CALL TO ORDER

Panel Chair Jayne Weiss, M.D., called the meeting to order at 9:01 a.m. and noted that a quorum was present. Panel Executive Secretary Sara Thornton welcomed participants and announced the appointment of William D. Mathers, M.D., as a voting member. She noted that Andrew Balo was acting industry representative for the meeting on February 5, 2004, and asked the panel members to introduce themselves.

Executive Secretary Thornton then read the conflict of interest statement. Full waivers had been granted to Michael R. Grimmett, M.D., Oliver D. Schein, M.D., and Woodford S. Van Meter, M.D., for their interests in firms that could be affected by the panel’s recommendations. She noted for the record that the Agency had taken into consideration other matters involving Drs. Grimmett and Schein and Arthur Bradley, Ph.D., Anne L. Coleman, M.D., Ph.D., Andrew J. Huang, M.D., Marian S. Macsai-Kaplan, M.D., and Jayne S. Weiss, M.D., all of whom reported past or current interests involving firms at issue but in matters not related to the day’s agenda. They may participate fully. She read the appointment to temporary voting status, which granted voting status to panel consultants Karen Bandeen-Roche, Ph.D., Richard Casey, M.D., Andrew J. Huang, M.D., Marian S. Macsai-Kaplan, M.D., Oliver D. Schein, M.D., Janine A. Smith, M.D., and Woodford S. Van Meter, M.D., for the duration of the meeting.

OPEN PUBLIC HEARING

Executive Secretary Thornton read a letter into the record from Peter D. Van Patten, M.D., Duluth Clinic Virginia, Virginia, MN, who received Artisan lens implants after experiencing increasing problems with contact lenses. His sight improved significantly after receiving the implants. He now wears glasses only for night driving. He experiences minimal night glare. The Artisan lens is an important investigational surgical option for his patients. The lens is safe and effective when implanted by a skilled surgeon.

Leslie Woodlock, patient advocate, Surgical Eyes Foundation, noted that she became involved with the organization after failed LASIK surgery in 2000. She asked the panel to address numerous issues as it reviewed the PMA, including diameter selection, endothelial cell loss, anterior chamber depth (ACD), risks involving later cataract surgery, risk for unwanted halos and glare, and proper informed consent procedures.

Glenn Hagele, Executive Director, Council for Refractive Surgery Quality Assurance (CRSQA), noted that the phakic intraocular lens (PIOL) has been available outside the United States for the better part of a decade. The panel should consider including in the physician and patient labeling that it is difficult to determine the probability of induced night vision problems when the scotopic pupil is larger than the size of the full optical correction of the device is not easily determined. Patient labeling should include a representation of these effects, including difficulty driving at night and reading in low-light environments, and it should include a statement indicating that training and practical experience of the surgeon may be an important factor in the probability of a desirable outcome. In addition, the patient labeling should indicate the type and frequency of probable surgery-related long-term care; for example, patients will require periodic evaluation of intraocular pressure (IOP) after PIOL implantation. No clear consensus exists on the long-term effects of PIOL on endothelial cells. The functional life of a PIOL may be as much as 40 years; during this time, the need for regular evaluation of endothelial cell loss is clear, but who will pay for those costs? PIOL implantation is an elective, arguably cosmetic procedure. If patients are properly informed of the immediate and long-term issues relating to the sponsor’s PIOL, those who elect to have lens implants will have reasonable expectations and will be able to make the decision that best meets their needs.

Morris John, Ophthalmalogist, Louisville KY, implanted the first five Artisan lenses in the United States and has implanted more than 200 lenses to date. The Artisan lens has a short but steep learning curve for surgeons. The lens needs adequate ACD in order to be successfully implanted. Many of his patients do not have glare or have had glare all their lives and experience the lens as an improvement. Other problems are surgeon related. Many surgeons prefer this lens to other PIOLs. With this lens, patients see well and experience minimal side effects.

OPEN COMMITTEE SESSION

Division Updates

A. Ralph Rosenthal, M.D., stated that the Agency strongly recommends that all companies schedule a pre-PMA meeting with the Agency to discuss accountability, stability, and safety and efficacy, even if the company has previously submitted numerous PMAs. Doing so will help ensure a better submission and one that will be less likely to result in a “non-filable” decision or a major deficiency letter.

Donna R. Lochner, Former Chief, Intraocular and Corneal Implants Branch, stated that the Morcher GmbH endocapsular tension ring (P010059), which was reviewed at the January 2002 panel meeting, was approved October 23, 2003. The device is indicated for the stabilization of the crystalline lens capsule in the presence of weak or partially absent zonules in adult patients undergoing cataract extraction with IOL implantation.

The Eyeonics (formerly C&C Vision) CrystaLens™ Accommodating Intraocular Lens (P030002), which was reviewed at the May 2003 panel meeting, was approved November 14, 2003. The device is intended for primary implantation in the capsular bag of the eye for the visual correction of aphakia in adult patients in whom a cataractous lens has been removed. It is intended to provide near, intermediate, and distance vision without spectacles. The lens provides approximately 1.00 diopter (D) of monocular accommodation.

Everette T. Beers, Ph.D., Chief, Diagnostic and Surgical Devices Branch, stated that three PMAs have been approved since the last panel meeting. The Wavelight Allegretto Laser Myopia + Astigmatism device (P020050) was approved for LASIK correction of myopia of up to –12.00 D with or without astigmatism of up to –6.00 D. The Wavelight Allegretto Laser Hyperopia + Astigmatism device (P030008) was approved for LASIK correction of hyperopia up to +6.00D sphere with up to +5.00 D cylinder, with manifest refractive spherical equivalent (MRSE) up to + 6.00 D. The B&L Zyoptix device (P990027/S6) was approved for wavefront-guided LASIK correction of myopia of up to –7.00 D with up to –3.00 D of astigmatism and MRSE up to –7.50 D.

Approximately 36 510(k)s were cleared in 2003.

SPONSOR PRESENTATION

Rick McCarley, President, Ophtec, thanked the FDA review team and introduced the sponsor presenters and consultants.

Vance Thompson, M.D., Sioux Falls, SD, presented information on the design features and history of the lens and described his experience with it. He implanted his first lens in 1998 and since then has implanted the lens in 95 eyes. All of his patients are pleased with the outcome. The Artisan lens has some unique safety features that explain its positive results.

The device is a single-piece, elliptical, polymethylmethacrylate (PMMA) lens with a slight anterior vault. It is designed for implantation into the anterior chamber of the phakic eye. It is fixated to the mid-periphery of the iris by incorporation of the iris into a cap in the haptics, a process called enclavation. Proper fixation requires about 1 mm of iris tissue. An advantage of the lens is its ease of attachment and detachment. It can be repositioned during surgery or easily removed, if necessary. It is available in two sizes, 6 mm and 5 mm, each with a different diopter range. Because the lens attaches to a relatively immobile part of the iris, the pupil can be dilated.

Dr. Thompson then summarized the development of the Artisan PIOL. The current design has been in use since 1991 around the world. It is the most commonly implanted lens in the world today. It is frequently used as a secondary implant, particularly during penetrating keratoplasty (PK). It offers stable fixation over time with normal pupillary function and no iris atrophy. To date, more than 100,000 myopic, hyperopic, and toric lenses have been implanted worldwide by 5,000 physicians.

A European multicenter study of 518 eyes implanted from 1991 to 1999 found low amount of endothelial cell loss and good stabilization over time. Mean endothelial cell density change was –4.8 percent at 6 months and –2.4 percent from 6 months to 1 year; the change was –0.7 percent from Year 2 to Year 3. Best corrected distance visual acuity (BSCVA) was ≥20/40 for 93.9 percent of participants, and uncorrected visual acuity (UCVA) was ≥20/40 in 76.8 percent of participants. A total of 57.1 percent of study participants were within 0.50 D of the target, and 76.8 percent were within 1.00 D of the target. The results demonstrate refractive stability and good predictability. The risk–benefit ratio is favorable, and the study demonstrated safety and efficacy. No reports in the literature indicate long-term safety concerns with the lens design.

Doyle Stulting, M.D., Ph.D., Emory University, Atlanta, GA, presented findings from the U.S. clinical investigation. Dr. Stulting was one of the a medical monitors of the clinical study and is a paid consultant to the sponsor. The clinical study was an open label,

non-comparative study in patients with 4.60 to 22.0 D of myopia. The lenses were provided in 1.00 D power increments; the 5 mm lens is available in –5.00 to –20.00 D, and the 6 mm lens is available in –5.00 to –15.00 D. Patients had eight postoperative visits.

Patients were age 21 to 50 with stable manifest refraction and ACD ≥ 3.2 mm and refractive cylinder ≤ 2.00 D. Endothelial cell density was ≥ 2,000 cells/mm², and pupil size was ≤ 4.5 mm. No study participants had an ocular disease or abnormality that would affect safety. Protocol waivers were requested and granted by FDA until November 2000, when the protocol was changed to include patients with preexisting clinically insignificant and stable peripheral lens opacities, astigmatism of ≥2.50 D, ACD <3.2 mm, age >50, pupil size > optic size, preoperative BSCVA <20/40, and inability to completely correct refractive error. Results were obtained for all eyes and participants.

Outcome measures included uncorrected distance visual acuity (UCVA), best spectacle-corrected distance visual acuity (BSCVA), manifest and cycloplegic refraction, contrast sensitivity, intraocular pressure, pupil shape, endothelial cell density, and slit lamp exam. Cataract formation was not identified as a significant risk because of the device’s 6-year history of implantation internationally and anterior placement of the IOL. The approved protocol required only clinical grading of cataracts rather than standardized grading. As the available technologies and knowledge advanced, the sponsor changed investigational procedures consistent with FDA, ANSI and ISO discussion in developing guidelines. The study enrolled 684 participants between October 1997 and July 2003: 662 participants were in the primary study, 478 of whom were bilaterally implanted. Twenty-two patients were implanted for compassionate use. Participants were divided into several groups for the purposes of analysis. The safety analysis is based on results in both eyes, but the efficacy analysis is based on results in first eyes.

The data are from 386 eyes followed for 3 years. The study was originally designed and powered as a 2-year study; some participants therefore did not return for the 3-year follow-up visit. 8 percent were lost to follow-up. Mean patient age was 39.6 years; many study participants were high myopes who were at high risk for undesirable outcomes.

The safety analysis found that 100 percent of study participants had BSCVA ≥20/40 at 2 or 3 years after surgery. At 3 years, 49 percent had gained BSCVA. Losses were due to measurement variability. The results demonstrate improvement after surgery, which other lenses do not provide. Any induction of astigmatism was due to the surgery, not device failure. Early postoperative findings included flare; corneal edema; iris pigment precipitates; increased IOP; and mild, asymptomatic ovalization of pupil. The effects decreased with time. Eighteen of 1,140 eyes experienced acute elevation in IOP, most of which occurred 1 day postoperatively; all resolved by 20 days. IOP increases were attributed to retained viscoelastic or steroid response.

The adverse events of greatest concern are secondary surgical interventions that are lens related, medically necessary (not prophylactic), not treatable with common technologies that would be available after approval, and not preventable. Twenty-seven of 41 adverse events fell outside these criteria. Most secondary surgical interventions occurred during early surgical experience, and a disproportionate number (12 of 31, or 38.7 percent) occurred at one site. Most secondary surgical interventions (22/31) were due to improper lens fixation. Fifty percent of events occurred among the first 10 participants implanted. Ten lenses required reattachment, two lenses were exchanged, and two were explanted. Twenty preventative repositionings took place. Half of the secondary surgical procedures were due to trauma. Retinal detachment occurred in six eyes, all of which had preoperative MRSE between –11.50 and –18.60 D. Those results are not inconsistent with the literature.

Three of 1,179 eyes (0.25 percent) required cataract extraction; the incidence of cataracts in the study population is not unexpected. Only two eyes lost more than 2 lines of BSCVA; one was due to retinal detachment and subsequent macular hole, and one was due to posterior capsular haze following cataract extraction and PCIOL implantation. The sponsor recommends extensive physician training to reduce secondary procedures.

Two additional adverse events occurred after PMA submission: one consisted of IOL removal, cataract extraction, and PCIOL implantation in an eye that underwent repair of retinal detachment, and the other consisted of IOL reattachment following IOL dislocation due to boxing.

The original protocol did not provide good statistical power to rule out significant changes in endothelial cell density, but the data presented are consistent with the guidance provided to industry by the FDA. A review of raw data indicated that the quality of images could be improved. A recount was done at 12 sites, and one reading center was used to ensure consistency. The best quality image read per eye per visit was used. A total of 353 eyes (representing 215 participants) and a consistent cohort of 57 participants were analyzed. Endothelial cell density was measured at 6 months, 1 year, 2 years, and 3 years. At 3 years, the mean percentage change from baseline was –4.76 percent ± 7.8 percent for all recounted eyes, which is an equivalent yearly rate of –1.59 percent; for the consistent cohort, the mean percentage change from baseline was –3.80 percent ± 9.8 percent, which is an equivalent yearly rate of –1.27 percent. In both groups, the change between consecutive periods was not statistically significant. One site had a statistically significantly larger loss at 3 years; results from that site may not be poolable, and removing that site from the analysis improves the endothelial cell loss data. In addition, based on measurement variability alone, a cell loss measurement of 10 percent or more would be expected in 13 percent of eyes when no real change in endothelial cell density had occurred. The results are not significantly different from the guidance. Average cell loss over time was 1.72 percent per year. Hexagonality and coefficient of variation data support the conclusion that the lens does not stress the endothelium, and no consistent statistically significantly associations were found with various demographic and physiologic variables. The Artisan lens has an excellent safety profile.

UCVA was measured in first eyes at 3 years, and the results were excellent. Seven of 87 eyes did not achieve UCVA, primarily because of residual astigmatism or residual myopia. Only 1.00 D lens power increments were available in the study and that the study included participants with more than 2.50 D of astigmatism without astigmatic correction. UCVA is expected to increase after approval, because 0.50 D power increments are available and astigmatic corrective procedures are likely to be performed. Manifest refraction data show that 94.7 percent of study participants were within 1.00 D of the target refraction and that the mean spherical equivalent remained stable over time.

Patient satisfaction was high; less than 10 percent of participants gave “unfavorable” ratings to quality of vision, satisfaction with surgery, and willingness to recommend the procedure. Most patients had no change in glare, halos, and starbursts. However, the proportion of patients who did not experience halos before surgery but experienced halos postoperatively was 65 percent, a statistically significant difference. Nighttime visual symptoms were not significantly correlated with lens optic size being larger than mesopic pupil size, lens power, or refractive cylinder (except for halos). Symptoms will likely diminish postapproval due to the availability of 0.50 D lens power increments and additional surgery for residual astigmatism.

A substudy at one site found no decrease in contrast sensitivity under different conditions. Statistically significant differences, where present, usually show better contrast sensitivity postoperatively than preoperatively.

Finally, Dr. Stulting presented the sponsor’s labeling and training proposals and asked the panel to recommend approval of the PMA.

Panel Questions for Sponsor

Panel members raised issues concerning outcomes when pupil size was larger than optic size; whether any study participants were on Alphagan at night; whether data from other sources were available that could be useful; the number of and rationale for protocol deviations; the role of magnification in the improved visual acuity reported; appropriateness of the procedure for people who are in sports careers or were otherwise prone to head trauma; appropriateness of the procedure for relatively young patients; the small number of minority patients in the study; how the sponsor ensured that patients with glaucoma were excluded from the study; the adequacy of the sponsor’s training program for preventing adverse events; safety and efficacy in low-myope patients; and possible hindrance of activities among patients experiencing nighttime visual symptoms.

Panel members were concerned about methodology of the sponsor’s endothelial cell count data, particularly comparability of the 12 sites that contributed data to those sites that did not contribute data. They expressed concern about additional endothelial cell loss in study participants who required second surgeries and requested endothelial cell count data on patients in the subgroup the sponsor designated as Group E, which includes all eyes not included in the subgroups designated as Groups A and B (i.e., all first and second eyes) as well as compassionate use eyes in eyes with replacement lenses.

FDA PRESENTATION

Jeffrey Toy, Ph.D., Toxicologist, Intraocular and Corneal Implants Branch, and Team Leader, PMA P030028, listed the review team members and introduced the FDA speakers.

Bernard P. Lepri, O.D., M.S., M.Ed., Optometrist, Vitreoretinal and Extraocular Devices Branch, and Clinical Reviewer, PMA P030028, summarized the risks and benefits of the Artisan lens. Operative risks may include improper enclavation, which can lead to surgical repositionings; wound leakage; infection; induced cataract; and corneal damage due to surgical trauma. Postoperative risks include elevated IOP, inflammatory responses, the potential for pigmentary glaucoma as a result of iris irritation, critical losses of corneal endothelial cells and function, retinal detachment, and dislodgement of the IOL itself with concomitant optical side effects such as glare and halo. Benefits include correction of high refractive errors without the optical limitations imposed by spectacles or the complications of long-term wear contact lens. Reversibility and expanded options for treatment of high refractive errors benefit both the practitioner and the patient.

In the sponsor’s clinical study, UCVA of 20/20 or better was achieved by more than 30 percent of the total treated population at 1, 2, and 3 years. UCVA of 20/40 or better was achieved by proportions ranging from 84 to 87 percent over the 3-year period of the study. At least 79 percent of study participants had 20/20 BSCVA or better and 100 percent had 20/40 or better in the overall treated population. In the consistent cohort, mean differences in refraction between visits ranged from –0.02 D to –0.05 D over the 3-year period. Of the 49 lens opacities reported, 4 were visually significant: 3 required extraction, and 1 eye lost 2 lines of BSCVA. After 30 years the endothelial cell count may drop to 1,272 cells/mm². The inclusion criteria specify ≥2,000 cells/mm² as the lower limit for preoperative endothelial cell count, but that may not be sufficient for younger patients. The two lens sizes directly relate to pupil sizes in mesopic conditions and associated glare and halos.

Gerry W. Gray, Ph.D., Statistician, Office of Surveillance and Biometrics, reviewed the sponsor’s endothelial cell count data. Endothelial cell counts and measurements were taken at baseline; 6 months; and years 1, 2, and 3. A total of 353 available eyes from reliable machines were recounted in one reading center. That was a total of 1,144 observation eyes by visit. . No control group was available.

It is important to have reasonable assurance that endothelial cell density is preserved. The point for concern is 1,000 to 1,200 cells/mm². The ANSI and ISO standards documents suggest that one calculate a sample size for this kind of study using a 2.0 upper 90 percent confidence interval. The FDA draft guidance sets an acceptable loss rate with an upper confidence limit of 90 percent at 1.5 percent per year. The estimates reflect steady-state long-term loss.

Annual rates of endothelial cell loss are highest in the first 3 years, then low thereafter. The data do not indicate any perioperative period with increased endothelial cell loss. Much variability exists in individual rates of loss. The calculations assume a linear loss rate, but it is not clear that is the case. The data conflict with expected outcomes in all guidance documents. The percentage change from baseline is not equivalent to the steady-state long-term rate. The estimate depends somewhat on whether the baseline count is included in the regression.

Extrapolation is always a questionable exercise. If one starts with a baseline endothelial cell density of 2,700 cells/mm², at the estimated loss rates, it would take 12 to 17 years to reach 2,000 cells/mm². How individual patients fare is perhaps more important than average cell loss through time. It is difficult to answer with any confidence what proportion of patients will show cell loss greater than some critical amount or what proportion will have cell densities of less than 1,500 or 800 cells/mm² at a given time point.

Dr. Lepri reviewed the panel questions and presented data tables.

Panel Questions for FDA Personnel

The panel’s questions focused on Dr. Gray’s extrapolation methodology and findings, which he clarified to their satisfaction.

COMMITTEE DELIBERATIONS

The sponsor provided clarification in response to various panel questions concerning pupil size, explantation, and bias in selection of endothelial cell recount patients.

Panel Review

Dr. Mathers provided the first primary panel review. He raised several safety concerns, primarily related to endothelial cell loss over time and changes in endothelial cell density resulting from lens insertion. For the entire group of participants in the sponsor’s study, the endothelial cell loss rate was 1.58 percent per year in the first 3 years; however, the normal loss rate is 0.6 percent over 3 years—2.5 percent at 10 years after cataract surgery. Patients who received the lens at age 20 would reach the point of risk for corneal failure and cataract in 30 years. Although the lens has not been removed from any markets for safety concerns, it would take more than 15 years to achieve a sufficiently low endothelial cell density to create corneal edema. The rate of cataract development in the study group is already higher than average, and postoperative inflammation in the form of cell and flare was persistent in 1.3 percent of subjects at 6 months. The accuracy of the implant appears to be excellent considering the difficulties in determining chamber depth and refractive error in high myopes. MRSE was quite good, and most participants gained at least 1 line of BSCVA. Halos can be expected in night when the pupil is largest and light passes outside the limits of the lens. Responding to the FDA questions for the panel, Dr. Mathers stated that the lens is not safe for the current intended population. Patients should be required to have a preoperative endothelial cell count of more than 2,400 cells/mm² and should be at least 35 years old, regardless of cell count. The restriction would delay onset of the mean risk point to age 75. As an alternative or additional method to reduce risk, the lens should be limited to patients most in need who had refraction of ≥–9.00 D; to those with ACD > 3.2 mm. Lens diameter should be limited to the size of the dark-adapted pupil to reduce halos.

Dr. Schein in his primary panel review raised concerns over how the sponsor reported data. The sponsor should not have excluded any patients from the safety analysis, and the safety data and adverse events should have been reported by person rather than by eye, because so many participants were bilaterally implanted. The sponsor was able to report on less than half of the potential 3-year data.

The sponsor also created an arbitrary division between complications and adverse events; for example, lens opacity, but not cataract extraction, was defined as a complication. Medical and surgical complications with potential to cause harm should be distinguished from trivial events. The lens and the surgical procedure are inextricably linked. Lens opacities were reported in about 5 percent of eyes, but no standardized grading system was used. What proportion of patients receiving the lens will need cataract surgery within 10 years? Comparisons with outcomes for anterior chamber intraocular lenses (ACIOLs) are inappropriate for this device. Patients reported several visual side effects; 16 to 30 percent had symptoms not noted preoperatively. Further analysis is needed to ascertain whether certain subgroups had intolerable adverse event rates.

Finally, with regard to endothelial cell count, the sponsor’s data have limitations. Although little evidence indicates systematic bias, the evaluation of means is not helpful, given that about 25 percent of patients lost 10 percent or more cells. How were discontinued participants or those with secondary procedures handled? The reanalyzed endothelial cell count data appear to represent only about 15 percent of images. Canadian and European data are not reassuring.

On the basis of what has been reported to date and the incompleteness of the data, the safety of the device is a concern. Additional analyses on the complete cohort would help alleviate the concern. Should the lens be approved, postmarket surveillance is warranted. Dr. Schein also listed several labeling suggestions, which he had submitted previously.

Dr. Macsai in her primary panel review reiterated many of the concerns of the other panel reviewers and pointed out that the lack of standardization and aspects of the protocol design of the PMA limit the ability to evaluate safety and efficacy of the lens. The sponsor’s safety criteria are inadequate. PIOLs should not be compared with ACIOLs because the device is not being used to treat patients with cataracts who have had vision loss. Use of the FDA grid for ACIOLs to determine acceptable levels of safety is therefore inappropriate. PIOLs must be held to a much higher standard than the FDA grid. In addition, the summary of key safety and efficacy variables was not submitted in a stratified manner for patients from Group E. The lack of this data is a significant deficiency. Consumers must have this information.

Twenty-six eyes had preoperative lens opacities that were not measured in any standardized manner; this oversight invalidates the comparison of the preoperative incidence of lens opacities with the postoperative incidence. In addition, 41 eyes were enrolled with corneal abnormalities. The definition of corneal abnormality is not clear. Without the information it is not possible to tell if the endothelial cell count data may be skewed from including these 41 eyes.

The adverse event rate was 3.9 percent, which is significantly higher than the 1 percent suggested as an approvable level for this PMA. The sponsor cannot arbitrarily decide what an adverse event is—anything that happens that is bad is an adverse event. It is unclear what the real number of adverse events is. It is significant that 23.8 percent of patients with pupils greater than 5.5 mm under mesopic conditions reported halos. These are high numbers and are induced problems. Sixty-seven patients experienced spikes of more than 30 mm of Hg, and gonioscopy was not performed in any of those patients preoperatively or postoperatively. The role of pigment dispersion, flare, some level of chronic inflammation, and possible acceleration of cataract formation or glaucoma from an IOL that is stabilized by enclavation of the iris has not been ruled out.

Finally, the endothelial cell data submitted by the sponsor were difficult to analyze. Only 12 sites that used the Konan microscope had endothelial cell images that could be evaluated. Loss of endothelial cells was higher between Years 2 and 3. The data demonstrate an increase in cell loss over time. Eyes with ACD of 3.0 to 3.2 mm had higher rates of cell loss, indicating that ACD plays a role. The data show that the endothelial cell count has not stabilized. The estimated endothelial cell loss rate of 1.58 to 3.05 percent is too high for a young person.

FDA QUESTIONS FOR PANEL

1. Do the endothelial cell data presented above in the overall analysis, stratified by anterior chamber depth and the extrapolations over time, provide reasonable assurance of safety of the Artisan myopia lens?

The panel concurred that the data provided in the overall analysis do not demonstrate reasonable safety.

2. Do the other data presented in the PMA provide reasonable assurance of safety?

Many panel members felt that the data presented in the PMA do not provide reasonable assurance of safety. Lens opacity, retinal detachment, increased IOP, and the need for revision surgery were of concern. The adverse event rates do not take into account the time under observation. Chronic inflammation and other issues may lead to accelerated cataract formation. The sponsor should provide adverse event rates by patient and by eye, along with a timeline. Adverse events that could cause harm or loss of vision should be separated from those that do not have major clinical significance. Data should also be stratified by lens power and should be provided for Groups C–E or all groups together without the separate groupings. The panel was also concerned about cataract formation and retinal detachment, noting that the absence of a control group makes the assessment of cataract formation extremely difficult. The sponsor did not provide adequate data on minority patients. One of the issues with high myopes is that they are at increased risk for glaucoma and there could be a lot of undiagnosed glaucoma that may or may not have gotten worse by the placement of this lens; however, there is no data for this. Also gonioscopy was not performed to determine the status of subjects on medication for increased intraocular pressure. The sponsor needs to address the panel’s safety concerns, whether with new data or reanalysis of existing data. Additional follow-up data on the patients enrolled in the clinical study are needed; data for only 60 percent of patients’ data are available now. A postmarket study may be appropriate.

Panel members noted that this device is trying to address a real need and may be suitable for a narrow range of patients who have few alternatives. However, they were concerned about the device’s impact on long-term endothelial cell loss and the inadequacy of the sponsor’s data for answering questions on the subject. Extrapolated data are not sufficient to determine safety. Agency staff commented that the sponsor had provided data for 300 eyes and had therefore met the Agency’s requirements for adequately powering the study’s safety analysis. Overall, a majority of the panel felt they needed more premarket data to decide whether the device is reasonably safe.

3. The proposed statement of indications reads: “The reduction or elimination of myopia in adults with myopia ranging from greater than –5 to less than –20 D with less than 2D of astigmatism at the spectacle plane; Patients with documented stability of refraction for the prior 6 months, as demonstrated by a spherical equivalent change of less than or equal to 0.50D.” Does the panel recommend any modifications to the proposed statement of indications with respect to: (a) minimum anterior chamber depth of <3.2 mm were excluded in the study); (b) maximum pupil size (the 2 models of Artisan are intended for patients with pupil sizes up to 5.0 mm and up to 6.0 mm); and (c) minimum preoperative endothelial cell density? The outcomes of ECC changes reported in number 1 above could be used to determine acceptable minimum endothelial cell densities.

Panel members concurred that ACD should be “greater than 3.2 mm.” They also generally agreed that the pupil size should not be larger than the optic, although some panel members stated that the data did not support that conclusion. The panel asked the Agency to use a 2 percent annual cell loss rate to calculate the minimum endothelial cell density for patients at any given age who are contemplating receiving the Artisan lens. The sponsor’s data alone were insufficient to determine minimum preoperative endothelial cell density.

4. Do the panel members have any additional labeling recommendations?

Panel members suggested including the following changes to the labeling:

· Include the table of preoperative and postoperative visual symptoms of glare, starbursts, and halos, by mesopic pupil size

· Possibly include a statement that patients should have explored other options for refractive correction before proceeding to having the surgery

· Dr. Coleman had numerous edits to the labeling involving the language concerning use of the lens in patients with glaucoma, risks involving IOP, and glossary terms; she submitted her recommendations in writing to the panel executive secretary.

· The labeling should state that the effects of loss of endothelial cell density are unknown.

· Long-term effects on corneal function, lens opacities, and corneal edema have not been established.

· The sponsor should not claim that the lens improves contrast sensitivity and add lines of vision, because those effects are artifacts of magnification. The product should clearly state that when switching from spectacle correction to this IOL, magnification will result in myopic eyes, with potential improvements in visual acuity.

· Both physician and patient labeling should include a clear, understandable statement describing the panel’s concerns about the future risks of this product.

· The adverse event rates as written imply that the data are based on the full cohort, which is not accurate. The term “nonadverse event” should not be used in the patient labeling.

· The data should list how many people required additional refractive procedures.

· Complications should include cataract and lens opacity.

· Endothelial cell data should be presented in terms of thresholds.

· The reference to the FDA grid for ACIOLs should be deleted.

· Risk of dislocation due to trauma should be listed under precautions.

· Precautions should include risk of starbursts and halos in low-light conditions.

· The patient brochure uses terminology patients are not likely to understand and should be revised accordingly.

· The glossary is inadequate.

Some panel members felt that the lens should not be approved for use in patients under age 18 because they were not in the study population. Most panel members declined to specify a minimum age, but they were comfortable with the Agency determining appropriate age/endothelial cell density parameters for patients considering the lens. The panel members also concurred that the minimum refractive error should be 9.00 D. The sponsor should conduct a postmarket study on a new cohort of patients for 2 to 3 years to determine rates of serious adverse events.

OPEN PUBLIC HEARING

Morris Johns, ophthalmologist, Louisville, KY, spoke in favor of approving the lens. Patients outside the 20/40 range benefit the most from the surgery. Refractive surgeons do not have many options. A prudent doctor would do endothelial cell counts every year. It is wise for the panel to suggest that ACD be greater than 3.2 mm because specifying the minimum ACD will reduce some complications. Retinal detachment and cataract are not of great concern. The panel is making a mistake by limiting the minimum refractive error to 9.00 D—the device works well for patients with thin corneas who are not candidates for LASIK.

Sponsor Closing Comments

Dr. Stulting said that he appreciated the panel’s concerns. An effective training program can be constructed so that the average ophthalmologist can do the procedure. The technology is available everywhere but the United States. If endothelial cell loss were an issue, it would have appeared after 100,000 implants.

VOTE

Ms. Thornton read the voting options. The panel vote ended in a tie, with 6 voting for and 6 voting against recommending approvable with conditions. Panel Chair Weiss cast the tie breaking vote in the affirmative for approval with the following conditions:

1. Patient ACD should be >3.2 mm.

2. The device is approved for a dioptric range of –9.00 D to –20.00 D.

3. The Agency should determine the age as well as the minimal cell count from which they will work backward as well as whether it will be quartile versus two percent cell loss in order to determine the cell count allowable for implantation of the lens at a given age.

4. A 2- or 3-year postmarket study should evaluate the incidence of retinal detachments, lens explants, and cataract formation with a sample size calculated by the Agency followed for two to three years.

5. Existing data should be reanalyzed for pigment dispersion and increased IOP with respect to the minority cohort subset.

6. The sponsor should revise the labeling as follows:

State that trauma is a risk factor for IOL dislocation.
Provide an accurate definition of “adverse event” for consumers.
Properly stratify data by lens power (±0.50 D or 1.00 D).
State that 38 percent of participants achieved 50 percent reduction in endothelial cell density in 25 years.
State that when pupil size is greater than the optic size, visual aberrations may result.
The table summarizing data on preoperative and postoperative glare, starburst, and halo should be included.

In the physician’s draft directions for use

Item 5h. Replace “medically uncontrollable glaucoma” with “glaucoma”
Item 7. Revise to state “Elevated intraocular pressure has been reported occasionally in patients who have received lens implants. The intraocular pressure of patients should be monitored postoperatively.”
Under Summary of Other Complications – Delete “No incidence of pupillary block” because there was an incidence of presumed pupillary block. Delete “persistent raised IOP” and mention that slightly less than 1% of the patients need medication for intraocular pressure control.
Include a statement that the patient’s risk of glaucoma in the future is unknown.
Include a statement that the effect on the drainage angle is unknown because they didn’t do gonioscopy pre and postoperatively.

In the patient labeling

1. Under No.10, Warnings substitute “glaucoma” for “medically uncontrollable glaucoma”.

2. Under Precautions replace “secondary glaucoma” with “elevated eye pressures” and change the second sentence to “Intraocular pressures of patients should be monitored postoperatively.

3. To the index add the terms glaucoma, intraocular pressure or eye pressure.

Delete statements referring to “improved” visual acuity and “improved” contrast sensitivity. In the patient information booklet it should be stated that the patient’s visual acuity at distance will be “improved” rather than using the word “clear
If the lens is approved, delete the statement that safety and efficacy have not been established
State that long-term risk to corneal endothelial cells has not been
established and that the short term cell count decreases.
A suggestion that physicians could perform a contact lens refraction to improve the accuracy of IOL power prediction for higher myopes.
Adverse events should be provided on a per eye and per patient basis. Risk for future lens opacities, retinal detachment and cataract formation should be mentioned.
The contrast sensitivity information should state that spectacle use in the re-op testing versus iris plan IOL testing does not indi

Voting Members

Consumer Representative

FDA Participants

CALL TO ORDER

OPEN PUBLIC HEARING

OPEN COMMITTEE SESSION

Division Updates

Ms. Thornton read the voting options. The panel vote ended in a tie, with 6 voting for and 6 voting against recommending approvable with conditions. Panel Chair Weiss cast the tie breaking vote in the affirmative for approval with the following conditions: