you have keratoconus as a contraindication.  I think it should say keratoconus and ectatic -- other ectatic conditions such as if you have pellucida, that is obviously also--

            DR. SCHEIN:  A history of RK. 

            CHAIRMAN WEISS:  You are right, prior refractive surgery -- Now is that an absolute?

            DR. SCHEIN:  RK, I said, rather than refractive surgery. 

            CHAIRMAN WEISS:  Incisional keratotomy.  So we could add that. 

            DR. MACSAI:  We don't have data on the other refractive surgeries.  That has to be put in there.

            CHAIRMAN WEISS:  Yes, I think you have to -- and I don't know if it's in there already -- say that prior refractive surgery may be a contraindication.  There is no data on the results of this after prior refractive surgery.  Then that will include everything.

            DR. GRIMMETT:  But I'd like to add something.  Mike Grimmett.  I think with incisional keratotomy, in particular, there is reason to believe that shrinking the cornea may put additional stress on wounds that may not be totally healed and may cause additional irregular astigmatism.  I believe Marguerite McDonald made a comment agreeing with that fact or alluding to that.

            CHAIRMAN WEISS:  She is nodding her head.

            DR. GRIMMETT:  So I think incisional keratotomy probably warrants a special line, and the other ones just say there is no data.

            CHAIRMAN WEISS:  So separate that out.  Okay, we'll separate that out.  Likewise --

            DR. McMAHON:  You are going to put that in contraindications?

            CHAIRMAN WEISS:  Radial keratotomy?  Incisional keratotomy will be in contraindications, yes, or can be.  Likewise, it may already be in the labeling, the effective of other refractive procedures after CK is not known.  I don't know.  If that is not in the labeling, that should be in both of them.  Dr. Coleman.

            DR. COLEMAN:  Yes.  Under physician precautions on page 12, I would add steroid-responsive intraocular pressure or pressure greater than 21 millimeters of mercury to patients with history of glaucoma as a precaution.

            CHAIRMAN WEISS:  I'm going to ask you to scribe these again.  Thank you so much.  You are anticipating.

            DR. COLEMAN:  Those individuals weren't allowed to participate in the study.  Then for the patient precautions, you should also add the same thing, instead of just putting -- You know, it says if you have a history of glaucoma, but also if you had a history of elevated intraocular pressures.

            CHAIRMAN WEISS:  The other thing in patient labeling, it had that there is no effect on -- There could be an effect on stereovision, and I think it indicated that there wasn't.  But the way the study was done, one wouldn't know.  So this is on page 27 of -- This is actually the physician's reference guide.  I would change it also in the patient reference guide, if it is listed.

            It says this just near correction did not have an adverse impact on binocular uncorrected distance acuity.  This is on page 27 of the physician's reference guide draft, and I think we don't know.

            Okay.  Dr. Bandeen-Roche, then Dr. Schein and then Dr. Grimmett, Mr. McCarley.  Ms. Such if you have any comments as well, I'll ask you to chime in.  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  Yes.  Just two points.  The first goes to the definition of temporary.  I hope that it will be stressed even more than it is in the patient information guidebook the fact that it is temporary, that we do not know beyond two years how long the correction lasts and that sort of thing.

            I would urge FDA to look into some of the analyses we talked about yesterday, for instance, that Dr. Gray presented maybe with manifest refraction going to percentages who lose a certain amount, and not only with the mean manifest refraction loss is.

            Then the second point would just be concerns about the consistent cohort.  Honestly, the data that I requested, you know, certainly were consistent with the comments that we have heard, that the six and 12 month cohorts don't look dramatically different.  But there is the potential to mislead on a table, any one of these tables, where you have only half the people at 12 months that you do at six months.  I would just urge FDA to make sure that there isn't a misleading comparison by virtue of there not being a consistent cohort.

            CHAIRMAN WEISS:  Dr. Schein.

            DR. SCHEIN:  For label, I'm concerned about an overemphasis on this word temporary, because I think it may be irreversible for many people and, if you really emphasize the temporary, you give the impression that something is reversible.

            So I -- apologies to the sponsor -- see this a bit like offering a facelift to a patient.  It is not reversible, but it may only be temporary.  I think it is not a play on words.  It really gives the impression of reversibility when something in the label has to say it is presumed not to be reversible, although it may be temporary.

            DR. SMITH:  Actually, it already says -- In the patient information part it says it is not reversible on page 48 of 33.

            DR. SCHEIN:  Okay.  I missed that, but that's a difficult concept.

            DR. SMITH:  I agree, it should be emphasized.  It actually is not in the physician section, but it is in the patient section.

            CHAIRMAN WEISS:  Maybe just for FDA, there is a way to indicate that this -- that additional data has been requested for the two-year.  So maybe you will have some curve to show how much this wears off over what period of time.  But if that is not clear, then you will have to put in there, we don't know what an individual -- how much effect they will lose over what period of time, and put that next to, I guess, the fact that this is not reversible, but some of the effect wills be lost, and how much over what period of time we don't know.  Dr. Bandeen-Roche, is that okay?

            DR. BANDEEN-ROCHE:  That's good.  Thank you.

            CHAIRMAN WEISS:  That's good.  Dr. Schein.

            DR. SCHEIN:  The other labeling comment I have was a mention that this has not been studied in pseudophakic patients.  My concern here would be with unknown effect of spots near a corneal incision. 

            CHAIRMAN WEISS:  Then you will have to -- Then if you are going to say this has not been studied in pseudophakic, it hasn't been studied in corneal transplants.  It hasn't been studied in a lot of other things.  So do you have a wish list of things you want to indicate it wasn't studied in?

            DR. SCHEIN:  Well, this is distinctive because of the age and prevalence.  I can think of lots of rare things, but --

            DR. GRIMMETT:  Would you rather than just say that there are unknown effects near corneal incisions, because that is what you are worried about, rather than the type of surgery?

            CHAIRMAN WEISS:  Or when someone who has had prior ocular surgery.

            DR. SCHEIN:  Right.  The other thing, you know, a pseudophakic patient has absolutely zero accommodative reserve, and the efficacy may be completely different in that group as well.

            CHAIRMAN WEISS:  Well, I'm going to leave that one up to the agency in terms of having another warning to patients that, if it got used -- and I don't recall if that was a contraindication if you are pseudophakic, but if get used in off-label ways, maybe we can make it a little bit broad, not just if you've had prior refractive surgery but if you have had corneal incisions, if you are pseudophakic, if you had -- and maybe you have a laundry list of things.  Dr. Grimmett.

            DR. GRIMMETT:  Dr. Grimmett.  Earlier there was raised an issue about intraocular lens calculation formulae with the alteration in corneal curvature from this device.  Dr. Durrie indicated that he hasn't seen a problem in hyperopes, but I'm not aware that there is a body of data that we actually know the answer. 

            I would be in favor in an older population that may be undergoing cataract surgery to make some affirmative statement that outcomes of IOL power formulae are unknown after this procedure, and the implications of changing a corneal curvature on all of our regression formulas for lenses.

            CHAIRMAN WEISS:  Were there any other tables or charts that were mentioned in the discussion that we have not mentioned in labeling?  Dr. Macsai.

            DR. MACSAI:  Well, in the patient information booklet, page 25, there's Table 11 and 12.  We talked about the fact that these are not great surveys and not validated, and they are not standardized, and they could be misleading to the consumer when you look at these.

            So there should be some warning about that, about the interpretation of these two tables.  It is the table of spectacle dependence for near vision -- That's the title, Table 11 and 12, and they talk about wearing spectacles at six and 12 months for working on a computer, reading, all near activities, night driving, watching TV, etcetera. 

            There's got to be some sort of disclaimer that these are nonvalidated questionnaires, and not standardized.  As Ms. Such brought up, you know, computers come in thousands of forms nowadays.

            CHAIRMAN WEISS:  We could put a little disclaimer there.  Any other -- Ms. Such?

            MS. SUCH:  Actually, speaking to that, talking about computers, I actually would like to see the computer component taken out of this, because of the amount of variables that were never taken into consideration at all in this study. 

            There's just too many of them, and by admission from the sponsor that they were not considered, I'd like to see the words "for computer" removed from this entire study, from physicians as well, because it's not been actually proven.  There's just too many things, distance, size, contrast, everything that you can imagine.

            The other thing I would like to mention, not on this topic, is I'd like to see -- I'm sorry to say to my colleague -- that I would like to have put back in the patient "What You Should Ask Your Doctor" the issue about nystagmus. 

            Even though it is going to be brought up in contraindications, if you look at what you are asking your doctor, most of these things are redundant.  Most of the things that you see in there are brought up over and over and over again.  It's just once again bringing it up so somebody thinks about it.

            So if we were to take apart things that are mentioned in contraindications, precautions or warnings, we would be left probably with nothing left on the list.  So I think that we need to really think about putting that back in.

            The only one that I think that really bothers me in that list is one that feels a bit insulting, and that is the one about being able to follow your doctor's instructions about leaving your contact lens out, like as if you wouldn't be able to follow instructions.

            CHAIRMAN WEISS:  Oh, I would really want that in, because many patients don't, and I'm a patient as well.  So this is not meant as an insult to patients.  At some point, we all become patients, but some patients take it very cavalierly, and it's terribly important to the result of your procedure, and many contact lens wearers do not want to give up their contact lens wear even for a moment.

            So this is not to insult people.  This is to ensure a better result by underscoring it is very important that they do this.

            MS. SUCH:  So perhaps we could wordsmith that better to say to understand the importance that you need to leave in.

            CHAIRMAN WEISS:  That's fine.  We can tell the agency to make it less insulting, if that is how it comes across.

            MS. SUCH:  Yes, I'd like to see that a little bit better.  That's all from my end.

            CHAIRMAN WEISS:  In terms of whoever wanted that item to be -- nystagmus to be taken out, I would assume they are in agreement.  It can get put back in.  Dr. McMahon?

            DR. McMAHON:  Sure, if it's a question.

            CHAIRMAN WEISS:  Fine.  So it's back. 

            DR. GRIMMETT:  Nystagmus under topical anesthesia.  That was your intent, right?  We are not talking about blocking or putting people under general anesthesia here.  Right?

            DR. McMAHON:  Correct.  And I don't -- It's not inappropriate.  The question is asked about what the fact that I have nystagmus, which I think is what Glenda is getting to.

            CHAIRMAN WEISS:  Any other labeling issues?  So the agency is clear what extra charts in terms of two-year data from the prior PMA and the change with time over the year of the various treatments that the Panel wanted, if that is the case, if agency doesn't have any other -- Does agency have any other requests or questions?  No. 

            So we have now ended the Panel discussion.  We are going to go to the Open Public Hearing session.  Is there anyone who wanted to address during the open public hearing session?  Seeing no one, we will close the open public hearing session.

            Does the FDA have any closing comments?  No closing comments from the FDA.

            The sponsor has five minutes for closing comments, if they desire.

            DR. GORDON-MEYER:  I'll be very brief.  We appreciate all of the good input from the Panel, and we look forward to providing the additional analyses, including equivalence of the stability, and we welcome and appreciate this good review.  Thank you all very much.

            CHAIRMAN WEISS:  And I want to thank the sponsor for a very clear review and a very excellent presentation.

            DR. GORDON-MEYER:  Thank you.

            CHAIRMAN WEISS:  So now we will have Sally Thornton read the voting options.

            MS. THORNTON:  The medical device amendments to the Federal Food, Drug and Cosmetic Act, as amended by the Safe Medical Devices Act of 1990, allows the Food and Drug Administration to obtain a recommendation from an expert advisory panel on designated medical device pre-market approval applications 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 probable benefits to health under conditions of 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 option for the vote are as follows:  Approval, if there are no conditions attached; approvable with conditions, the Panel may recommend that the PMA be found approval subject to specified conditions such as physician or patient education, labeling changes or a further analysis of existing data.  Prior to voting, all of the conditions should be addressed by the Panel -- discussed by the Panel, sorry.

            Not approval:  The Panel may recommend that the PMA is not approvable if the data do not provide a reasonable assurance that the device is safe or if a reasonable assurance has not been given that the device is effective under the conditions of use prescribed, recommended or suggested in the proposed labeling.

            Following the voting, the Chair will ask each Panel member to present a brief statement outlining the reasons for their vote.  Thank you.

            CHAIRMAN WEISS:  Thank you, Sally.  Does anyone want to propose a main motion?  Dr. Van Meter?

            DR. VAN METER:  I would like to move that the PMA be approvable with the conditions that we have discussed.  Now we have to list the conditions again.  Is that correct?

            CHAIRMAN WEISS:  Yes.  The first motion being approvable with conditions.  Does anyone second that?

            DR. MATHERS:  Second.

            CHAIRMAN WEISS:  Dr. Mathers seconds that.  So now we will go on to discussion of that and, if there is no discussion, then we can just go on to each of the conditions that anyone wants to propose.

            I think we should start with Dr. Grimmett, who has been scribing for us.  If you could introduce the conditions, and I would ask perhaps introduce the indication condition first.

            DR. GRIMMETT:  Condition Number 1:  Change the indication statement to the intended range of effect; that is, 1.00 diopter to 2.25 diopters of effect, as suggested by Dr. McMahon.

            CHAIRMAN WEISS:  Anyone second that?

            DR. MACSAI:  Second.

            CHAIRMAN WEISS:  Dr. Macsai seconds.  All of those in favor -- As we typically do, we will vote on each of the individual conditions before voting on the main motion.  So for this particular condition of the indications, all of those in favor, please signify by raising your hand. 

            MS. THORNTON:  Voting for the condition, Dr. Huang, Bandeen-Roche, Smith, McMahon, Coleman, Van Meter, Bradley, Grimmett, Casey, Mathers, Schein, Macsai.  That is unanimous.

            CHAIRMAN WEISS:  This passes unanimously.  Then I believe Dr. Grimmett will read the labeling conditions, as it appears that most of the other condition items are labeling and, if they are not, then we will just pick them out and subsequently do them.

            So these will be a list of all the labeling issues.  This will be voted on as one condition.  If you can propose the condition, and then someone will second it.

            DR. McMAHON:  So move.

            CHAIRMAN WEISS:  I don't think the condition was proposed yet.

            MS. THORNTON:  Would you state that, please, Dr. McMahon?

            DR. McMAHON:  That is actually standard Robert's Rules.  You just gave it, and I just --

            CHAIRMAN WEISS:  Well, I didn't want to give it, but okay.  That's fine.  Second.

            DR. GRIMMETT:  This is Dr. Grimmett.  I believe most of them are labeling.  If one of them is not, we will decide it as I go through sequentially.

            There was a comment that there was a claim that the depth perception is unchanged, but the comparison was not fair, if you will.  It compared pre-op contact lens monovision and not spectacles.  That needs to be better defined in the labeling of what was being compared, and it saying that there is no change in depth perception is probably not really correct.  Do we vote on that?

            CHAIRMAN WEISS:  No.  We are going to list all the labeling -- The condition is that of labeling, and all the labeling things will be listed as one.

            DR. GRIMMETT:  List them as you go.  If anyone disagrees with any of these, just speak right up.

            CHAIRMAN WEISS:  Yes.

            DR. GRIMMETT:  In the labeling, include a graph of treatment effect that is regression with time, both for the overall cohort, the emmetropes, the hyperopes, this PMA and the prior PMA. 

            In the labeling, include information on the spot pattern efficacy as well as the efficacy with intended correction.  Include it both ways.

            Include in the labeling information regarding spectacle dependence issues, with Dr. Macsai, I believe, making a provision on that, that the data are from nonvalidated questionnaires.

            Dr. McMahon submitted 13 suggested items that he read on his typewritten page 11 and 12.  Would you like me to reread all 13 or can I include those as "the McMahon 13"?

            CHAIRMAN WEISS:  I would love to hear them again.

            DR. GRIMMETT:  Okay.  McMahon Subgroup I:  As the sponsor has already agreed to remove the term "blended vision" as a euphemism -- that was his first suggestion -- use the word monovision.

            Number 2:  On page 11 of 31, add the term "keloid" in parentheses after "scars."

            On page 11 of 31, include nystagmus as a contraindication under topical anesthesia.

            Number 4:  On page 14 of 31, state that the  effectiveness and safety of re-treatments have not been determined in this trial.

            Number 5:  Page 13 and 14 of 31, mention in this section regarding the need for a monovision trial, as it was part of the entry criteria for this protocol.

            Number 6:  Page 12 of 31, a housekeeping item regarding moving a couple of paragraphs of first days after paragraphs of the weeks.

            Number 7:  page 23 of 31, in Table 8, wanted a row added regarding "worse" data.

            Number 8:  Page 24 of 31, regarding questions to ask your doctor.  Recommending omitting the first bullet, if nystagmus is ultimately contraindicated. 

            Number 9:  Adding a table defining the frequency of induced cylinder and the effect this had on near and distance vision in the trial.

            Number 10:  Adding a cautionary statement after Table 1, page 8 of 31, indicating that the equivalent outcomes in non-Caucasians have not been determined. 

            I'm back to the reading glasses here.  My accommodation ran out. 

            Number 11:  The recommendation was to remove nystagmus from the warning, but Glenda Such recommended that it be left in, in several sections, including in contraindications as well as in other sections.  I agree with that.  You okay with the amendment to your original suggestion?

            DR. McMAHON;  Yes.  That was in the "Ask the Doctor" part.

            DR. GRIMMETT:  Yes.  Thank you.

            Number 12:  Recommendation regarding adding the statement that a stable refraction should be determined if at any visit the pre-operative corneal topography is abnormal, especially with rigid gas perm lenses.

            Number 13: Add a statement:  The effectiveness of this procedure or device has not been determined for patients with less than 20/25 best spectacle corrected visual acuity pre-operatively.

            That concludes the McMahon 13.

            Dr. Huang wanted included the data table on excluded eyes. 

            CHAIRMAN WEISS:  Are we also including the data table on the 32 spots?

            DR. GRIMMETT:  That is one and the same?  Isn't that correct?  That's one and the same?

            CHAIRMAN WEISS:  That's one and the same.

            DR. GRIMMETT:  Okay. 

            CHAIRMAN WEISS:  So all the 32-spot eyes, not just the excluded ones.

            DR. MACSAI:  Correct.

            DR. GRIMMETT:  The more, the better. 

            Dr. Van Meter suggested in the physician labeling to emphasize the importance of proper centration on the visual axis for a multitude of reasons, including irregular astigmatism induced cylinder, so on and so forth. 

            Someone made a statement regarding a contraindication or a consideration for keratoconus and other ectatic diseases.  I believe that was the phrase that needed to be added.  Is that correct?

            CHAIRMAN WEISS:  Yes.

            DR. GRIMMETT:  Add a statement, from Dr. Schein, that prior incisional keratotomy is a contraindication.  The next statement:  There are no data on eyes with prior refractive surgery.

            Dr. Coleman had --

            DR. MACSAI:  I thought it was prior --

            DR. SCHEIN:  Cataract surgery, aphakic.

            DR. MACSAI:  Or prior surgery, prior ophthalmic surgery.

            DR. GRIMMETT:  Okay.  No data regarding prior refractive surgery or other ophthalmic surgery.

            CHAIRMAN WEISS:  Just I'm wondering, with keratotomy, if you have a limbal relaxing incision, that is a keratotomy, but the CK is not going to be in that area.  Well, is it a contraindication or is it I don't know?

            DR. GRIMMETT:  Well, there is just a statement being made that there is no data.

            CHAIRMAN WEISS:  I think the one -- The complication of which I am aware was a radial keratotomy. 

            CHAIRMAN WEISS:  Do you want to specify, instead of incisional keratotomy, to just radial keratotomy or astigmatic keratotomy?  Are we leaving out limbal relaxing incision?

            CHAIRMAN WEISS:  Well, an LRI is an "I don't know" as opposed to a contraindication.

            DR. SMITH:  The current language is in the precaution section for the physicians, and it says corneal or intraocular surgery.

            CHAIRMAN WEISS:  Fine.  Let's leave it as that, so we don't even have to -- Dr. Beers and then Dr. McMahon.

            DR. BEERS:  Yes.  We can certainly put for ophthalmic surgery "such as," and make some examples.  However, the importance of this in the patient labeling is, for anything, is that they should speak with their doctor if they have had this, not -- You  know, we don't want to define it too closely.  It's just, if you had something, talk to your doctor about it.  Let him know, and you all discuss it.

            CHAIRMAN WEISS:  Okay.  So you have the sentiment of it.  You don't need anymore particulars, it sounds like.  Yes?

            DR. GRIMMETT:  Dr. Coleman's suggestions in the physician precautions, page 12 of 57, regarding steroid response pressure rise or IOP greater than 21 -- That's a contraindication, Anne?

            CHAIRMAN WEISS:  Dr. Coleman.

            DR. COLEMAN:  Just as a precaution.

            DR. GRIMMETT:  A precaution?

            DR. COLEMAN:  Add it to the precaution section.

            DR. GRIMMETT:  Okay.  Precaution section regarding steroid response, glaucoma or pressure greater than 21, patients with ocular hypertension and patients with a history of glaucoma.  You want it added just to the physician and patient precaution section?  Is that the intent?

            DR. COLEMAN:  Correct.  Yes, because there is a place where it says patients with a history of glaucoma, but to also add that to that precaution.

            DR. GRIMMETT:  All right.  Dr. Weiss' statement, add a statement specifically stating that monovision may affect depth perception.  That is probably already in there, I'll bet.

            Dr. Bandeen-Roche emphasizing the importance of the temporary effect of the data, some way emphasizing that or showing that information, as well as my previous recommendation showing the mean manifest refraction loss data.  I think I already recommended that.

            Dr. Schein recommended some type of wordsmithing trying to discuss the differentiation between temporary and reversible. 

            CHAIRMAN WEISS:  I think it was listed in there already that it is irreversible.

            DR. GRIMMETT:  Okay.  Add a statement regarding the information that effects of the change in corneal curvature have unknown effects on current lens power calculation formulae and cataract surgery.

            Glenda Such recommending delete the reference altogether to the patient's functioning with computers, given the data was not sufficiently studied.

            Then the suggestion to re-wordsmith the following instructions regarding taking out your contact lens to eliminate any condescending or insulting type of inference.

            CHAIRMAN WEISS:  Well, no, we are going to keep that in there, I think.

            DR. GRIMMETT:  Keep it in, but re-wordsmith to get rid of the inference.

            CHAIRMAN WEISS:  Yes, to make it sound better.

            DR. GRIMMETT:  And I believe that is all I have on labeling.

            CHAIRMAN WEISS:  Mr. McCarley.

            MR. McCARLEY:  Just one comment.  I think the reversibility issue should be there is no evidence.  You should not put it that it is not reversible, because you don't know whether it is or not.

            CHAIRMAN WEISS:  It's 100 percent not reversible.  You can't stick a needle in the eye and then --

            MR. McCARLEY:  The effects are what you were talking about, though, weren't they?  The effects are --

            CHAIRMAN WEISS:  -- not reversible.  They actually had it in the labeling that it is irreversible.  So it's really not an issue.

            MR. McCARLEY:  So we are talking about the effects of the surgery.  I understood from Dr. Durrie that, in fact, he had reversed the effects.  He had re-treated a patient with -- So he changed the effect is what I'm saying.

            CHAIRMAN WEISS:  Well, he needed to do a re-treatment, but he didn't reverse the effect.

            DR. SMITH:  Can I suggest one sentence?

            CHAIRMAN WEISS:  Sure.  Dr. Smith.

            DR. SMITH:  "Although the effect of CK on near vision is temporary, the overall effect of CK on the cornea is not reversible." 

            CHAIRMAN WEISS:  It's more than that.  It is not only the effect on the cornea.  It is also the refractive effect.  Maybe you will get a temporary effect, but you will get half as much eventually as what you wanted.  So it's not just the cuts into the cornea, but it's also the refractive.

            DR. SMITH:  The temporary aspect is really the effect on near vision. 

            CHAIRMAN WEISS:  I would defer to agency.  I think you probably get -- We would like to convey to the patient as well as the physician as well as possible that, one, there is no eraser on the edge of this probe and, two, that unless you can edify us further with the addition of the two-year data, we can't guaranty someone where they are exactly going to end up when they spin the wheel. 

            DR. GRIMMETT:  Those are all the labeling conditions I have.

            CHAIRMAN WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  Yes.  Just to update the labeling packet with the most complete one-year data available as it is ready to go.

            CHAIRMAN WEISS:  Good suggestion.  So we will add that.

            If there is no other additions to the laundry list, then I would like to have a vote on the labeling.  All of those who agree with the labeling as listed, can you please raise your hand in the affirmative.

            MS. THORNTON:  In the affirmative, Dr. Huang, Dr. Bandeen-Roche, Smith, McMahon, Coleman, Van Meter, Bradley, Grimmett, Casey,  Mathers, Schein, Macsai.  That is unanimous, 12.

            CHAIRMAN WEISS:  So the condition of labeling is unanimously accepted.  Are there any other conditions that you have listed, Dr. Grimmett?

            DR. GRIMMETT:  There are no others that I have listed.

            CHAIRMAN WEISS:  Are there any other conditions that anyone on the Panel -- Dr. Grimmett?

            DR. GRIMMETT:  I think it was implicit, but even though the indication we read limiting up to 2.25, I would feel strongly that the data that they have higher than that should be included in the  current labeling, because the procedure is already out in the marketplace.

            CHAIRMAN WEISS:  So we had said in the labeling with Dr. Huang's exclusionary 11 eyes of the 32, that at the same time we would include that chart on the 32.

            DR. GRIMMETT:  I want not only just -- I want all 32 spot or greater than 2.25 diopter data included regarding the effectiveness outcomes, irrespective of the fact we have limited the procedure to 2.25.

            DR. BEERS:  We will do that, because the fact is we can't lock it out at that point.

            DR. GRIMMETT:  Excellent.  So that doesn't even need to be a condition.  It sounds like you are going to do it anyway.

            DR. BEERS:  Yes.

            CHAIRMAN WEISS:  The other thing is I could use someone to refresh my memory.  There were some members of the Panel that proposed that the effectiveness in the 8-spot has not been determined, because there weren't enough patients.  I don't know if that was addressed in any of these motions or if that was not. 

            If that was not addressed, does anyone want to propose that as a motion or as a condition, which basically would mean that you need -- the FDA would have to look at further data or put it in the labeling. 

            DR. McMAHON:  Well, I had proposed that the indication would be as it is, and then there would be a statement that there is insufficient data to validate the use of 8 spots in the treatment.

            CHAIRMAN WEISS:  You want to say 8 spots or the refractive error that you would be using the 8 spots for, because a patient wouldn't know what 8 spots mean?

            DR. MACSAI:  Leave it to the agency.

            DR. McMAHON:  That is a wordsmithing thing.  The agency can deal with it, but I got around that by doing the 1.00 to 2.25, which eliminates 8 and 32.  So I think you just leave it that way.

            CHAIRMAN WEISS:  So you are basically giving an indication.  You are getting rid of the low end, and you are getting rid of the high end, as far as efficacious.  Then would you like to put in there then -- As long as you are putting in the data for the 32, do you want to put in the data for the 8?

            DR. McMAHON:  More data is better.

            DR. GRIMMETT:  It sounds like the agency would do that anyway.

            CHAIRMAN WEISS:  The agency is putting in the data for the 8, in any case?  So the way it is presently listed, you would not need anything else from us?

            DR. BEERS:  I just wanted to clarify the indication, because when you started asking again about 8-spot, I thought, as Dr. McMahon said, that from 1.00 to 2.25 is eliminating 8, the low end and the high end, just to make sure this is what you all were saying.

            CHAIRMAN WEISS:  So the Panel has agreed to eliminate the low end and the high end, but put all the data in there, if a physician intends to treat off-label.  We have that as an indication.  So the indication is for +1.00 to +2.25. 

            We are listing it as a refractive indication, but basically the 8-spot was less than 1 diopter of attempted treatment, and the 32-spot was more than 2.25 diopter of attempted treatment.  So, effectively, those two were eliminated by that indication.  Dr. Macsai.

            DR. MACSAI:  We had also requested the 24-month data with the establishment of substantial equivalence included.

            CHAIRMAN WEISS:  Was that listed in your--

            DR. GRIMMETT:  I intended to include that.  If it's not clear, but I did intend to include that when I asked for the 24-month data on the old PMA.  Yes.

            DR. MACSAI:  Okay.

            CHAIRMAN WEISS:  So I don't think we need to vote on that again, because the Panel agreed to that.  Just so the agency knows that, if that wasn't included in the transcript, substantial equivalency between the two groups was also requested, between the previous PMA group and this group.

            Any other conditions?  Okay, so if there are no other conditions, then we will have a vote on the main motion, the motion being approvable with conditions for PMA PO10018/S005.

            Those of you who are in agreement to approve this PMA with conditions, can you raise your hand, if you are voting in the affirmative?

            MS. THORNTON:  Voting in the affirmative, Dr. Huang, Bandeen-Roche, Smith, McMahon, Coleman, Van Meter, Bradley, Grimmett, Casey, Mathers, Schein, and Macsai.  It is unanimous, 12 votes.

            CHAIRMAN WEISS:  So the PMA has passed unanimously.  I am going to now poll the members of the Panel as to why you voted the way you did.  Dr. Macsai?

            DR. MACSAI:  I voted in the affirmative.  The device is already on the market.  Safety has been established.  The effect is temporary.

            CHAIRMAN WEISS:  Dr. Schein.

            DR. SCHEIN:  The excellent safety profile excuses moderate effectiveness.

            CHAIRMAN WEISS:  Dr. Mathers.

            DR. MATHERS:  I believe it offers considerable patient satisfaction and has excellent safety.

            CHAIRMAN WEISS:  Dr. Casey.

            DR. CASEY:  The procedure seems to be safe, and patients are satisfied.  It seems to be effective in the limited range that we have discussed.              CHAIRMAN WEISS:  Dr. Grimmett.

            DR. GRIMMETT:  I am in favor of the proposal, because even though the treatment range is limited, the data available to both patients and physicians will now be available for a previous practice that was off-label.

            CHAIRMAN WEISS:  Dr. Bradley.

            DR. BRADLEY:  The device is clearly safe  and sufficiently effective.

            CHAIRMAN WEISS:  Dr. Van Meter.

            DR. VAN METER:  I agree with Dr. Grimmett.

            CHAIRMAN WEISS:  Dr. Coleman.

            DR. COLEMAN:  I voted approvable with conditions, because I had reasonable assurance of safety and effectiveness.

            CHAIRMAN WEISS:  Dr. McMahon.

            DR. McMAHON:  I voted for approvable with conditions on the basis that the procedure appears to be safe and effective within the limits that we have defined.

            CHAIRMAN WEISS:  Dr. Smith.

            DR. SMITH:  I agree with Dr. McMahon.

            CHAIRMAN WEISS:  Dr. Bandeen-Roche.

            DR. BANDEEN-ROCHE:  I also agree with Dr. McMahon.

            CHAIRMAN WEISS:  Dr. Huang.

            DR. HUANG:  I voted for approvable with conditions based on the limited efficacy and good safety.  In addition, I also feel approval will provide a guideline to the general public that this is a viable alternative for us.  Some of the patients may be benefiting from this procedure.

            CHAIRMAN WEISS:  Mr. McCarley, do you have  any comments?

            MR. McCARLEY:  The only comment is I am glad the Panel saw this, taking the opportunity to take a device that is already being used on the market and allowing the company to reasonably provide additional information to doctors and to patients.  Otherwise, they would have continued to use this without it.  So I think it was the right decision.

            CHAIRMAN WEISS:  Ms. Such?

            MS. SUCH:  I would like to thank the Panel for the time that they spent in considering the patients' concerns and for also including them in the passage of this particular device.

            CHAIRMAN WEISS:  I wanted to thank members of the Panel and the primary reviewers for their excellent reviews, and the FDA for their usual thorough job, and the sponsor for making it so easy to evaluate their study and for their hard work.

            Sally, do you have any closing comments?

            MS. THORNTON:  I just wanted to thank the Panel for bearing with us all and for two days of very good work, and also for the staff putting their heart behind this.

            I also want to announce to everyone that there is going to be another Panel meeting March 5th, and it is going to be a general issues discussion surrounding the use of intraocular lenses with clear lens extraction.  So we will see you then.

            CHAIRMAN WEISS:  The Open Meeting is adjourned.

            (Whereupon, the foregoing matter went off the record at 3:09 p.m.)