FOOD AND DRUG ADMINISTRATION






                        OPHTHALMIC DEVICES PANEL


                             108TH MEETING






                         Friday, March 5, 2004


                               9:00 a.m.




                       Gaithersburg Holiday Hotel

                      2 Montgomery Village Avenue

                         Gaithersburg, Maryland




                        P A R T I C I P A N T S

         Jayne S. Weiss, M.D., Chairperson

         Sara M. Thornton, Panel Executive Secretary




         Arthur Bradley, Ph.D.

         Michael R. Grimmett, M.D.

         Allen C. Ho, M.D.

         William D. Mathers, M.D.

         Timothy T. McMahon, O.D.




         Ronald E. McCarley




         Neil M. Bressler, M.D.

         Jeremiah Brown, Jr., M.D.

         Alexander J. Brucker, M.D.

         Frederick J. Ferris, M.D.

         Leo J. Maguire, M.D.

         Janine A. Smith, M.D.

         Walter J. Stark, M.D.




         A. Ralph Rosenthal, M.D.

         Malvina B. Eydelman, M.D.

         Joseph N. Blustein, M.D.

         Don Calogero, M.S.

         Gene N. Hilmantel, O.D., M.D.




                            C O N T E N T S




      Call to Order, Jayne W. Weiss, M.D.                        4


      Introductory Remarks and Introductions,

         Sara M. Thornton, Executive Secretary                   4


      Conflict of Interest Statement,

         Sara M. Thornton, Executive Secretary                   7


      Branch Updates, Karen F. Warburton, M.S.,

      Vitreoretinal and Extraocular Devices Branch               9


      FDA Presentation:


      Clear Lens Extraction for the Correction of



         Malvina B. Eydelman, M.D., Division of

         Ophthalmic and Ear, Nose and Throat Devices            11


         Joseph N. Blustein, M.D., M.P.H., Division of

         Ophthalmic and Ear Nose and Throat Devices             14


         Malvina B. Eydelman, M.D., Division of

         Ophthalmic and Ear, Nose and Throat Devices            28


      Open Public Hearing:


         Adrian Glasser, Ph.D., College of Optometry,

         University of Houston                                  42


         Stephen Lane, M.D., University of Minnesota            51


         Randall J. Olson, M.D., University of Utah

         (Letter Read by Ms. Thornton)                          65


      Panel Deliberations                                       68




  1                      P R O C E E D I N G S


  2                          Call to Order


  3             DR. WEISS:  I would like to call this


  4   meeting of the Ophthalmic Devices Panel to order,


  5   and we will have introductory remarks from Sarah


  6   Thornton, the Executive Secretary of the Panel.


  7             MS. THORNTON:  Good morning.  On behalf of


  8   the FDA, I would like to welcome you to the 108th


  9   meeting of the Ophthalmic Devices Panel.


 10             Before we proceed with today's agenda, I


 11   have a few short announcements to make.  I would


 12   like to remind everyone to sign in on the


 13   attendance sheets in the registration area, just


 14   outside the meeting room.  All public handouts for


 15   today's meeting are available at the registration


 16   table.  Messages for panel members and FDA


 17   participants, information or special needs should


 18   be directed through Ms. Annemarie Williams who is


 19   available in the registration area.  The phone


 20   number for calls to the meeting area is


 21   301-977-8900.


 22             In consideration of the panel, the sponsor


 23   and the agency, we ask that those of you with cell


 24   phones and pagers either turn them off or put them


 25   on vibration mode while in this room, and make your




  1   calls outside the meeting area.


  2             Lastly, will all meeting participants


  3   please speak clearly into the microphone and give


  4   your name so that the transcriber will have an


  5   accurate recording of your comments?


  6             At this time I would like to extend a


  7   special welcome and introduce to the public, the


  8   panel and the FDA staff two new panel consultants


  9   who are with us at the table today for the first


 10   time.


 11             On my right, Dr. Neil Bressler, Professor


 12   of Ophthalmology, with an international referral


 13   practice in the Retinal Vascular Center at the


 14   Wilmer Eye Institute of The Johns Hopkins


 15   University School of Medicine; and Dr. Jeremiah


 16   Brown, Jr., who is the director of Ophthalmology


 17   Research at the Walter Reed Army Institute of


 18   Research Laboratory at Brooks Air Force Base in San


 19   Antonio, in addition to maintaining a private


 20   retina practice with Ophthalmology Associates of


 21   San Antonio.  Welcome, gentlemen.


 22             Will the remaining panel members please


 23   introduce themselves, beginning with Rick McCarley?


 24             MR. MCCARLEY:  Good morning.  My name is


 25   Rick McCarley.  I am President of Ophtec and I am




  1   the industry representative.


  2             DR. BRUCKER:  Alexander Brucker,


  3   Philadelphia, Pennsylvania, Professor of


  4   Ophthalmology at the University of Pennsylvania


  5   Scheie Eye Institute.


  6             DR. FERRIS:  Rick Ferris, I am the head of


  7   the Division of Epidemiology and Clinical Research


  8   at the National Eye Institute.


  9             DR. BRADLEY:  Arthur Bradley, Professor of


 10   Vision Science, Indiana University.


 11             DR. MCMAHON:  Tim McMahon, Professor of


 12   Ophthalmology, Department of Ophthalmology,


 13   University of Illinois in Chicago.


 14             DR. WEISS:  Jayne Weiss, Professor of


 15   Ophthalmology and Pathology, Kresge Eye Institute,


 16   Wayne State University, Detroit.


 17             DR. GRIMMETT:  Michael Grimmett, Bascom


 18   Palmer Eye Institute, University of Miami.


 19             DR. MATHERS:  Bill Mathers, Professor of


 20   Ophthalmology at Oregon Health Sciences University.


 21             DR. HO:  Good morning.  Allen Ho,


 22   vitreoretinal surgeon, Wills Eye Hospital, Thomas


 23   Jefferson University.


 24             DR. SMITH:  Janine Smith, Deputy Clinical


 25   Director of the National Eye Institute.




  1             DR. BRESSLER:  Neil Bressler, already


  2   introduced.


  3             DR. BROWN:  Jeremiah Brown.


  4             DR. STARK:  Walter Stark, Professor of


  5   Ophthalmology, Wilmer Eye Institute, Baltimore,


  6   Maryland.


  7             DR. MAGUIRE:  Leo Maguire, Associate


  8   Professor, Mayo Clinic, Rochester, Minnesota.


  9             DR. ROSENTHAL:  Ralph Rosenthal, Division


 10   Director, Ophthalmic and ENT Devices.


 11             MS. THORNTON:  Thank you.  I would like to


 12   note for the record that the panel consumer


 13   representative, Ms. Glenda Such, will not be in


 14   attendance today due to illness.  Thank you, Jayne.


 15                  Conflict of Interest Statement


 16             I would now like to read the conflict of


 17   interest statement for today's meeting.  The


 18   following announcement addresses conflict of


 19   interest issues associated with this meeting, and


 20   is made part of the record to preclude even the


 21   appearance of an impropriety.


 22             To determine if any conflict existed, the


 23   agency reviewed the submitted agenda for this


 24   meeting and all financial interests reported by the


 25   committee participants.  The conflict of interest




  1   statutes prohibit special government employees from


  2   participating in matters that could affect their or


  3   their employers' financial interests.  However, the


  4   agency has determined that participation of certain


  5   members and consultants, the need for whose


  6   services outweighs the potential conflict of


  7   interest involved, is in the best interests of the


  8   government.


  9             Therefore, a waiver has been granted to


 10   Dr. Alexander Brucker for his interest in a firm at


 11   issue that could potentially be affected by the


 12   panel's recommendations.  The waiver allows him to


 13   participate fully in today's deliberations.  Copies


 14   of this waiver may be obtained from the agency's


 15   Freedom of Information Office, Room 12A-15 of the


 16   Parklawn Building.


 17             We would like to note for the record that


 18   the agency took into consideration certain matters


 19   regarding Drs. Alexander Brucker, Neil Bressler,


 20   Frederick Ferris, Michael Grimmett, Allen Ho and


 21   Jayne Weiss.  They reported interests in firms at


 22   issue but in matters not related to today's agenda.


 23   The agency has determined, therefore, that they may


 24   participate fully in all discussions.


 25             In the event that the discussions involve




  1   any other products or firms not already on the


  2   agenda for which an FDA participant has a financial


  3   interest, the participant should excuse himself or


  4   herself from such involvement and the exclusion


  5   will be noted for the record.


  6             With respect to all other participants, we


  7   ask in the interest of fairness that all persons


  8   making statements or presentations disclose any


  9   current or previous financial involvement with any


 10   firm whose products they may wish to comment upon.


 11   Thank you, Jayne.


 12             DR. WEISS:  Thank you.  We are going to


 13   now have branch updates, Karen Warburton.


 14                          Branch Updates


 15             MS. WARBURTON:  Good morning.  I would


 16   like to present one item of interest from our


 17   Branch.  One of the device types that the VEDB


 18   reviews is the ophthalmic sponge, which is used


 19   during LASIK surgery.  We have recently become


 20   aware of Medical Device Reports, or MDRs, that


 21   identified an association between ophthalmic


 22   sponges and diffuse lamellar keratitis.  Testing of


 23   a sample of ophthalmic sponges from a lot


 24   associated with a cluster of DLK cases showed


 25   significantly higher levels of bacterial endotoxin




  1   than a different lot.  Additional MDRs have also


  2   reported an association between microkeratomes and


  3   DLK, although most of those reports did not


  4   implicate endotoxin per se.


  5             Endotoxin has been shown to cause DLK in a


  6   rabbit model and there have been reports in the


  7   literature implicating endotoxin from sterilizer


  8   water reservoirs as a cause of DLK outbreaks.


  9   Additionally, a variety of other etiological


 10   factors have been suggested.  However,


 11   endotoxin-contaminated ophthalmic sponges have not


 12   previously been identified as a possible cause of


 13   DLK.  Endotoxin-contaminated water used during


 14   device manufacture is a potential source.


 15   Historically, FDA has not required that ophthalmic


 16   sponges or other devices used in LASIK surgery be


 17   pyrogen or endotoxin free, and they are typically


 18   not labeled as such, although many may, in fact, be


 19   endotoxin free.


 20             Our Branch is working with other Center


 21   offices to make the ophthalmic community aware of


 22   this potential cause of DLK through letters to


 23   professional organizations and letters to the


 24   editor in journals which we anticipate will be


 25   published in the near future.  We hope to encourage




  1   reporting of DLK to FDA through MDR reporting, and


  2   to stimulate both user and FDA investigation into


  3   these outbreaks so that we can better understand


  4   the role that ophthalmic devices and endotoxin in


  5   particular play in DLK, and make changes in our


  6   product review policies if necessary.  That


  7   concludes my update.  Are there any questions?


  8             DR. WEISS:  Seeing no questions, thank you


  9   very much, Karen.  We will now begin the open


 10   committee session with the general issues


 11   discussion and the FDA team presentation.  Dr.


 12   Eydelman?


 13                      FDA Team Presentation


 14             DR. EYDELMAN:  Good morning.


 15             [Slide]


 16             Today's discussion is centered around


 17   clear lens extraction for the correction of


 18   presbyopia.  I want to thank Dr. Blustein, Don


 19   Calogero and Gene Hilmantel for organizing today's


 20   presentation and preparing all the materials.


 21             [Slide]


 22             Clear lens extraction--or CLE as we will


 23   be referring to it for the rest of the day--for the


 24   correction of presbyopia is an intraocular surgical


 25   procedure where non-cataractous lens is removed and




  1   replaced with a multifocal intraocular lens,


  2   allowing for both distance and near vision.  The


  3   sole purpose of this procedure is for refractive


  4   correction.


  5             [Slide]


  6             There are several points I wanted to make


  7   sure panel members are clear on.  CLE is not


  8   currently approved in U.S. for any indication.  It


  9   has been performed, as all of you know, as an


 10   off-label practice for several years but mainly in


 11   eyes with high refractive errors.


 12             [Slide]


 13             There are currently no standards or


 14   guidances available for clear lens extraction with


 15   IOL implantation.


 16             [Slide]


 17             There is currently only one multifocal IOL


 18   approved in U.S., but there are quite a few under


 19   investigation.  Only two IOLs are approved for


 20   improving near vision acuity in presbyopic


 21   patients, and that is the AMO Array and the CMC


 22   Vision.  Several different devices utilizing quite


 23   various approaches are under investigation.  Again,


 24   there are no standards or guidances for devices


 25   solely intended for the correction of presbyopia.




  1             [Slide]


  2             An estimated 1.5 billion people worldwide


  3   have presbyopia.  Therefore, devices approved for


  4   the correction of presbyopia will have a very


  5   significant public health impact.


  6             [Slide]


  7             The challenge that faces us today is in


  8   trying to design a study which will be least


  9   burdensome for establishing safety and efficacy of


 10   the device for the correction of presbyopia while


 11   making sure that the significance to public health


 12   impact due to improper trial design is considered.


 13             [Slide]


 14             We want to make sure that we address all


 15   the appropriate aspects of the appropriate study


 16   design.  So, today we will ask for your


 17   consideration on the control population;


 18   inclusion/exclusion criteria; acceptable adverse


 19   event rates; sample size; study duration; variables


 20   to be investigated; efficacy endpoints and quality


 21   of life assessment.


 22             [Slide]


 23             The goal, of course, is designing an


 24   appropriate clinical trial for evaluation of clear


 25   lens extraction for the correction of presbyopia. 




  1   The first step in pursuing that goal was


  2   identification of all relevant adverse events and


  3   their anticipated time course.  In order to address


  4   that, we did quite an extensive literature search


  5   which Dr. Blustein will summarize for you.


  6             [Slide]


  7             DR. BLUSTEIN:  Initially we looked for


  8   studies that related specifically to clear lens


  9   extraction for presbyopia.  There were very few


 10   articles that addressed this topic.  There were two


 11   that we found, Dick and associates and Packer and


 12   associates, that dealt with clear lens extraction


 13   for presbyopia.  Both studies were using the Array


 14   multifocal IOL.


 15             [Slide]


 16             Dick and associates--their study was a


 17   prospective study with 25 patients.  They were


 18   bilateral CLE with MIOL.  The average patient age


 19   was 51, with a range of 44-62.  The preop spherical


 20   equivalent ranged from minus 25.5 to plus 5.75


 21   diopters.  Follow-up was at 6 months and the


 22   outcomes for efficacy were very good, 100 percent


 23   binocular uncorrected visual acuity of 20/30 and J4


 24   or better.  However, 48 percent of the patients


 25   complained of star bursts and 36 percent complained




  1   of halos.


  2             [Slide]


  3             Packer and associates, in a retrospective


  4   study of 68 eyes and 36 patients--their study was


  5   not limited to just clear lens extraction but 34


  6   percent of the eyes had received additional


  7   procedures for astigmatism.  The average age was 58


  8   years old and the range was from 45-81.  Preop


  9   spherical equivalent ranged from minus 7.5 to plus


 10   6.5 diopters.  Follow-up was at 3 and 6 months.


 11   The outcomes--again, there was good efficacy with


 12   94 percent binocular uncorrected visual acuity of


 13   20/40 and J5 or better.  Close to 6 percent had


 14   symptomatic posterior capsular opacities requiring


 15   YAG capsulotomies.  There were no complication


 16   rates and there were no reports or assessment of


 17   visual symptoms.


 18             [Slide]


 19             Clear lens extraction with monofocal


 20   IOLs--because there was limited information for the


 21   multifocals we looked at what was done with


 22   correcting other refractive procedures with clear


 23   lens extraction so we looked at three areas for


 24   ametropia, hyperopia and myopia.


 25             [Slide]




  1             Vicary and associates, in a retrospective


  2   study of 138 cases with average patient age of


  3   close to 49 years of age, ranging from 22-69 years


  4   of age, with a range of preop spherical equivalent


  5   of minus 23.75 to plus 11.62 diopters, with an


  6   average follow-up time of 5 months, with a range of


  7   2-26 months, reported on the following outcomes:


  8   They had uncorrected visual acuity at 3 months with


  9   90 percent at 20/40 or better and close to 50


 10   percent had 20/20 or better.  Retinal detachment at


 11   5 months, there was one case so that gave a rate of


 12   0.7 percent.  Uveitis, again one case with the same


 13   rate.  Posterior capsular opacification requiring


 14   YAG capsulotomies was at 8 percent.  Additional


 15   refractive surgeries were performed in 7 cases.


 16             [Slide]


 17             For clear lens extraction for hyperopia


 18   there were several studies that were performed in


 19   U.S., England, Belgium, India and Greece.  They


 20   overall reported good efficacy in these studies.


 21   The sample sizes were relatively small, ranging


 22   from 18 to 50 eyes.  Patient age ranges were from


 23   19-86, and this is across all these studies.  The


 24   preop spherical equivalent ranged from plus 2.75 to


 25   plus 13 diopters.  The follow-up was anywhere from




  1   1-60 months in these patients.


  2             [Slide]


  3             The complications reported for the clear


  4   lens extraction for hyperopia collectively in these


  5   studies were that for posterior capsular


  6   opacification requiring YAG capsulotomy ranged from


  7   5.6 percent to 54 percent in these studies.


  8   Posterior capsular tears at the time of surgery


  9   ranged from close to 3 percent to a little over 5


 10   percent.  Two cases required IOL exchange.  Then,


 11   there were single case events reported of iris


 12   prolapse, iridodialysis, corneal burn and malignant


 13   glaucoma.  The malignant glaucoma case occurred two


 14   years after implantation.  Endothelial cell loss


 15   was reported for one study after 12 months at 7.38


 16   percent.


 17             [Slide]


 18             Then we looked at clear lens extraction


 19   for high myopia.  There are several reported


 20   studies with high efficacy.  The problems with


 21   these studies is that there are short follow-up


 22   times that are associated with them and also


 23   exclusion of lost to follow-up on patients.


 24             [Slide]


 25             Colin and associates had a 7-year




  1   follow-up of their study of clear lens extraction


  2   for high myopia.  There were 52 eyes in 30


  3   patients.  Preop spherical equivalent average was


  4   minus 16.9 diopters and the axial length in 64


  5   percent was greater than 29 mm.  Average patient


  6   age was 36, a little over 36 years of age, with a


  7   range of 22-51 years of age.  They had performed


  8   laser pre-treatments on anyone who had suspicious


  9   lesions for future retinal detachments, treating


 10   lattice, retinal tears and retinal holes.  The


 11   results of this study showed that close to 60


 12   percent were within 1 diopter of emmetropia and


 13   approximately 85 percent were within 2 diopters of


 14   emmetropia.


 15             [Slide]


 16             Colin and associates reported the retinal


 17   detachment rate at 4 years and then again at 7


 18   years.  At 4 years it was 2 percent and at 7 years


 19   it was 8.1 percent.  This points out the importance


 20   that retinal detachments can occur later in the


 21   postop period.


 22             [Slide]


 23             In this study 75 percent of the retinal


 24   detachment had YAG capsulotomies prior to the


 25   retinal detachments.  One eye had YAG one year




  1   before the retinal detachment and two eyes had YAG


  2   two years before the retinal detachment.  In the


  3   four eyes that had retinal detachments the best


  4   corrective visual acuity ranged from 20/30 to


  5   20/200 and the visual acuity in the fellow eye


  6   ranged from 20/30 to 20/100 in the untreated eye.


  7             [Slide]


  8             The slide on the right shows the posterior


  9   opacification with YAG capsulotomies.  At 4 years


 10   it was approximately 37 percent and 61 percent


 11   after 7 years.  So, again, this is to illustrate


 12   that complications of posterior opacification can


 13   occur beyond the follow-up time, short follow-up


 14   time.  So, after 7 years there was a significant


 15   number that also had complications of


 16   opacification.


 17             [Slide]


 18             The mean time to YAG in this study was a


 19   little bit over 48 months, ranging from 9-75


 20   months.  Close to 37 percent within 4 years of


 21   clear lens extraction had significant posterior


 22   capsular opacification and 61 percent within the 7


 23   years.  The odds ratio of retinal detachment after


 24   clear lens extraction and YAG versus no YAG was


 25   2.0.  Other complications that were reported in




  1   Colin's study were subfoveal choroidal


  2   neovascularization in one eye which occurred 9


  3   months after surgery, and there was a decrease in


  4   best corrected visual acuity in that eye from 20/50


  5   to 20/200.


  6             [Slide]


  7             Ripandelli and associates were reporting


  8   from the refractive surgeons studies.  They were


  9   reporting from the retinal surgeons perspective.


 10   They reported on retinal detachment secondary to


 11   clear lens extraction for high myopia.  they saw 53


 12   eyes in their practice.  The preop spherical


 13   equivalent average was minus 19.5 diopters, ranging


 14   from minus 14 to minus 29.  Patient age was an


 15   average of 37.5, ranging from 25-58 years of age.


 16   This is in Italy, this practice.  Laser pre-clear


 17   lens extraction was performed in close to 58


 18   percent of these eyes.  The time after clear lens


 19   extraction to the retinal detachment average was


 20   2.25 years and ranged anywhere from 1 month to 4


 21   years.  YAG capsulotomies had been performed in a


 22   little bit over 25 percent of these patients.


 23   Then, macular involvement was in 100 percent of the


 24   eyes that had been operated on.


 25             [Slide]




  1             Twelve eyes were lost to follow-up because


  2   they didn't come back for surgery even though that


  3   was recommended.  For retinal detachment repair, 88


  4   percent had the retina reattached; 41.5 percent had


  5   proliferative vitreoretinopathy; 34 percent had


  6   posterior retinal breaks.  The results are that 22


  7   percent had best corrected visual acuity of 20/60


  8   or better.  One patient had hand motion in one eye


  9   and 20/100 in the other.  The pre-clear lens


 10   extraction visual acuity in this patient was 20/20


 11   and 20/25.


 12             [Slide]


 13             O'Brien and associates reported that for


 14   clear lens extraction for high myopia the efficacy


 15   is certainly encouraging, that this seems to be


 16   very beneficial in terms of correcting the


 17   refractive error.  However, the potential


 18   complications still outweigh the risks.


 19             [Slide]


 20             Literature review for clear lens


 21   extraction--there was only one study with long-term


 22   follow-up.  That was the Colin study that followed


 23   for 7 years.  The rates of retinal detachment


 24   continue to increase postop, 2 percent at 4 years


 25   and then 8 percent at 7 years.  Lack of long-term




  1   retinal detachment rates post clear lens extraction


  2   is a concern.  So, we did a little literature


  3   search on retinal detachment rates post cataract


  4   extraction.


  5             [Slide]


  6             About 40 percent of all retinal


  7   detachments occur post cataract extraction.


  8   Patient-dependent risk factors include age, gender,


  9   refractive state, fellow eye, status of the


 10   posterior vitreous.  Those are patient-dependent


 11   risk factors.


 12             [Slide]


 13             Surgeon-dependent risk factors include


 14   surgical technique, whether it is intracapsular or


 15   extracapsular, phacoemulsification and also


 16   incision size, capsulotomy and maintaining anterior


 17   chamber depth.  Intraoperative complications are


 18   also risk factors--torn posterior capsule or


 19   vitreous loss.


 20             [Slide]


 21             Then, postoperative risk factors include


 22   trauma and YAG capsulotomy.


 23             [Slide]


 24             Norregaard and associates had a


 25   population-based Danish study which looked at all




  1   cataract inpatient surgeries done from 1985 to 1987


  2   with 4-6 years follow-up and patient age of 50 or


  3   over.  They used a reference group of a cohort that


  4   was age matched, gender matched and had no previous


  5   intraocular surgery.


  6             [Slide]


  7             The 4-year retinal detachment risk after


  8   cataract surgery for various surgical techniques


  9   was shown to be 3.2 percent for extracapsular


 10   without IOL; 2.8 percent for intracapsular cataract


 11   extraction without IOL; and 0.93 percent for


 12   extracapsular without IOL.  The reference group had


 13   retinal detachment rate of 0.21 percent.


 14             [Slide]


 15             The 4-year retinal detachment risk after


 16   extracapsular cataract extraction with IOL was


 17   stratified by age.  There were increasing rates


 18   with decreasing age, 2.43 percent for the age group


 19   of 50-59 years of age; 60-69 years of age, 1.51


 20   percent; 0.82 percent for 70-79 years of age; and


 21   80 and above was 0.47.


 22             [Slide]


 23             This relative risk for retinal detachment


 24   stratified by age, with the reference group having


 25   no intraocular surgery, shows that there is a




  1   significant relative risk in the younger age


  2   groups.  In the 50-59 group, they are over 20 times


  3   more likely to have a retinal detachment having had


  4   surgery; for 60-69 they are 12.5 times more likely


  5   to have retinal detachment; 70-79, close to 7 times


  6   more likely; and even 80 and older still, close to


  7   4 times more likely to have retinal detachment when


  8   no surgery was performed.


  9             [Slide]


 10             Javitt and associates, did a U.S.


 11   population-based study looking at all Medicare


 12   beneficiaries having cataract extraction in the


 13   year 1984, with a sample size of over 300,000 and


 14   they excluded the younger age Medicare


 15   beneficiaries and only included the 66 and older


 16   group.  Extracapsular extraction was done in 60


 17   percent of these patients; intracapsular was done


 18   in 31 percent; and phacoemulsification in 9


 19   percent.  They followed this in the database for


 20   rehospitalization for retinal detachments over 4


 21   years.


 22             [Slide]


 23             In their study, they showed that the risk


 24   factors were dependent on race, with whites being


 25   1.7 times more likely to have a retinal detachment




  1   than Blacks and with the various surgical


  2   techniques the intracap having the greatest risk


  3   and phacoemulsification the lowest.  The younger


  4   age is also at greater risk for retinal detachments


  5   compared to the older, and we will go into that a


  6   little bit more.


  7             [Slide]


  8             For 4-year retinal detachment risk after


  9   cataract surgery stratified by age, they found 2.2


 10   percent for 65-59 years of age patients; 1.3


 11   percent for 70-79 year-old patients; 0.6 percent


 12   for 80-89; and 0.2 percent for 90 and above.


 13             [Slide]


 14             When you look at the relative risk, the


 15   65-69 year age group were 18 times more likely to


 16   have retinal detachment than the no surgery group;


 17   70-79 years old, close to 11 times more likely to


 18   have retinal detachment; 80-89, 5 times more


 19   likely; and 90 or above, 1.67 times more likely to


 20   have retinal detachment.


 21             [Slide]


 22             Javitt did another study.  This was based


 23   on a 5 percent sample of Medicare beneficiaries.


 24   They looked at inpatient and outpatient surgeries


 25   between 1986 and 1987.  The sample size was over




  1   57,000, and they looked at 3-year follow-up for


  2   retinal detachment.


  3             [Slide]


  4             The cumulative 3-year retinal detachment


  5   rate was 0.81 percent, which was a rate similar to


  6   the previous inpatient study.  Also, they showed


  7   that younger patients were more at risk than older


  8   patients.


  9             [Slide]


 10             This is from the 3-year retinal detachment


 11   risk after extracapsular cataract extraction,


 12   showing 0.95 percent for the 65-69 year-old group;


 13   0.51 percent for the 70-79 year-olds; 0.24 percent


 14   for the 80-89 year-olds; and 0.08 percent for the


 15   90 and above.


 16             [Slide]


 17             Looking at the slide on your right,


 18   summarizing the Danish study and the earlier Javitt


 19   study, they found one-year rates for retinal


 20   detachment with extracapsular with IOL and for the


 21   Danish study it was 0.42 percent and the 4-year


 22   rate was 3.2 percent for extracapsular without IOL


 23   and then 0.93 percent for extracapsular with IOL.


 24             In the Javitt study the one-year rate for


 25   combining extracapsular cataract extraction whether




  1   it was with or without IOL was 0.3 percent and for


  2   phacoemulsification it was 0.4 percent.  The 4-year


  3   rate was 0.9 percent for extracapsular cataract


  4   extraction and 1.17 percent for


  5   phacoemulsification.


  6             [Slide]


  7             The relative risk for retinal detachment


  8   at one year in the Danish study, extracapsular


  9   cataract extraction with IOL was 14 times more


 10   likely to have retinal detachment than no surgery.


 11   At 4 years, extracapsular cataract extraction with


 12   IOL was 26.67 times more likely to have retinal


 13   detachment than no surgery; and extracapsular


 14   cataract extraction with IOL was 7.75 times more


 15   likely.


 16             In the U.S. study at one year


 17   extracapsular cataract extraction was 10 times to


 18   have a retinal detachment, and with


 19   phacoemulsification it was 13.3 times more likely


 20   to have a retinal detachment.  At 4 years the


 21   relative risk for retinal detachment with


 22   extracapsular cataract extraction was 7.5 times and


 23   for phacoemulsification was 9.75 times.


 24             [Slide]


 25             Rowe and associates reported on cumulative




  1   retinal detachment rates after extracapsular


  2   cataract extraction and phacoemulsification.  It


  3   was a population-based study in Olmstead County,


  4   Minnesota.  It was an incidence study.  They looked


  5   at retinal detachment diagnosed between 1976 and


  6   1995.  The retinal detachment rates were adjusted


  7   for age and gender and they were compared with


  8   non-surgical retinal detachment rates.


  9             [Slide]


 10             The cumulative retinal detachment rates


 11   after extracapsular cataract extraction and


 12   phacoemulsification at 2 years was 0.36 percent


 13   compared to 0.034 percent with no surgery.  At 5


 14   years it was 0.77 percent compared to 0.13 percent


 15   with no surgery.  At 10 years it was 1.29 percent


 16   compared to 0.25 percent with no surgery.


 17             [Slide]


 18             Looking at this as relative risk, at 2


 19   years it is 10.59 times more likely to have a


 20   retinal detachment with cataract surgery; at 5


 21   years it was 5.92 times more likely; and at 10


 22   years it was 5.16.


 23             [Slide]


 24             DR. EYDELMAN:  In light of the literature


 25   summary that you just heard, the first question we




  1   would like you to consider is do you recommend a


  2   control population for studies of clear lens


  3   extraction for the correction of presbyopia, or do


  4   you believe that the study subject's own


  5   preoperative data is sufficient for comparison?


  6             [Slide]


  7             If you do recommend a control population,


  8   which one of the following do you believe to be


  9   appropriate?  Is it historical control, active


 10   control or some other control?  Active control


 11   would imply concurrent enrollment in a study of


 12   subjects with no previous ocular surgery.  For


 13   historical control that you would obtain from the


 14   literature, there are several options, subjects'


 15   status post CLE for correction of presbyopia or


 16   those that have had a composite of all different


 17   refractive indications; subjects' status post


 18   cataract extraction or those that had no previous


 19   ocular surgery.  Those are, obviously, all choices


 20   we would like you to consider.


 21             [Slide]


 22             Any time we define an appropriate study


 23   population for the investigation the real issue is


 24   identifying patients for whom risk/benefit


 25   assessment warrants enrollment in such a study.




  1             [Slide]


  2             Therefore, the question we ask you is


  3   should the clinical study inclusion/exclusion


  4   criteria limit subject enrollment based on the


  5   criteria listed below?  If yes, we would like you


  6   to discuss the appropriate ranges of each limiting


  7   criteria for inclusion in the study.


  8             [Slide]


  9             Under (a) is refractive error and axial


 10   length, and we would like you to consider each one,


 11   the hyperopia and its associated refractive range;


 12   emmetropia; myopia with its range; (b) subject's


 13   age.


 14             [Slide]


 15             (c) Degree of accommodative loss, and in


 16   that discussion we would like you to consider based


 17   on what measurement you are making your


 18   recommendations; (d) preoperative endothelial cell


 19   count; and (e) any other factors, such as BCVA.


 20             [Slide]


 21             As you heard from Dr. Blustein, there are


 22   several numbers that are reported in the literature


 23   but all the literature essentially concurs that


 24   subjects with no surgery have much less chance than


 25   those that do undergo a lens extraction.




  1             [Slide]


  2             With that in mind, we would like you to


  3   consider what should be the primary safety endpoint


  4   for the study?


  5             [Slide]


  6             Another consensus from the literature is


  7   that the younger subjects do, indeed, have higher


  8   cumulative RD rates and that is basically due to


  9   the vitreoretinal interface characteristics and the


 10   fact that the risk continues to increase over time


 11   and these subjects have essentially a greater


 12   number of years left to life after the lens


 13   extraction.


 14             [Slide]


 15             So, is retinal detachment primary safety


 16   endpoint?


 17             [Slide]


 18             After clear lens extraction with MIOL


 19   subjects might experience visual symptoms requiring


 20   IOL exchange.  Therefore, endothelial cell


 21   densities should be adequate to withstand


 22   additional surgery.  From the literature review you


 23   have heard only one number, 7.38 percent


 24   endothelial cell loss at 12 months after CLE.


 25   However, these losses are really consistent with




  1   operative losses themselves.


  2             [Slide]


  3             Several years ago Don Calogero, myself and


  4   Dr. Aresnoff, from Toronto, performed a


  5   meta-analysis of a literature review to try to


  6   determine what is the operative endothelial cell


  7   loss secondary to cataract surgery.  There we


  8   determined that 8.9 percent endothelial cell loss


  9   is seen secondary to extracap and 7.4 secondary to


 10   phaco.  These are losses that were secondary to


 11   operative loss itself, i.e., the range was 2-6


 12   months.


 13             [Slide]


 14             There is no long-term data on endothelial


 15   cell loss after clear lens extraction.


 16   Furthermore, there is very limited data on


 17   long-term loss after cataract surgery.  We all know


 18   from the last several panel meetings that Bourne


 19   et. al. reported 0.6 percent CLE loss for eyes


 20   without any surgery.  However, I don't think all of


 21   you might be aware of the fact that Bourne has also


 22   performed a study showing that after cataract


 23   surgery itself there is a 2.5 percent cell loss


 24   that continues annually.  Now, this was at 10-year


 25   follow-up of a rather small cohort, 64 eyes, and




  1   surgeries were performed from '76 to '82, both


  2   extracap and intracap, and some of the subjects


  3   were left aphakic.  So, the accuracy of that number


  4   with respect to modern surgery is questionable, but


  5   the fact that there is continuous loss secondary to


  6   cataract extraction itself seems to be implicit.


  7             [Slide]


  8             In light of that, is endothelial cell loss


  9   perhaps a primary safety endpoint, or if not a


 10   primary, should it be a safety endpoint?


 11             [Slide]


 12             Once you discuss what should be the


 13   primary safety endpoint, we would like you to


 14   concentrate on the acceptable adverse event rate


 15   associated with this safety endpoint.


 16             [Slide]


 17             The next question that we would like you


 18   to consider is sample size and follow-up


 19   appropriate for clear lens extraction studies.  Not


 20   to give you a blank screen, we did several sample


 21   size assessments so you have something to work


 22   with.


 23             The slide on the left summarizes


 24   statistics that we ran for the sample sizes that


 25   would be required for maximum allowable RD rate per




  1   year.  Here we assume a historical control rate of


  2   0.01 percent annual RD.  So, in the first column we


  3   have different study duration options, 1 year, 2


  4   years, 3 years.  Just to give you an example, if we


  5   assume that the maximum allowable RD rate per year


  6   should be 0.3 percent, a study design would require


  7   321 subjects.  That is how this table reads.  If


  8   you have any questions later I can describe it


  9   further.


 10             [Slide]


 11             We also ran sample size statistics for


 12   endothelial cell loss.  There are two tables, this


 13   and the next slide.  This one is assuming a fixed


 14   historical rate of 0.6 percent annual cell loss.


 15   Again, in the first column you have one, two or 3


 16   year study duration.  Across, 1,000, 1,200, 1,400


 17   and 1,500 are some of the cell densities that we


 18   assumed for you to choose from as the minimum cell


 19   density that you would like subjects to have at age


 20   75.  As a reference, down below, in the yellow, I


 21   put down that the normal ECD at age 75 is 2,400


 22   with a standard deviation of 500.  So, once again


 23   just to try to explain to you how this table works,


 24   if you say that you would like for a subject at age


 25   75, after having clear lens extraction performed




  1   somewhere in their 40s, to end up with 1,200 cells,


  2   for a one-year study that would require 319


  3   subjects and for a three-year study only 26


  4   subjects.


  5             [Slide]


  6             As I showed you before, this is the same


  7   table but now assuming active control, i.e., you


  8   would enroll patients who are not operated and you


  9   measure their cell loss.  With the same examples,


 10   one year for 1,200 would be 638 and for three years


 11   it would be 48.


 12             [Slide]


 13             So, the question is in order to adequately


 14   determine the rates of all the adverse events and


 15   complications of concern, what do you feel is the


 16   appropriate sample size and follow-up period for a


 17   CLE study for the correction of presbyopia prior to


 18   the submission of the PMA?


 19             [Slide]


 20             I stress "prior" because the next question


 21   deals with post-market studies.  To clarify, the


 22   post-market process can detect, identify and


 23   describe new or previously undetected medical


 24   device hazards.  It also has the advantage of using


 25   real-world medical device experience to confirm the




  1   safety profile of the device that was established


  2   in the pre-market submission and it could be a


  3   condition of approval.


  4             [Slide]


  5             In light of that, do you believe a


  6   post-market study is indicated?  If so, what is the


  7   appropriate type of study, sample size and length


  8   of follow-up for such a study?


  9             [Slide]


 10             Acceptable adverse event rates for


 11   posterior chamber IOLs at one year following


 12   cataract extraction are in the FDA grid.  The


 13   updated FDA adverse event rates are listed for you


 14   on the left, and I will spare you going through


 15   them.  Are these rates applicable for correction of


 16   presbyopia in non-cataractous eyes for CLE at one


 17   year postop?  Again, we are comparing one year to


 18   one year but adverse events that were historically


 19   acceptable after cataract surgery now to eyes which


 20   have not had cataracts.


 21             [Slide]


 22             Should the acceptable adverse event rates


 23   be adjusted for the study duration recommended?  If


 24   yes, how?  Furthermore, do additional adverse


 25   events need to be collected?  If so, what should be




  1   their acceptable rates?


  2             [Slide]


  3             FDA believes that all multifocal IOLs'


  4   safety and efficacy profiles will have to be


  5   established in a cataractous population prior to


  6   initiation of a clinical trial in a non-cataractous


  7   population.  MIOL performance in a cataractous


  8   population will, therefore, be known for all tests


  9   and sub-studies outlined in ANSI draft standards


 10   for MIOLs.


 11             [Slide]


 12             On the slide on the left I summarized for


 13   you in the first column all the measurements that


 14   are recommended to be performed on all study


 15   populations.  In the column on the right are those


 16   that are done in sub-studies.  Just to clarify, it


 17   is best spectacle corrected visual acuity at


 18   distance; near visual acuity with distance


 19   correction; uncorrected visual acuity at distance;


 20   uncorrected visual acuity at near; pupil size; lens


 21   stability; and subject survey.  The sub-studies are


 22   defocus curves; fundus visualization; far contrast


 23   sensitivity; and functional performance.


 24             [Slide]


 25             Which sub-studies do you recommend for




  1   inclusion in the clear lens extraction protocol for


  2   evaluation of performance in this non-cataractous


  3   population?  A) is functional performance and the


  4   functional performance study determines deficits in


  5   functional vision secondary to optical effects or


  6   multifocal IOLs.  An example is a driving


  7   simulation study which was performed for MIOLs.


  8             B) is contrast sensitivity and the current


  9   recommendation is for grading contrast sensitivity


 10   tests to assess threshold for spatial gradings.


 11             C) is defocus curves and defocus


 12   evaluation comparing clinical performance to the


 13   theoretical lens design.  What is done is that a


 14   subject's best spectacle corrected visual acuity at


 15   distance is obtained for the subject, and then the


 16   subject is defocused in 0.5 diopter steps to minus


 17   5 diopters.


 18             D) is fundus visualization and the current


 19   recommendation is for the investigators to rate the


 20   clarity of the retinal image through multifocal


 21   versus monofocal IOLs.


 22             Then there is the endothelial cell


 23   evaluation and I think you all know about that by


 24   now, and any others that you might recommend.


 25             [Slide]




  1             The only current performance efficacy


  2   endpoint for aphakic posterior chamber IOLs, from


  3   the FDA grid once again, is post-operative BCVA of


  4   20/40 or better in 92.5 percent of the subjects.


  5   Is this applicable to non-cataractous eyes


  6   undergoing CLE for the correction of presbyopia?


  7             [Slide]


  8             Question 7 B), are the predictability--75


  9   percent of eyes with MRSE plus/minus 1 diopter and


 10   50 percent with MRSE plus/minus 0.5 diopter and


 11   UCVA endpoint of 85 percent with 20/40 or better,


 12   outlined in FDA's draft guidance for refractive


 13   implants, applicable for this scenario?


 14             [Slide]


 15             Do we need to establish a performance


 16   efficacy endpoint for UCVA at near in this


 17   population of subjects who are undergoing surgery


 18   for the correction of presbyopia?  If yes, what do


 19   you recommend?


 20             [Slide]


 21             What additional performance efficacy


 22   endpoints, if any, need to be set?


 23             [Slide]


 24             Something that you all need to consider is


 25   whether a general population of presbyopes without




  1   cataracts will be tolerant of potential optical


  2   aberrations associated with MIOLs.


  3             [Slide]


  4             How do you recommend that we evaluate


  5   patient's quality of life issues?


  6             [Slide]


  7             There are several questionnaires which are


  8   validated and recommended in our ANSI standards,


  9   Javitt, Vitale, Schein and NEI refractive.  If you


 10   can make a specific recommendation about the


 11   applicability of these questionnaires or


 12   combination of them, we would greatly appreciate


 13   it.  This concludes our presentation.


 14             DR. WEISS:  Dr. Eydelman and Dr. Blustein,


 15   your presentation was absolutely superb and I hope


 16   the clarity of your questions can be met by the


 17   panel's answer to your questions.


 18             DR. EYDELMAN:  Thank you.


 19             DR. WEISS:  Thank you very much.  We are


 20   now going to open the open public hearing session.


 21   Before we do, there is a statement that the FDA


 22   requires me to read.  Both the Food and Drug


 23   Administration and the public believe in a


 24   transparent process for information gathering and


 25   decision-making.  To ensure such transparency at




  1   the open public hearing session of the advisory


  2   committee meeting, FDA believes that it is


  3   important to understand the context of an


  4   individual's presentation.  For this reason, FDA


  5   encourages you, the open public hearing speaker, at


  6   the beginning of your written or oral statement to


  7   advise the committee of any financial relationship


  8   that you may have with a sponsor its product and,


  9   if known, its direct competitors.  For example,


 10   this financial information may include the


 11   sponsor's payment of your travel, lodging or other


 12   expenses in connection with your attendance at the


 13   meeting.  Likewise, FDA encourages you at the


 14   beginning of your statement to advise the committee


 15   if you do not have such financial relationships.


 16   If you choose not to address this issue of


 17   financial relationships at the beginning of your


 18   statement it will not preclude you from speaking.


 19             We have two speakers today.  I will ask


 20   Dr. Adrian Glasser, Associate Professor at the


 21   College of Optometry, University of Houston, to


 22   come forward for his presentation.  I will inform


 23   members of the panel that there will be an


 24   opportunity to ask questions, both to the FDA team


 25   as well as the open public hearing presenters, at




  1   the beginning of the panel deliberations.


  2                       Open Public Hearing


  3             DR. GLASSER:  Thank you.  I would just


  4   like to start by saying thank you very much for the


  5   opportunity to present.


  6             [Slide]


  7             I am going to be talking on the topic of


  8   pseudophakic accommodation measurements.  As


  9   mentioned, my name is Adrian Glasser.  I am an


 10   Associate Professor at the College of Optometry at


 11   the University of Houston.


 12             [Slide]


 13             I am a scientist with research interest in


 14   accommodation and presbyopia.  I have research


 15   funding and I serve as a consultant to several


 16   companies with interests in accommodation


 17   restoration concepts.  I am here in my capacity as


 18   an interested scientist and as a consultant to


 19   industry.


 20             My attendance at this meeting has been


 21   sponsored by a company with interest in


 22   accommodation restoration concepts.  I am not


 23   talking about any specific devices so I have no


 24   proprietary interests in anything I will be


 25   presenting in this talk.




  1             [Slide]


  2             The purpose of my presentation is to


  3   attempt to open a healthy, constructive and


  4   informed dialogue between the FDA, researchers,


  5   clinicians and companies with interests in


  6   accommodation restoration concepts on the issues


  7   and challenges of pseudophakic accommodation


  8   measurement.


  9             [Slide]


 10             The presentation that I will make is


 11   primarily directed at accommodative IOLs rather


 12   than multifocal IOLs.  Accommodative intraocular


 13   lenses are IOLs designed to provide uncorrected


 14   vision over a continuous range of distances without


 15   multifocality by producing an optical change in the


 16   power of the eye through movement or through change


 17   in shape of the optic.  These are IOLs designed to


 18   provide dynamic accommodation.  Demonstrated proof


 19   of efficacy is important for accommodative IOLs


 20   and, perhaps even more so, if they are to be used


 21   for the correction of presbyopia after clear lens


 22   extraction.


 23             [Slide]


 24             Pseudophakic accommodation measurement is


 25   important for patient informed consent, for patient




  1   risk/benefit analysis, for clinical study design


  2   and testing, for selection of clinical control


  3   groups, for inclusion/exclusion criteria in


  4   clinical trials, and in patient populations and for


  5   product labeling following FDA approval.


  6             [Slide]


  7             I am going to ask more questions in this


  8   presentation than I have answers for, and here are


  9   some to start.  What will the FDA consider as the


 10   gold standard for pseudophakic accommodation


 11   measurement?  How will the FDA determine if the


 12   benefits of an accommodative IOL outweigh the risks


 13   of clear lens extraction?  What kind of


 14   accommodation testing will the FDA require for


 15   accommodative IOL clinical study designs?  Will


 16   these be subjective tests, objective tests or a


 17   combination of both?  What tests or instrumentation


 18   should researchers and clinical investigators


 19   become familiar with for these clinical trials?


 20   And, what kind of instruments will the FDA consider


 21   as appropriate for objective accommodation


 22   measurement, refraction to measure an optical


 23   change in the eye versus, for example, A-scan


 24   biometry to measure movements of an optic in the


 25   eye?




  1             [Slide]


  2             I want to talk a little about subjective


  3   testing of accommodation.  Distance corrected near


  4   visual acuity with subjective push-up test and


  5   negative lens-induced defocus have long been, and


  6   remain, clinical standards for accommodation


  7   testing.  These and other subjective tests are


  8   easily implemented, are routinely used clinically.


  9   They could readily by used in clinical trials and


 10   they provide widely accepted indicators of


 11   functional near vision, both for patients as well


 12   as for clinicians.  However, these tests are not


 13   quantitative measures of accommodative amplitude


 14   and they do not unequivocally demonstrate an


 15   accommodative change in optical power of the eye.


 16   What reliance will the FDA place on these and other


 17   subjective tests for future clinical trials of


 18   accommodative IOLs?


 19             [Slide]


 20             I want to talk a little about producing an


 21   accommodative response.  To measure accommodative


 22   amplitude a full and maximum accommodative response


 23   must be elicited from the subject or patient.


 24   Accommodation can be stimulated with near or


 25   proximal targets by inducing blur such as by




  1   presenting minus lenses to induce defocus on a


  2   distant letter chart, or with pilocarpine drops


  3   directly applied to the eye.  Some individuals


  4   accommodate poorly in some conditions to pure blur


  5   fuse for example.


  6             If no accommodation is recorded, it does


  7   not necessarily mean that the eye cannot


  8   accommodate.  It may simply mean the subject has


  9   chosen not to accommodate.  Pilocarpine drops on


 10   the eye can be used to stimulate an involuntary


 11   accommodative response.  Will the FDA consider


 12   pharmacologically stimulated accommodation for


 13   determining efficacy of accommodative IOLs?


 14             [Slide]


 15             I would like to talk a little about


 16   objective measurement of accommodation.  Clinical


 17   infrared autorefractors rely on analysis of


 18   reflected light signals and often fail or are


 19   inaccurate when light is reflected off high index


 20   IOL materials.


 21             Instruments often used to measure


 22   accommodation objectively in research labs are no


 23   longer commercially available.  New developing


 24   instruments are lacking validation, are not


 25   routinely available now, and their availability in




  1   the future may be uncertain.


  2             Standard clinical autorefractors, while


  3   tested and validated on phakic eyes, have not been


  4   tested and validated in pseudophakic eyes and may,


  5   in fact, not measure accurately or may not measure


  6   at all in pseudophakic eyes.  Lower accommodative


  7   amplitudes expected of pseudophakic eyes will place


  8   higher demands on the resolution of these


  9   instruments.


 10             [Slide]


 11             Continuing with objective measurement of


 12   accommodation, there is considerable uncertainty as


 13   to the availability of instruments that are capable


 14   of objective pseudophakic accommodation measure.


 15             What objective instruments will the FDA


 16   accept or mandate for future clinical trials of


 17   accommodative IOLs?  Have these instruments been


 18   validation to accurately measure accommodation


 19   either in pseudophakic or, in fact, in phakic eyes?


 20   Will these instruments be able to reliably measure


 21   pseudophakic eyes, and will these instruments be


 22   generally available for placement at multiple


 23   clinical sites?


 24             [Slide]


 25             I would like to talk a little about




  1   comparison of performance with the standard or


  2   monofocal IOL.  Comparison with the standard


  3   non-accommodative, non-multifocal IOL using


  4   accepted subjective clinical tests, such as


  5   distance corrected near visual acuity, can provide


  6   an indication of whether an IOL provides functional


  7   near vision beyond that which would be provided by


  8   the standard IOL.


  9             Will the FDA accept subjective comparisons


 10   of near visual performance with standard IOLs for


 11   clinical trials of accommodative IOLs?  If so, what


 12   level of improvement over the performance of a


 13   standard IOL should be demonstrated?  How many


 14   standard IOL control patients are required to


 15   demonstrate efficacy of an accommodative IOL?


 16             [Slide]


 17             Finally, I will end by asking a few


 18   general questions about what is required to


 19   establish efficacy.  For accommodative IOLs is it


 20   more important to establish the existence of


 21   accommodation or to establish the amplitude of


 22   accommodation?


 23             If distance corrected patients can read at


 24   near after implantation of an accommodative IOL, is


 25   this adequate to establish efficacy?




  1             Many products are FDA approved without a


  2   fully elucidated mechanism of action because they


  3   work.  Would this be adequate for accommodative


  4   IOLs?


  5             How long a follow-up will be required to


  6   demonstrate longevity of efficacy of accommodative


  7   IOLs?  And, will testing standards for FDA approval


  8   be different for accommodative IOLs versus for


  9   multifocal IOLs?  Thank you very much.


 10             DR. WEISS:  Thank you, Dr. Glasser.  If


 11   you would remain at the podium for a moment, are


 12   there any questions from the panel while Dr.


 13   Glasser is up at the podium?  Dr. Bradley?


 14             DR. BRADLEY:  Thank you, Dr. Glasser for


 15   that presentation.  I think you raise a very long


 16   and challenging list of questions for the FDA and


 17   it really would take too long to go through all of


 18   them, but just a general question, you ask whether


 19   pharmacologically induced accommodation would act


 20   as a substitute for, let's call it, voluntary


 21   accommodation.  In your experience, do you have any


 22   reason to believe that it is an effective


 23   substitute, or do you think there may be, for


 24   example, a possibility that although one can induce


 25   accommodation pharmacologically the patient could




  1   not activate their accommodative mechanism


  2   willfully?  Is that a possibility?  Or, should we


  3   be happy with pharmacologically induced


  4   accommodation?


  5             DR. GLASSER:  I wouldn't suggest that as a


  6   substitute.  I don't think that it should be the


  7   sole means of identifying whether an accommodative


  8   IOL can produce an accommodative change.  I do


  9   think that it is an important addition perhaps to


 10   the armament of tools that can be used to assess


 11   the accommodative ability of an IOL.


 12             Let me just add to that by saying that it


 13   is well-known from the literature that myopes, for


 14   example, have lower stimulus response functions


 15   than emmetropes.  So, there may well be some


 16   individuals in the patient populations who struggle


 17   to elicit an accommodative response even if active


 18   accommodation is truly there, and it might be


 19   important to understand whether the lens inside the


 20   eye is capable of accommodation.  I think the


 21   pharmacological approach provides a useful tool in


 22   that regard.


 23             DR. BRADLEY:  Thank you.


 24             DR. WEISS:  Seeing no other questions from


 25   the panel, thank you very much, Dr. Glasser, for




  1   your presentation.  We are going to then have Dr.


  2   Lane.


  3             DR. LANE:  Thank you, Dr. Weiss and


  4   members of the panel for inviting me to share some


  5   comments with you today about intraocular lenses


  6   for presbyopia.


  7             [Slide]


  8             I am in private practice in the Twin


  9   Cities.  I am a clinical professor at the


 10   University of Minnesota in ophthalmology and among


 11   a number of different hats that I wear, I am a


 12   clinical monitor for Alcon Surgical, for which I am


 13   a consultant, and I am here today representing them


 14   and they have paid my expenses to be here.


 15             [Slide]


 16             As a means of introduction, I would like


 17   to talk about presbyopia as not being a normal


 18   state and, as I take out my reading glasses to try


 19   and read some of my notes, that certainly becomes


 20   very evident.  It is a progressive, degenerative


 21   loss of the ability to accommodate and it is really


 22   no different than an eye with any other refractive


 23   error in that there is no structural damage done


 24   but, clearly, it is not a normal eye.


 25             The impact on the quality of life is




  1   driving an increasing patient demand for spectacle-


  2   and contact lens-free vision.  There are very high


  3   expectations of the generally younger patient


  4   population for this as is certainly evidenced by


  5   the popularity of corneal refractive surgery.


  6             [Slide]


  7             As I look at things, there are really two


  8   pathways in which I think the agency can proceed.


  9   One is with the practice of medicine, that is to


 10   say let the market forces play themselves out.  The


 11   second is to recommend formal clinical trials.


 12             [Slide]


 13             With regard to the practice of medicine,


 14   the existing off-label practice medicine approach


 15   of refractive lens exchange--which I am using


 16   synonymously with clear lens extraction so it


 17   depends whether you are coming from a cataract


 18   point of view or you are coming from a refractive


 19   surgeon point of view--is accepted in the


 20   ophthalmic community and is continuing, and this is


 21   continuing without the approved surgical options to


 22   address safety and efficacy.  As we have already


 23   heard, there have been no studies that have been


 24   done looking at this in any long-term prospective


 25   fashion, and despite inadequate information for




  1   surgeon and patient informed consent.


  2             [Slide]


  3             Therefore, what is probably reasonable and


  4   prudent is a refractive lens exchange clinical


  5   trial.  The development of a reasonable, adequate


  6   and well-controlled study focusing on safety and


  7   efficacy assessment that will allow for the


  8   appropriate informed consent is essential.  Well,


  9   "reasonable" is certainly a very nebulous term but


 10   what we are really talking about here is being


 11   practical.  What we are talking about is using the


 12   already established safety record of modern


 13   cataract surgery, and what we are talking about is


 14   encouraging the use of existing regulatory


 15   framework and guidance, wherever possible, from the


 16   already existing body of information that we have


 17   about cataract extraction and about refractive


 18   surgery.  We believe the study should also address


 19   the functional outcomes which are so important to


 20   this group of patients and is really what is


 21   driving the entire procedure.


 22             [Slide]


 23             The parameters to measure are very


 24   well-known and I don't think we have to reinvent


 25   the wheel here.  Existing regulatory guidance




  1   already provides the sound basis for many study


  2   measurement parameters: distance, intermediate and


  3   near visual acuity and binocular defocus; stability


  4   of refraction; contrast sensitivity; pupil size,


  5   visual disturbances and adverse events; intraocular


  6   lens observations and position; and certainly


  7   quality of life.


  8             [Slide]


  9             As we look through the data, and we have


 10   also done a very thorough literature search similar


 11   to what was presented by Dr. Eydelman, we need to


 12   mitigate the perceived risks with known outcomes


 13   for modern cataract surgery.  This would include


 14   things like endothelial cell loss.  Certainly, the


 15   similarity, however, of this refractive posterior


 16   chamber lens procedure to modern cataract surgery


 17   eliminates, we feel, any need for ongoing


 18   endothelial cell count measurements.  We have a


 19   body of evidence in terms of modern clinical


 20   cataract surgery done in a modern fashion.


 21             But retinal detachment--again, the


 22   numbers, depending on where you look, vary all over


 23   the board.  The numbers that we looked at are


 24   similar to those that were presented by Dr.


 25   Eydelman and show that anywhere from 0.0-0.9




  1   percent incidence of retinal detachment with modern


  2   phacoemulsification techniques in the post-1980


  3   era.  This was modern cataract literature that was


  4   surveyed for retinal detachment risk factors.


  5             [Slide]


  6             The risk factors that we identified that


  7   we believe should be proposed as potential


  8   exclusion criteria are similar to those that were


  9   discussed by Dr. Eydelman.  We too found that age


 10   is a risk factor, especially less than 40; that


 11   high myopia is a risk factor, especially greater


 12   than 8 diopters; that axial length is a risk


 13   factor, especially greater than 25 mm; and that any


 14   history of peripheral retinal disease is a risk


 15   factor.


 16             Certainly, there are surgically-related


 17   risk factors.  Posterior capsule integrity is


 18   critical.  There is loss of posterior capsule if


 19   there is vitreous loss.  If there is a YAG laser


 20   capsulotomy the incidence, as has been seen,


 21   increases.  However, with the use of modern lens


 22   removal techniques and new foldable intraocular


 23   lenses, I think that many of these risks can be


 24   minimized.  Most of the studies Dr. Eydelman


 25   presented were from the early 1990s with larger




  1   incisions, with PMA lenses, with different edge


  2   designs and with different surgical techniques.


  3   This is going to be a population of people that, by


  4   and large, will have larger pupils; will have


  5   softer lenses; will have many of the decrease in


  6   risk factors that we now see in the cataract


  7   population of patients that we are having to deal


  8   with.  So, we should be able to perform safer


  9   surgery.


 10             [Slide]


 11             The results of our retinal detachment


 12   literature survey shows that the retinal detachment


 13   rate in lens removal patients, when applying the


 14   proposed exclusion criteria that were just


 15   mentioned on the slide, was no different than that


 16   occurring in the untreated population, which is


 17   between 0.0 and 0.1 percent with up to 8 years of


 18   follow-up.


 19             [Slide]


 20             With regard to control groups, and we


 21   certainly understand that this is a concern that


 22   has been voiced by the agency with regard to the


 23   study, efficacy goals really should be reasonably


 24   met without creating overly burdensome


 25   requirements.  We feel we must reasonably weight




  1   the potential issues for the patients against the


  2   value of the information to be gathered.  Is it


  3   reasonable?  Is it fair?  Is it practical for a


  4   patient who comes in desiring refractive lens


  5   exchange to be randomized to no treatment?  I think


  6   we must use the existing guidelines that we already


  7   have in place for refractive procedures, for laser


  8   procedures as we proceed and look at the choice of


  9   control groups.


 10             [Slide]


 11             In summary, we have a number of proposals


 12   that we would like the panel to consider.  First,


 13   we would like to minimize the study size and the


 14   duration by employing the proposed exclusion


 15   criteria derived from the retinal detachment


 16   survey.  Based on an incidence of retinal


 17   detachment of 1/1,000 using this exclusion


 18   criteria, a clinical study that would be powered to


 19   detect a difference would need to be an exceedingly


 20   large sample size.


 21             We would recommend that we apply the study


 22   subject's own preoperative data to provide the best


 23   method of control  This provides roughly the same


 24   statistical power as using a non-operated control.


 25   It is consistent with current guidance documents




  1   and, importantly, it addresses the patient


  2   considerations discussed previously.


  3             [Slide]


  4             We would ask to utilize the preoperative


  5   endothelial cell minimum as an exclusion criteria


  6   based on the FDA phakic IOL requirement in the


  7   guidance that has already been given in that


  8   respect.  Finally, we would ask to employ the


  9   appropriate quality of life assessments, as an


 10   example the RSVP survey.


 11             [Slide]


 12             In conclusion, I would like to take off my


 13   Alcon hat here for a moment and put on my hat as a


 14   teacher and as a practitioner and as a leader of a


 15   number of ophthalmic organizations.  I recognize


 16   that there are a number of various interests at


 17   play here.  From the patient's standpoint, we want


 18   to meet the demand of their increasing interest in


 19   being totally spectacle and contact lens free.


 20             We want to provide safe and effective


 21   treatment that is based on real information and


 22   true informed consent.  As a surgeon, I want to


 23   provide the opportunity to deliver a service


 24   desired by our patients which we can feel confident


 25   about with regard to safety and efficacy.




  1             As the FDA, I think you need and want to


  2   fill a vacuum that presently exists and to set a


  3   threshold of safety which we can live by and


  4   industry, while certainly not in this for only


  5   altruistic reasons, does want to produce products


  6   that are safe and effective to fulfill patient


  7   needs.


  8             Finally, one that is not listed is


  9   societal.  Refractive lens exchange allows the


 10   potential for generations to come to reach Medicare


 11   age with their lenses already removed, saving


 12   government billions of dollars and, thus, becoming


 13   the ultimate cataract preventative.


 14             [Laughter]


 15             All joking aside, I do see a real


 16   opportunity here but unless reasonable and


 17   practical considerations are employed, this


 18   increasingly popular procedure will continue to be


 19   performed outside the scope of the best interests


 20   of the above parties.  Thank you.


 21             DR. WEISS:  Thank you, Dr. Lane.  Do we


 22   have any questions from the panel?  Dr. Grimmett?


 23             DR. GRIMMETT:  Dr. Lane, thank you for


 24   your presentation.  I have a question regarding


 25   slide 7.  I did a literature review over the last




  1   year or so when we discussed phakic IOLs and


  2   endothelial cell loss and the long-term endothelial


  3   cell loss rates we have been basing off old data


  4   from Bill Bourne regarding procedures that we


  5   really no longer perform.  You indicated on your


  6   slide that we have known outcomes with modern


  7   cataract surgery for endothelial cell loss rates


  8   and I was wondering if you could direct me to the


  9   literature reference or data regarding those known


 10   outcomes.


 11             DR. LANE:  I am sorry, Mike, I misspoke.


 12   As you well know, there are no known--basically I


 13   am using the numbers that have been used, and have


 14   been used by the agency to go forward with a number


 15   of the other studies that have gone forward and


 16   approval processes for new intraocular foldable


 17   lenses, and so on, using those data.  I guess from


 18   a historical perspective, if you will, the basis of


 19   the endothelial cell counts from studies that have


 20   been performed most recently with more modern


 21   intraocular lenses, foldable intraocular lenses,


 22   that have achieved approval by the agency seems to


 23   be sufficient to allow approval of those particular


 24   lenses.  So, really I guess what I am referring to


 25   is data that has been presented from previous




  1   applications, if you will, of foldable intraocular


  2   lenses and the endothelial cell counts coming from


  3   those and coming from oncoming studies that will be


  4   looking at some new foldable lenses coming down the


  5   line.  So, from a literature standpoint in terms of


  6   going back and looking at the literature and is


  7   there something out there that you have missed, the


  8   answer is no.


  9             DR. WEISS:  Dr. Mathers?


 10             DR. MATHERS:  Thank you for your


 11   presentation.  I have a similar question regarding


 12   the rate of retinal detachment.  It would seem that


 13   your slide suggesting that the rate of retinal


 14   detachment in a select group after cataract surgery


 15   is no greater than those that do not have cataract


 16   surgery.  But we heard this morning of several very


 17   large studies indicating that the retinal


 18   detachment rate is considerably higher, and also is


 19   highest in the youngest population for which we


 20   seem to have the least amount of data.  Could you


 21   explain this discrepancy?


 22             DR. LANE:  I really don't see that there


 23   is a discrepancy, Dr. Mathers, because the


 24   literature that was discussed this morning included


 25   the entire cohort.  What we are doing is separating




  1   out the high risk factors.  We are separating out


  2   the patients with high axial lengths.  We are


  3   separating out the patients with high degrees of


  4   myopia.  We are separating out patients with known


  5   peripheral retinal disease.  So, the numbers that


  6   were given that are higher are based on the entire


  7   cohort that would include those while this group


  8   includes only those that have those exclusion


  9   criteria.


 10             DR. MATHERS:  But do we have literature


 11   that shows what the detachment rate in the younger


 12   population with cataract surgery actually is?


 13             DR. LANE:  I don't know the answer to


 14   that, and I certainly don't think we know--I don't


 15   know the answer to that.


 16             DR. WEISS:  Just as a follow-up question


 17   to that, if we are going to be suggesting that they


 18   should be used in younger patients or used in


 19   higher myopes, what would you suggest then be used


 20   in those cases that we don't have the answer for


 21   adverse event follow-up in terms of duration as


 22   well as percentage?


 23             DR. LANE:  A very good question.  I don't


 24   obviously have the answer to that either, but I


 25   think that in the same way in which Dr. Eydelman




  1   suggested that the introduction of any presbyopic


  2   lens be performed in a cataract population first,


  3   the next logical step to me would be to perform it


  4   in a group that included certain exclusion criteria


  5   that we are talking about.  If that trial proves to


  6   be successful, as it would have to be if it was


  7   going on to the next step, then the next step would


  8   be to try some of the higher risk population and


  9   perform adequate studies to be able to show that.


 10             DR. WEISS:  Just a follow-up question, if


 11   you were putting this study together what would you


 12   want in terms of range of refractive error?  It


 13   sounds like you would be suggesting that the


 14   refractive errors that are most in demand to have


 15   this done, namely the very high myopes, be


 16   eliminated from an initial study and the younger


 17   patients be eliminated from an initial study.  Or,


 18   am I misreading what you are saying?


 19             DR. LANE:  No, you are not misreading what


 20   I am saying.  I think that, you know, based on the


 21   literature search that we did looking at the


 22   exclusion criteria that are present, that is the


 23   group of patients that I think should be targeted.


 24   While, yes, the high myopes would certainly benefit


 25   potentially from this kind of technology and may be




  1   the ones who would really sort of gather at your


  2   doorstep to do this in greatest numbers, for the


  3   time being certainly all of the literature suggests


  4   that those patients are at higher risk.  So, I


  5   think, again, that may be a study that needs to be


  6   done in a better fashion using more modern


  7   techniques but I think we have to get there


  8   probably in a step-wise fashion rather than trying


  9   to do it.


 10             I wouldn't necessarily agree that the


 11   majority of patients who would want to have this


 12   are necessarily the high myopes.  There is a whole


 13   group of presbyopic patients out there who would


 14   want to have this for presbyopic reasons.  While


 15   that certainly is an important group, it is


 16   certainly not the only group and may not even be


 17   the largest group.


 18             DR. WEISS:  Dr. Stark, did you have a


 19   question?


 20             DR. STARK:  You did show a reference on


 21   slide 9, Solomon, indicating that the retinal


 22   detachment risk was 0.1 percent.  It went by so


 23   fast I didn't get it--


 24             DR. LANE:  That is in the untreated


 25   population.  That is very similar to the




  1   information that Dr. Eydelman presented.  It is


  2   essentially a control group, if you will.


  3             DR. STARK:  Oh, okay.  Good.


  4             DR. WEISS:  Seeing no other questions from


  5   the panel, thank you very much, Dr. Lane, for your


  6   presentation.  Dr. Randall Olson has a letter that


  7   Sally Thornton will be reading as part of the open


  8   public hearing presenters.


  9             MS. THORNTON:  This is a letter from Dr.


 10   Randall Olson, who is the John A. Moran


 11   Presidential Professor and Chair of the Department


 12   of Ophthalmology and Visual Scientists, and


 13   Director of the John A. Moray Eye Center at the


 14   University of Utah Health Science Center:


 15             I would like to comment on the use of


 16   intraocular lenses for correction of presbyopia


 17   after clear lens extraction, a topic that is to e


 18   discussed by the Ophthalmic Devices Panel of the


 19   Medical Devices Advisory Committee on Friday, March


 20   5, 2004.  We have performed about 100 "clear"


 21   lensectomy procedures in presbyopes over the past


 22   two years.  The term "clear" lensectomy is a


 23   misnomer for us.  In our patient population, it is


 24   rare for a presbyopic patient not to have some


 25   level of lens opacification, even though it may not




  1   be significantly decreasing their Snellen visual


  2   acuity.  In a study, done by Waltz, Wallace in


  3   Ophthalmic Practice, 2001, of over 200 refractive


  4   lensectomy patients, the average age at surgery was


  5   53 years, our average is even older.  We feel that


  6   we are doing these patients a disservice to perform


  7   corneal surgery, such as LASIK, when cataract


  8   surgery due to further lens opacification may be


  9   just around the corner.  The precision of the


 10   refractive component of cataract surgery drops


 11   precipitously for post corneal refractive patients,


 12   and it is precisely this group that demands


 13   refractive precision.


 14             For the patient, clinical studies have


 15   shown a high rate of patient satisfaction with


 16   refractive lensectomy.  They perceive being


 17   "spectacle free" as an improvement in their quality


 18   of life.  With the present levels of refractive


 19   precision, the acceptance rate is as good as, or


 20   better than, LASIK.


 21             The only concern for refractive lensectomy


 22   that could conceivably be greater than cataract


 23   complications is the possibility of an increased


 24   rate of retinal detachment following surgery in


 25   high myopes.  The retinal detachment risk is not




  1   germane for emmetropes or hyperopes.  We have


  2   published several studies in this area, Powell,


  3   Olson Journal of Cataract and Refractive Surgery,


  4   1995, Olsen and Olson in the Journal of Cataract


  5   and Refractive Surgery, 1995, and Olsen and Olson


  6   in the Journal of Cataract and Refractive Surgery,


  7   2000, showing a decrease in the rate of retinal


  8   detachment as surgical techniques and equipment


  9   have improved.  For high myopes, the risk probably


 10   can be reduced by careful prescreening and the use


 11   of a phaco technique that maintains the depth of


 12   the anterior chamber during surgery.  It should


 13   also be noted that the lens is less dense and more


 14   easily removed in refractive lensectomy patients


 15   than cataract patients.  This reduces surgical


 16   complications for this group.


 17             In spite of the issue of retinal


 18   detachment in high myopes, which has been


 19   investigated in multiple studies, a prospective


 20   study of "clear" lensectomy does not seem


 21   warranted, in that our cataract database is already


 22   so large and so inclusive.  In additional, to truly


 23   study "clear" lensectomy in presbyopic patients


 24   would be extremely difficult since few of these


 25   patients have clear lenses.




  1             Signed, Randall J. Olson, M.D.  Thank you.


  2             DR. WEISS:  Thank you, Sally.  That will


  3   conclude the open public hearing session.  We will


  4   break for 15 minutes before beginning the panel


  5   deliberations.


  6             [Brief recess]


  7                       Panel Deliberations


  8             DR. WEISS:  We are now going to open the


  9   panel deliberations session and I will ask, Dr.


 10   Eydelman, if you could come to the podium and


 11   perhaps we could use the questions as a guidance.


 12   Actually, perhaps Dr. Blustein could come forward


 13   as well so that if there are any questions for the


 14   FDA from their panel presentation we could have the


 15   panel ask those at this time.  Do any of the panel


 16   members have questions for FDA?  Dr. Ho?


 17             DR. HO:  Malvina, just a question on the


 18   FDA grid for PC IOLs, what is that data derived


 19   from?


 20             DR. EYDELMAN:  One second and I will show


 21   you, I am just going to put the slide up.


 22             [Slide]


 23             This was a composite of all the PMA data


 24   that was performed.  As you see, the total N was


 25   5,906 eyes.  This particular grid encompasses all




  1   surgeries from '87 to '96.


  2             DR. HO:  So, it is a mixed bag with


  3   respect to the way the cataracts were removed I


  4   suspect.


  5             DR. EYDELMAN:  Correct.  We actually


  6   looked at this specific question two days ago


  7   because we were considering it under ISO.  We have


  8   unofficially re-looked at what these numbers would


  9   be if we just moved it forward.


 10             MR. CALOGERO:  At the last ISO meeting


 11   this week we looked at updating the grid and we did


 12   some early, preliminary work.  Unfortunately, I


 13   don't have the grid values.  They changed somewhat


 14   but what we did, we truncated off the oldest PMAs


 15   and now, if you look at the data from 1994 out to


 16   2003, there are minor changes in these rates but


 17   the retinal detachment rate goes down somewhat.


 18             DR. EYDELMAN:  The only number that was


 19   significantly different was the CME.  It went from


 20   3 percent to 1.5 percent.  But since that was


 21   unofficial, sort of our little draft, we didn't put


 22   that up.  This is the official FDA grid that the


 23   companies have been comparing their IOLs to.


 24             DR. HO:  Thank you.


 25             DR. WEISS:  Dr. Grimmett?




  1             DR. GRIMMETT:  A question in follow-up,


  2   Dr. Eydelman, did the hyphema rate go down?


  3             DR. EYDELMAN:  Slightly.


  4             GRIMMETT:  Slightly?


  5             DR. EYDELMAN:  Slightly.  For the purposes


  6   of ISO, we were looking if it would change at all


  7   our sample size for determination and it didn't.


  8             DR. GRIMMETT:  That is surprising to me


  9   because, at least in my clinical practice, it is


 10   just not common to see hyphema after modern phaco


 11   surgery.  So, I am just surprised by that.


 12             DR. EYDELMAN:  I think it was 1.5.  I


 13   don't want to quote, I don't have the numbers but


 14   it was over 1 percent.  Again, cumulative is


 15   defined as occurring any time between surgery to


 16   one year.  It is just additive.


 17             DR. WEISS:  Mr. McCarley?


 18             MR. MCCARLEY:  Yes, Rick McCarley.  I have


 19   three quick questions.  Hopefully, they will have


 20   quick answers.  Are we limiting the discussion


 21   today to multifocal lenses and accommodative IOLs


 22   or are we also talking about standard monofocal


 23   IOLs where you would use monovision, for instance?


 24   In other words, any IOL that is placed in the eye


 25   to correct the patient who can no longer




  1   accommodate?


  2             DR. EYDELMAN:  The discussion was intended


  3   to be limited to the correction where the subjects


  4   have both distance and near VA for correction of


  5   presbyopia.


  6             MR. MCCARLEY:  So, not for monofocal IOLs?


  7             DR. EYDELMAN:  Well, it could include


  8   accommodative.


  9             MR. MCCARLEY:  That is not accommodative?


 10             DR. EYDELMAN:  Correct.  It is for those


 11   IOLs that simultaneously provide distance and near


 12   VA corrections.


 13             MR. MCCARLEY:  Okay.  The second question


 14   is what is the FDA's current labeling for, for


 15   instance, accommodative IOL or the multifocal IOL


 16   related to the age range that they suggest?  In


 17   other words, my understanding is it used to be 60


 18   years and older but that was changed later on to be


 19   adults not less than 18 or not less than 21.  Is


 20   that correct?


 21             DR. EYDELMAN:  Currently all IOL sponsors


 22   may require an indication for the adult population,


 23   but that is for IOLs status post cataract


 24   extraction, correct.


 25             MR. MCCARLEY:  My final question is the




  1   FDA knows that this clear lens extraction has been


  2   going on for a while and knows that it is


  3   increasing in popularity.  Has the FDA, in the


  4   interest of public health, done anything to inform


  5   doctors or patients now, working with maybe the AAO


  6   or the SCRS, to let them know what we know now so


  7   that they will be better informed for what we know


  8   is going on?  In fact, what do you have planned


  9   between now and when any study might be completed?


 10             DR. EYDELMAN:  Well, as I mentioned, it


 11   has only been done as off-label and, as such, it


 12   has been quite an issue.  Off-label means we do not


 13   have an approved indication with safety and


 14   efficacy data that we can share.


 15             MR. MCCARLEY:  So, you recognize there is


 16   a potential public impact but the FDA doesn't feel


 17   they can do anything right now to notify the


 18   doctors or the patients?


 19             DR. WEISS:  Do you want to comment on


 20   that, Ralph?


 21             DR. ROSENTHAL:  We are a regulatory agency


 22   that regulates the medical device industry and it


 23   is not our responsibility to inform the public


 24   about issues regarding off-label use unless we feel


 25   there is a significant public health issue.




  1             MR. MCCARLEY:  I thought that was how Dr.


  2   Eydelman's presentation started off, that this is a


  3   significant, major public health issue.


  4             DR. EYDELMAN:  No, my presentation started


  5   off that if CLE for correction of presbyopia


  6   becomes widely used it can have a significant


  7   health impact.  As an aside, I said that CLE has


  8   been performed as off-label use, mostly for high


  9   refractive errors.  Those two are two distinct


 10   ideas.


 11             DR. WEISS:  I think also some companies


 12   would like to get this on-label so I don't believe


 13   it is just being driven by FDA.  Dr. Mathers?


 14             DR. MATHERS:  Is there any data indicating


 15   that the movement of an accommodative IOL would


 16   have any bearing on, say, position of the vitreous


 17   space or affect retinal detachment, uveitis or


 18   endothelial cell loss?  In other words, there


 19   appears to be no downside to an accommodative IOL


 20   that changes its position but there might be


 21   compared to another kind of straight IOL.  Do you


 22   have any data on that?


 23             DR. EYDELMAN:  No, we don't.  We only have


 24   one, as you know, IOL currently approved so we have


 25   very limited information on that issue.




  1             DR. WEISS:  Any other questions from the


  2   panel?  Seeing no other questions, we can then


  3   address the first question that the FDA is asking.


  4             1 A), do you recommend a control


  5   population for studies of clear lens extraction in


  6   the correction of presbyopia, or do you believe


  7   that the study subject's own preoperative data is


  8   sufficient for comparison?


  9             This is basically going to be a yes or no,


 10   and I want to poll each of the panel members if


 11   they want a control population or is the study


 12   subject's own preoperative data sufficient?  We


 13   will start with Dr. Maguire.  Would you like a


 14   control population, Dr. Maguire, or is preoperative


 15   data from the patient enough?


 16             DR. MAGUIRE:  I am going to pass right


 17   now.


 18             DR. WEISS:  We have an abstention.  Dr.


 19   Stark?


 20             DR. STARK:  Well, I think it would be


 21   difficult to randomize patients, if they wanted


 22   this procedure, to no treatment or treatment.  So,


 23   I think we could get enough information on


 24   complications if we had adequate long-term


 25   follow-up.  My primary concern would be the retinal




  1   detachment rate even in young people who are not


  2   myopic.  So, I think we could get this from


  3   historical control or age-matched populations.  So,


  4   I don't think a randomized, controlled study is


  5   necessary in this.


  6             DR. WEISS:  I am just going to step back


  7   for this question, for part A), it is not actually


  8   the type of control population but whether or not


  9   you want a control population.  From what I


 10   understand from what you are saying, you do want a


 11   control population but not something so onerous


 12   but, still, you would like a control population.


 13   Is that correct?


 14             DR. STARK:  Yes.


 15             DR. WEISS:  Dr. Brown?


 16             DR. BROWN:  Yes, I do feel strongly about


 17   that.  I would like there to be a control


 18   population, particularly if we include high myopes


 19   in any of thee studies.


 20             DR. WEISS:  So, you would like a control


 21   population as well.  Dr. McMahon?


 22             DR. MCMAHON:  A question--we are jumping


 23   right into controls but are we talking from a


 24   perspective of efficacy or safety, or both?


 25             DR. EYDELMAN:  We are talking with respect




  1   to study design.


  2             DR. BRUCKER:  Can I raise a question?


  3             DR. WEISS:  Actually, what I would like to


  4   do is not have a discussion now but sort of get a


  5   feeling for where people are at.  Then, once we get


  6   involved in the type of control population we will


  7   break it up into discussion.


  8             DR. BRUCKER:  Could I still ask the


  9   question because it is applicable to what you are


 10   asking.


 11             DR. WEISS:  Okay, Dr. Brucker.


 12             DR. BRUCKER:  Clear lens extraction is a


 13   surgical procedure--


 14             DR. WEISS:  Yes.


 15             DR. BRUCKER:  That surgical procedure can


 16   be done by any physician at any time, period.


 17             DR. WEISS:  A hundred percent correct.


 18             DR. BRUCKER:  The risks and complications


 19   that we are talking about have to do with clear


 20   lens extraction.  It has nothing to do with the


 21   insertion of an IOL.  So, the question that you are


 22   posing seems to be a question that can't be taken


 23   out of that context.  The insertion of an


 24   intraocular lens is not assumed, from my


 25   understanding, to be the cause of the complication.




  1   Therefore, the use of a surgical procedure called


  2   clear lens extraction should have nothing to do, in


  3   my opinion, with whether you put in monovision,


  4   presbyopic vision or anything else; it is clear


  5   lens extraction.  Perhaps we should have a little


  6   bit of discussion about the issue of clear lens


  7   extraction before you start talking about


  8   intraocular lenses.


  9             DR. WEISS:  I think technically what you


 10   are saying from a purist standpoint is correct,


 11   however, when IOLs get evaluated they get evaluated


 12   in terms of hyphema and retinal detachment rate


 13   and, from what you are saying, they shouldn't be


 14   evaluated in that way either because the IOL is not


 15   causing the RD or the hyphema but, yet, it is


 16   included in the surgical procedure and when the


 17   patient is going in for that surgical procedure you


 18   can't separate out for them that, oh well, this is


 19   the part that caused it and this part didn't cause


 20   it.


 21             So, for the purpose of this discussion,


 22   although your points are well taken and FDA can


 23   correct me, I think it doesn't really apply.  We


 24   still have to put it all together because when a


 25   patient is looking at it, who is 45 years old, who




  1   is a minus 15, whether they are getting the RD 7


  2   years down the line from the IOL or they are


  3   getting it from the surgical procedure they are


  4   still going to end up with an RD and that is the


  5   information they need.  Agency, would you agree?


  6             DR. EYDELMAN:  You are absolutely correct


  7   because we are talking about approval of a


  8   particular IOL for a specific indication and that


  9   indication would incorporate a clear lens


 10   extraction which would precede the implantation.


 11   So, it is looked at as a package deal.


 12             DR. BRUCKER:  Yes, but you presented


 13   Ripandelli's work and many of the eyes in


 14   Ripandelli's work didn't have IOLs.  They had clear


 15   lens extraction and they had retinal detachments.


 16   It is the retinal detachment coming from the clear


 17   lens extraction that really is the subject of


 18   discussion.


 19             DR. WEISS:  Dr. Brucker, as I said, I


 20   think from a logical technology standpoint, you are


 21   right but it doesn't apply to what the agency wants


 22   at this point.  Dr. Bressler?


 23             DR. BRESSLER:  I think you do need a


 24   control, and it will be more interesting discussing


 25   what that will be on the second round.




  1             DR. WEISS:  Dr. Smith?


  2             DR. SMITH:  I agree, you need a control


  3   both for safety and efficacy.


  4             DR. WEISS:  Dr. Ho?


  5             DR. HO:  The clinician scientist in me


  6   wants an active control, however, I recognize the


  7   difficulty of executing a trial in which someone is


  8   seeking a refractive procedure and would be


  9   randomized--


 10             DR. WEISS:  Just to reiterate, we don't


 11   have to commit--


 12             DR. HO:  I would be okay with historical


 13   age and refractive-matched controls.


 14             DR. WEISS:  All I want from anyone right


 15   at this moment is do you want a control or you


 16   don't want a control.  I am going to keep it nice


 17   and simple.  It won't stay simple for long so enjoy


 18   it while you have it.  Dr. Mathers?


 19             DR. MATHERS:  By patients on control, are


 20   you supposing that you do the surgery in one eye


 21   and not on the other?


 22             DR. WEISS:  Well, any type of control you


 23   want.  It is just question 1 (A, do you want a


 24   control or you don't want a control?  You are going


 25   to tell us afterwards what sort of control you




  1   want.


  2             DR. MATHERS:  I want a control.


  3             DR. WEISS:  You want a control.  Dr.


  4   Grimmett?


  5             DR. GRIMMETT:  Yes.


  6             DR. WEISS:  Dr. Grimmett wants a control.


  7   Dr. McMahon?


  8             DR. MCMAHON:  Yes.


  9             DR. WEISS:  Dr. Bradley?


 10             DR. BRADLEY:  I am not sure.


 11             DR. WEISS:  Another abstention.  Dr.


 12   Ferris?


 13             DR. FERRIS:  We have to have some sort of


 14   comparison group so the answer of who wants some


 15   sort of comparison group is simple, so I want a


 16   comparison group.


 17             DR. WEISS:  Thank you.  Dr. Brucker just


 18   nodded in the affirmative.  Mr. McCarley, you can


 19   voice your opinion, of course.


 20             MR. MCCARLEY:  I was just thinking of the


 21   same patient control.


 22             DR. WEISS:  Okay, and Dr. Maguire, did you


 23   want to voice an opinion at this point?


 24             DR. MAGUIRE:  Well, yes, because we


 25   haven't really established what we are talking




  1   about so I don't want to say no.


  2             [Laughter]


  3             DR. WEISS:  I take that as a continuation


  4   of an abstention.  I am hearing somewhat of a


  5   consensus on 1 A), that most of the panel would


  6   like to have a control population.  So, now we get


  7   into 1 B), which is on the screen, what type of


  8   control population would you like.  We have the


  9   historical and the active, or if you can come up


 10   with anything else.  I don't believe the FDA was


 11   emphasizing doing a randomized study.  I don't


 12   really think anyone is talking about that, but if


 13   that is what you want to do you can certainly


 14   suggest it.  In the list of controls under


 15   historical under 1 B) there are subjects--well, you


 16   can read them yourself.  There are four different


 17   types of historical controls.  There is one type of


 18   active control, and then if there is anything else


 19   that you would like.  Dr. Rosenthal?


 20             DR. ROSENTHAL:  The active control would


 21   be a group of patients who had no surgery.  So, in


 22   fact--


 23             DR. WEISS:  It could be randomized.


 24             DR. ROSENTHAL:  --you could randomize or


 25   you could just collect a group of patients.




  1             DR. WEISS:  Then the randomization is


  2   actually another level of specificity.  You could


  3   have an active control of another group of, let's


  4   say, age- and gender- matched subjects, and how you


  5   wanted to include them in the study, actually, the


  6   FDA has not even asked us.  So, they haven't even


  7   asked us for that level of detail.


  8             Let's start with Dr. Maguire, if you


  9   wanted to voice your opinion on this.


 10             DR. MAGUIRE:  Yes, I think active control


 11   subjects with no previous ocular surgery and not


 12   planning on having any either for presbyopia would


 13   be reasonable.


 14             DR. STARK:  Agreed.


 15             DR. MAGUIRE:  Because we have no


 16   information on retinal detachment surgery in young


 17   people, or certainly not adequate information, and


 18   we would like to have more information on


 19   endothelial cell loss based on Dr. Lane's answer to


 20   Dr. Grimmett's question, so absolutely.


 21             DR. WEISS:  So, you would like an active


 22   control of subjects with no previous ocular


 23   surgery.  Dr. Stark agreed with that.  Dr. Brown?


 24             DR. BROWN:  Yes, an active case control


 25   study that is matched on criteria that we would set




  1   out in terms of refractive error and age, yes.


  2             DR. WEISS:  So, you would also like an


  3   active control.  Dr. Bressler?


  4             DR. BRESSLER:  I would like to discuss for


  5   a minute a couple of considerations for why a


  6   randomized control might be beneficial for getting


  7   the answer and then we can get back to would those


  8   people actually enroll.


  9             We may see some visual acuity loss in a


 10   few of these people that have this.  In the few


 11   studies that were done, granted in the high myopes


 12   with clear lens extraction they did have one or two


 13   people that are 40 losing a line of vision by six


 14   months, for example, in their best corrected visual


 15   acuity.  Now, that could be to the detriment of


 16   this if you didn't have a control group because you


 17   would say, well, they started at 20/16 and they


 18   dropped to 20/25, or something.  However, it could


 19   be that your control group developed some cataract


 20   along the way.  We are going to have 50 year-olds


 21   with presbyopic symptoms, or whatever, and they may


 22   drop to 20/25 just as often.  So, you never would


 23   have known that you weren't harming their vision,


 24   for example, more than if you left it alone if you


 25   didn't have a control group for that.




  1             In addition, if you are going to look at


  2   quality of life outcomes, for example, whatever


  3   answers or change in the quality of life you get in


  4   someone over time, you just won't know if that is


  5   just due to the person having the surgery done and


  6   being happy with their life or if it is due to


  7   other factors that you would only get from a


  8   control group.


  9             So, I am all for an active control and I


 10   think it needs to be considered as actually a


 11   randomized trial to be able to answer the important


 12   safety issue, which will be visual acuity besides


 13   the retinal detachment, which is much rarer and you


 14   may not be able to detect those changes, and any


 15   quality of life studies that might be considered


 16   down the line.


 17             DR. WEISS:  I would ask you if this could


 18   not be a randomized study because it was deemed


 19   that it would be too burdensome or the study


 20   wouldn't be able to accrue the patients because of


 21   that criteria, would you still want an active


 22   control?  Would that still be something that you


 23   would want?


 24             DR. BRESSLER:  If you couldn't have it,


 25   then yes, but you might not be able to answer these




  1   questions if you see that the visual acuity has


  2   declined.  So, I just don't want to have the


  3   industry paint themselves into a corner.  That is


  4   the whole advantage of doing this ahead of time.


  5             DR. WEISS:  Dr. Eydelman?


  6             DR. EYDELMAN:  Along the lines of what Dr.


  7   Bressler just mentioned, the panel certainly can


  8   consider whether they wanted two different controls


  9   for safety and efficacy outcomes.  If that is the


 10   case, that just puts a little further question into


 11   question 1 B).


 12             DR. BRESSLER:  I am not separating it


 13   because safety assessment depends on what the


 14   efficacy is as well.  You are willing to take big


 15   safety risks for one sort of efficacy and less


 16   safety risks for another.


 17             DR. EYDELMAN:  Right, but determination of


 18   safety and efficacy with an active control is going


 19   to require greatly different sample sizes.  Just


 20   keep that in mind.


 21             DR. WEISS:  Dr. Smith?


 22             DR. SMITH:  I would prefer to have an


 23   active control while recognizing these concerns


 24   that several have voiced regarding the feasibility


 25   of doing such a study, and I am open to discussing




  1   ways to do that other than randomization but I do


  2   believe in active controls.  It is critical to


  3   obtaining safety data in this age group for which


  4   we do not have good data.


  5             DR. WEISS:  Just to remind panel members,


  6   we welcome dissent.  We don't need unanimity on


  7   this.  This is really to guide the agency as far as


  8   the panel's sentiments so we don't have to have a


  9   continual roll here if you want to go in another


 10   direction.  Dr. Ho?


 11             DR. HO:  As I was saying before, as a


 12   scientist I think that I would love to have an


 13   active control.  I think it would be very difficult


 14   to execute that study.  I think Neil's concern and


 15   point is a good one, however, the duration of the


 16   study will likely not be long enough so that maybe


 17   those 1/40 patients that drop a line might not drop


 18   a line in the first few years.


 19             DR. WEISS:  Would you be able to get a


 20   little closer to the mike?


 21             DR. HO:  Sure.  Therefore, I would be open


 22   to a historical control but it would have to be an


 23   age-matched and refractive error-matched control.


 24             DR. WEISS:  Would that be difficult to do,


 25   Dr. Eydelman?  I just saw a change in your




  1   expression, not for the positive.


  2             DR. EYDELMAN:  Well, that would imply that


  3   each sponsor, depending on the inclusion/exclusion


  4   criteria, would have to go through the literature


  5   and try to see if they can pull--most of the


  6   articles don't have raw data so you would have to


  7   try to identify articles that have exactly the same


  8   age criteria as you wish to enroll.  It gets a


  9   little tricky.  We have done it for glaucoma


 10   devices and the sponsors found it quite difficult.


 11             DR. WEISS:  Dr. Bressler?


 12             DR. BRESSLER:  I just wanted to add to


 13   Allen's comment that in the small series we had


 14   from Dick and colleagues, that was only a six-month


 15   follow-up and they had 3/50--and I know these are


 16   broad confidence intervals but that was six percent


 17   losing one line.  So, you might get those answers


 18   even with just a year follow-up or safety beyond


 19   two years.


 20             DR. WEISS:  Dr. Ho?


 21             DR. HO:  That was also a group that was


 22   highly myopic that might be more susceptible than


 23   the general group you are speaking to here who


 24   would like to have presbyopic surgery.


 25             DR. WEISS:  So, Dr. Ho, you still would




  1   prefer to have a historical?


  2             DR. HO:  If that data can be derived, yes,


  3   because I think consideration of an active


  4   control--although burdensome and I would love it


  5   but I think it would be difficult to execute that


  6   trial.


  7             DR. WEISS:  Would I be able to ask you to


  8   sort of isolate one of the four listed here as far


  9   as what type of historical control?  No, I would


 10   not be able to?  Okay, well, I can ask.  Dr.


 11   Mathers?


 12             DR. MATHERS:  I don't think it would be


 13   that difficult to have an active control because


 14   you are not really doing too much for these people


 15   if they haven't had surgery.  You are just


 16   following them and you are doing some tests on


 17   them.  But I think that you would have to stratify


 18   them to answer some of the questions.  You would


 19   have to stratify them by axial length, refractive


 20   error, endothelial count and age.  If you did that,


 21   you could answer these questions and I do think it


 22   is extremely important to answer these questions.


 23   We are talking about really major health issues


 24   here that affect millions, if not billions, of


 25   people and, clearly, the private community or the




  1   academic community have all completely failed to


  2   look at this fundamental issue and maybe we have an


  3   opportunity to help them.  We haven't answered


  4   these questions yet.  Obviously, the literature


  5   shows we have not.


  6             DR. WEISS:  Dr. Grimmett?


  7             DR. GRIMMETT:  For effectiveness issues I


  8   would be in favor of an active control.  Certainly


  9   for quality of life issues it would be very nice to


 10   compare patients who have not had surgery with time


 11   to see how their quality of life compares to those


 12   who have had the surgery.


 13             Dr. Eydelman read my mind as far as


 14   separating safety and effectiveness.  I could go


 15   with a historical control for safety issues,


 16   perhaps patients who have had cataract surgery with


 17   IOLs.


 18             DR. WEISS:  I have just been informed


 19   that, unlike many panel meetings, my opinion is


 20   actually wanted on this one even though I am


 21   chairing this.  So, I think I would like an active


 22   control as well because of the frustration I think


 23   for a sponsor as well as the panel often when the


 24   PMA is presented and we don't have the information


 25   to assess--let's say, the risk or whatever--and the




  1   best way to do that is to compare it to an active


  2   control.  Although randomization would be


  3   wonderful, I think it would be too onerous on the


  4   sponsors so I wouldn't be supporting that.  Dr.


  5   McMahon?


  6             DR. MCMAHON:  I have a few comments on


  7   this issue.  I agree with Dr. Bressler that a


  8   randomized trial with an active randomized control


  9   group would be ideal, but I also agree with you


 10   that it would be a bit onerous to maintain an


 11   active control group for a period of three or four


 12   years.  Keep in mind, this is equivalent to a


 13   refractive surgery population and keeping track of


 14   the patients is hard enough, let alone controls who


 15   might also be interested in this procedure.  If you


 16   are going to hold them off for several years I


 17   think it would be very difficult to manage this.


 18             With regard to active controls, I think


 19   there are other mechanisms that can be played and I


 20   think it can be done in a variety of interesting


 21   ways.  For the less common but more devastating


 22   complications like retinal detachment I can see a


 23   design where you have a prospective case control


 24   kind of circumstance where you have a lot of active


 25   controls who are not interested in the procedure




  1   and a lesser number of actually operated patients.


  2             But for things like efficacy you are going


  3   to want more of a matched controlled set of


  4   patients in that circumstance.  So, I think an


  5   active control group is the thing to do.  I think


  6   randomization is likely not to be manageable but


  7   there are other options I think that can be looked


  8   at.


  9             DR. WEISS:  Dr. Bradley?


 10             DR. BRADLEY:  Yes, I have several


 11   comments.  I think taking Dr. Brucker's comment


 12   earlier to heart in that potentially the greatest


 13   risk here is the surgical procedure not the lens


 14   being inserted into the eye, one might not imagine


 15   dramatically different risks associated with


 16   different lenses.  So, we may, therefore, be able


 17   to employ historical literature controls for risk,


 18   particularly in the age group that has already


 19   undergone this particular surgery, which is


 20   obviously the 50-plus age group and they have


 21   obviously been having surgery for cataracts.  So,


 22   this may be effectively evaluated using historical


 23   controls in the older group.  That is certainly not


 24   the case if the lenses are going to be inserted in


 25   younger eyes.  I think in that case an active




  1   control for risk is required.


  2             Regarding controls for efficacy, clearly,


  3   if we are going to be reviewing novel multifocal or


  4   novel accommodative IOLs, I think efficacy will


  5   require an active control.  So, again, I am sort of


  6   dividing it between safety and efficacy.  I think


  7   efficacy will require active controls even in the


  8   older group but safety may not.


  9             DR. WEISS:  Dr. Ferris?


 10             DR. FERRIS:  Some people may be shocked to


 11   hear me say this.  In fact, I am shocking myself to


 12   say this, but I agree with Malvina that we need to


 13   look at this separately for safety and efficacy and


 14   I am saying that in part not, as Allen says,


 15   because of what is scientifically best but what is


 16   reasonable to do.  From my perspective the


 17   appropriate control group, particularly for these


 18   younger people that are considering to have this


 19   done for presbyopia, is the unoperated group.  The


 20   choice is wearing glasses and the risk of wearing


 21   glasses is pretty low.


 22             So, the underlying rates that have been


 23   presented today for retinal detachment and


 24   endothelial cell loss are probably the appropriate


 25   rates to look at.  They are so low that if you




  1   tried to figure out the sample size that would be


  2   necessary to have reasonable confidence intervals


  3   around those rates, it is sort of an impossible


  4   study.  So, from one perspective I would think that


  5   you would take the point of view that for safety


  6   the rate is almost zero or very low.  So, what you


  7   want to know is what is the rate if you do this


  8   procedure and I would bundle the whole procedure as


  9   you were mentioning, the surgery plus the lens,


 10   plus everything.  So, from the safety side I think


 11   that is the way that I would do it so I am saying I


 12   guess historical controls.


 13             Efficacy is a different issue I think


 14   because now you can have an appropriate sample size


 15   and, as Neil pointed out, whatever it was, 6


 16   percent loss or 3 percent one line loss is what you


 17   would find if you just repeated the visual acuity


 18   the same day.  There is a certain 5-letter change


 19   in our experience.  So, usually I say results are


 20   always improved by omitting the control group.  In


 21   this case they are worsened by omitting the control


 22   group.  So, i would think from the company's point


 23   of view they probably want an active control group


 24   and that control group may be several things.  One,


 25   as mentioned here, their preexisting state, which I




  1   think is a very important control group and,


  2   secondly, maybe a comparable group, particularly if


  3   you are going to look at changes over time and


  4   quality of life.  I also agree that doing a


  5   randomization trial is virtually impossible.  On


  6   the other hand, uncontrolled confounding is going


  7   to be an impossible issue to deal with when you


  8   don't have a randomization comparison.  So, it is


  9   sort of skewed either way.


 10             DR. WEISS:  I think both Dr. Bradley and


 11   yourself bring up a very good point.  Just to sort


 12   of elucidate it a little bit further, if you are


 13   going to be doing a historical control for safety,


 14   could you just clarify which one of those groups


 15   you would both be using?


 16             DR. FERRIS:  From my view, it is the


 17   untreated group, and the only caveat there is this


 18   untreated group is potentially treated.  As was


 19   pointed out in discussions, eventually a large


 20   proportion of these people are going to have


 21   cataract surgery in their lifetime.  The other


 22   thing that we will bring up later but what I think


 23   is very important is it is not the four-year risk


 24   of retinal detachment, it is the 25-year risk of


 25   retinal detachment.




  1             DR. WEISS:  So, you would like a


  2   historical control of subjects with no previous


  3   ocular surgery for safety but for efficacy have an


  4   active control.  Dr. Bradley?


  5             DR. BRADLEY:  I think my views on the


  6   safety control group would be, again, the untreated


  7   group.


  8             DR. WEISS:  Basically you are in agreement


  9   with Dr. Ferris.


 10             DR. BRADLEY:  Yes, the one qualifier is


 11   that there is a presumption that the literature


 12   provides adequate data to support a historical


 13   control, and my reading of the literature and the


 14   presentations today lead me to believe that within


 15   the cataract age group we have adequate data to


 16   have historical literature-based controls but we


 17   don't in the younger age group.


 18             Again, the question is where is the


 19   cut-off and I think that is perhaps for the FDA to


 20   determine.  Where does the literature adequately


 21   provide this control?


 22             DR. WEISS:  Dr. Eydelman?


 23             DR. EYDELMAN:  If you are choosing to talk


 24   about appropriate historical control being subjects


 25   with no previous ocular surgery, then we have




  1   adequate data in the literature for all ages.


  2             DR. WEISS:  Dr. Ferris?


  3             DR. FERRIS:  Well, just one other comment.


  4   The one place where perhaps an active control group


  5   would be useful for evaluating complications might


  6   be in the high myopes.  A side issue related to


  7   what was discussed earlier is that I actually think


  8   it might be a mistake not to include that group


  9   because whatever happens with this study, that


 10   group is going to be at excess risk of having this


 11   done because they have excess benefit of having


 12   this done.


 13             DR. WEISS:  So, basically a historical


 14   control of subjects in, let's say, your routine


 15   cataract if we are talking about doing a minus 3


 16   presbyope where you don't really expect there to be


 17   much difference from people without previous ocular


 18   surgery, but if you are doing the high risk


 19   patients, let's say the minus 20 myope, in that


 20   case you might want an active control.  If you were


 21   doing a minus 20 myope, then neither of you would


 22   like a historical control at that point and would


 23   have an active control.


 24             DR. FERRIS:  It is actually in the


 25   company's benefit.  This is one of those places,




  1   again, where you would like to have the control


  2   rate because it is going to make your treated rate


  3   look better because the control rate is actually


  4   going to be significant.  Otherwise, I am assuming


  5   the control rate is close to zero.


  6             DR. WEISS:  It gets a little sticky from


  7   the agency's standpoint--and correct me if I am


  8   wrong--if we are speaking about a historical


  9   control of subjects, except if we get involved in


 10   certain refractive categories in which case now we


 11   want to go on active control.  Is there any


 12   guidance you can give us on that?  I guess we will


 13   get involved in that when we get to question number


 14   two.  Dr. Brucker?


 15             DR. BRUCKER:  I think that we are making


 16   this very complicated and unnecessary.


 17             DR. WEISS:  Welcome to the panel, Dr.


 18   Brucker!


 19             DR. BRUCKER:  I have been here and I will


 20   tell you we are making it complicated and it need


 21   not be.  It seems to me that, unlike some of the


 22   comments around the table, these are patients who


 23   will go elsewhere for refractive surgery.  That is


 24   not the case.  These are patients who are perhaps


 25   45-55 years of age and, like myself, they are




  1   starting to have to use glasses.  It is a pain in


  2   the neck and it doesn't matter if they are minus 14


  3   or plano like I am.  The fact of the matter is that


  4   these are patients that could use glasses.  There


  5   is no reason that this isn't a randomization trial.


  6   It will make things simpler for the sponsor.  It


  7   will make things simpler for the patient.  It will


  8   make things simpler for the FDA.  It makes things


  9   simpler for everybody to get a group of patients


 10   randomized and some will wear glasses.  Okay, they


 11   have done it.  It is only for three more years.


 12   And, some are going to have surgery.  I don't see


 13   what the big deal is.  The end result is you are


 14   going to have an idea.  These patients are not


 15   going to have scleral depressed peripheral


 16   examinations.  You are not going to know if they


 17   have lattice.  You are not going to know what is


 18   going on in the back of their eyes.  All you need


 19   to do is take a look again at Ripandelli's paper.


 20   Sixty percent of those patients wound up having


 21   pre-treatment.  It doesn't matter if they are


 22   pre-treated or not.  It doesn't matter what their


 23   peripheral examinations are.  Randomize the


 24   patients.  Spread it out whether they are high


 25   myopes, plano emmetropes or hyperopes.  Give them




  1   all a chance to be in the study.  Make the sample


  2   size large enough.  Follow them for three years and


  3   you will have all of your answers and there weren't


  4   be any complications or problems--let's not say


  5   complications.


  6             DR. WEISS:  Mr. McCarley?


  7             MR. MCCARLEY:  I think a historical


  8   cataract group would be fine unless the National


  9   Eye Institute would be willing to fund and run a


 10   study because it is actually the procedure we are


 11   looking at, regardless of the intraocular lens.


 12             DR. WEISS:  I have a feeling that is not


 13   forthcoming.  Now we are going to go back; now that


 14   we have heard everyone's opinions, some of our


 15   opinions may have changed.  Dr. Bressler?


 16             DR. BRESSLER:  I just wanted to clarify,


 17   are we talking about active controls for safety or


 18   efficacy?  We haven't gotten to the question of


 19   what is the safety that we are looking at.  So, I


 20   know we are in a circle and jumping in.  I never


 21   foresaw in suggesting active controls that you want


 22   to power a study to see if there is a difference in


 23   the retinal detachment rate.  I mean, that is low


 24   in the non-high myope population and that would


 25   take 40,000 or more and it wouldn't be meaningful




  1   that you reduced it from 0.01 to 0.05 or something


  2   like that in percentage.


  3             So, for certain safety outcomes you may


  4   have to deal with historical controls and there is


  5   adequate information for some of those.  But for


  6   other safety outcomes, for example changes in


  7   visual acuity, you may be able to do it with


  8   randomized controls so you don't have all the


  9   confounding bias.  As Rick pointed out, it is true


 10   that we had 3/50 in our limited information here


 11   that lost one line by six months and that could be


 12   noise; it may not be noise.  It may be the


 13   beginning of two-line loss or three-line loss.  It


 14   was mainly in the hyperopes, not in the myopes in


 15   that small study.  That is 50 people versus--you


 16   know, there are 60 million over the age of 65 that


 17   are obviously going to be presbyopic.


 18             So, I think it is incumbent upon the


 19   safety, not the retinal detachment safety but some


 20   of the others, to be aware of what these are; get


 21   rid of the confounding bias and, although it may be


 22   hard and take a little further discussion to get a


 23   group who is willing to put this off for a few


 24   years until we know what the outcome is, there are


 25   enough presbyopes out there--it is not a rare




  1   disease--that it may be possible.  So, I just


  2   wanted to add that clarification that I think I


  3   agree with what most of the panel said but I am


  4   still believing we would need for some of the


  5   safety outcomes these controls.


  6             DR. WEISS:  I am going to have one comment


  7   from Dr. Maguire and then I am going to ask if the


  8   agency needs anything more from us on this


  9   question, just because we have eight of these to


 10   get through.  Dr. Maguire?


 11             DR. MAGUIRE:  I have a question for the


 12   agency.  Does FDA separate groups for presbyopic


 13   correction if it is reasonable to expect that one


 14   of those groups is more likely to have problems


 15   with safety and efficacy, specifically the high


 16   myope group?  That would be a reason to separate


 17   them out.  Is that correct?


 18             DR. EYDELMAN:  In any refractive


 19   indication we usually break it up into the ranges


 20   of refractive error.  For example, for LASIK we


 21   broke it up to 7 and above 7, and emmetropia would


 22   probably be analyzed separately.  So, yes, the data


 23   would come in and then we would ask for internal


 24   stratification of the data according to refractive


 25   indication.




  1             DR. MAGUIRE:  But you would still run the


  2   study as a whole?  In other words, you wouldn't


  3   place more stringent control requirements on


  4   patients with high degrees of myopia than the


  5   people with the other indications that led Dr. Lane


  6   to say they shouldn't be included at all in our


  7   discussion here.


  8             DR. EYDELMAN:  Well, it is certainly up to


  9   the sponsor to design what kind of trial they want


 10   to do and what inclusion criteria they want to


 11   expand their design to.  We would certainly take


 12   your recommendations from today and try to give


 13   guidance to the sponsor accordingly.


 14             DR. WEISS:  Dr. Rosenthal?


 15             DR. ROSENTHAL:  I know what Dr. Maguire is


 16   getting at, and I think if there is a marked


 17   discrepancy between two populations in the study


 18   one would probably ask to look at both of them


 19   together and then separately.


 20             DR. WEISS:  Dr. Smith has a quick


 21   question.


 22             DR. SMITH:  I just wanted to clarify an


 23   issue.  In the first question here we are talking


 24   about clear lens extraction in the correction of


 25   presbyopia.




  1             DR. WEISS:  Yes.


  2             DR. SMITH:  Some of those patients may be


  3   myopic, hyperopic.  We are not talking about their


  4   lens extraction for the treatment of high myopia.


  5             DR. WEISS:  We have not gone to question


  6   two, that is right.


  7             DR. SMITH:  But this is clear lens


  8   extraction and the indication is presbyopia.  So,


  9   that doesn't cover 25 year-olds who are minus 20.


 10             DR. WEISS:  You are a hundred percent


 11   right.


 12             DR. SMITH:  So, I think that myopes are


 13   complicating our discussion.


 14             DR. WEISS:  Well, you might have a 50


 15   year-old who is minus 20 and presbyopic.


 16             DR. SMITH:  Right.


 17             DR. WEISS:  We are going to then narrow


 18   things down as we go on, hopefully, but right now,


 19   from what I understand, most of the panel wants


 20   controls.  Most of the panel is talking about


 21   active controls.  Some of the panel is talking


 22   about historical controls for safety and active


 23   controls for efficacy, and some of the panel is


 24   talking about randomization.  I would sort of like


 25   to cut things off at this point because we have




  1   eight questions and we have sort of gone over on


  2   this one.  Does the agency need anything else from


  3   us on that particular question?


  4             DR. EYDELMAN:  No, thank you.


  5             DR. WEISS:  Fine.