FDA Panel Delivers Mixed Verdict on KAMRA Corneal Inlay

Miriam E. Tucker

June 09, 2014

Gaithersburg, MD — An advisory panel delivered a mixed opinion to the US Food and Drug Administration (FDA) about the safety and efficacy of the KAMRA Inlay (AcuFocus, Inc) for the improvement of near vision in patients with presbyopia, ending a day-long hearing with a split vote.

The device, a polyvinylidene fluoride ring that is placed intrasomally in the cornea of the nondominant eye, works like a camera, using a small aperture to expand depth of focus. Unlike current refractive surgeries, the KAMRA inlay does not diminish distance vision, which remains binocular, AcuFocus Chief Clinical and Regulatory Officer Nicholas Tarantino, OD, told the FDA's Ophthalmic Devices Advisory Committee.

Panel members were largely convinced of the removable inlay's efficacy, voting 7 to 1 that there is "reasonable assurance" that the product improves near vision in presbyopic patients who meet criteria in the indication.

However, the committee split down the middle, 4 to 4, on the question of reasonable assurance of safety, triggering a tie-breaking "no" vote from committee chair Neil M. Bressler, MD. On a third question, whether the inlay's benefits outweigh its risks, the vote was 4 yes, 3 no, and 1 abstention.

"There's likely something controversial going on if it's splitting down the middle," noted Dr. Bressler, chief of the Retina Division at The Wilmer Eye Institute and the James P. Gills Professor of Ophthalmology at the Johns Hopkins University School of Medicine, Baltimore, Maryland.

As it is currently worded, the entire proposed indication is "for the improvement of near and intermediate vision in presbyopic patients who require near or intermediate correction. The inlay is intended to be placed intrastromally in the cornea, on the visual axis, by way of a femtosecond laser-created pocket using a spot/line separation of 6×6 microns or less. The inlay should be placed at a depth equal to or greater than 180 μm."

Although the proposed indication did not include the word "emmetropic," that is, with intact distance vision, the clinical studies only enrolled emmetropic presbyopes, and several panel members advised the FDA to include that word in the product's label if it is approved. Of the 80 million people who develop presbyopia, approximately 14%, or about 11 million people, have emmetropic presbyopia.

KAMRA has been sold in the European Union since 2010 and marketed in a total of 33 countries; approximately 20,000 have been implanted, Dr. Tarantino said.

The AcuFocus View

John A. Vukich, MD, an ophthalmologist in Madison, Wisconsin, and a clinical investigator for AcuFocus, presented efficacy data from the 36-month prospective, open-label, multicenter pivotal trial, which enrolled a total 521 patients who had uncorrected near visual acuity worse than 20/40 but better than 20/100 and a best corrected distance visual acuity (BCDVA) of 20/20 or better (ie, emmetropic).

The primary effectiveness endpoint, 75% of the subjects achieving uncorrected near visual acuity of 20/40 or better at 12 months, was met, with that number actually reaching 83.5% of the 478 subjects who completed 12 months of the study and remaining consistent through 36 months. Participants had a mean 2.9-line gain at month 12, Dr. Vukich said.

On subjective patient satisfaction questionnaires, mean scores on a 1 to 7 scale for satisfaction with near vision improved from 1.7 at baseline to 4.7 at 12 months and remained consistent at 3 years.

Clinical investigator Jay S. Pepose, MD, PhD, professor of clinical ophthalmology at Washington University, St. Louis, Missouri, presented safety findings for the pivotal trial, including a 0.6% rate of persistent BCDVA loss of 2 lines or more at consecutive visits at 12 months, 0% incidence of BDCVA worse than 20/40 if 20/20 or better preoperatively, induced refractive astigmatism, or more than trace corneal haze.

However, other ocular adverse events occurring in 1% or more of patients included 3.3% with significant intraocular pressure increase and 5.9% with a decrease in BCDVA or more than 2 lines at month 3 or later.

In the pivotal trial, outcomes were found to be better for surgical procedures that involved use of a femtosecond laser to create a corneal pocket (rather than a flap) and a "smoother" lamellar resection with spot/line separation settings of 6 × 6 microns or less.

In a subsequent confirmatory trial of 151 subjects using the "6 by 6" surgical standard, the primary endpoint improved to 90.8%, with a drop in inlay removals caused by refractive change from 6.9% in the non-6 × 6 subjects in the pivotal trial to 2.9% and 2.7%, respectively, among the 6 × 6 groups in the pivotal and confirmatory trials. Hence, the proposed labeling specifies use of the 6 × 6 technique.

FDA's Take

FDA Chief Ophthalmic Medical Officer Eva Rorer, MD, faulted AcuFocus for excluding a total 8.7% (44) of patients with inlay removals from the safety analysis in the pivotal trial, as most of the removals were because of visual problems. With those patients included, the primary efficacy endpoint drops to 75.8%.

"FDA believes the excluded subjects should have been counted as failures," she told the panel.

Moreover, according to Dr. Morer, only a quarter of patients from both trials gained 4 or more lines of uncorrected near visual acuity, which is equal to 1 diopter of accommodation, without losing more than 1 line of letters of uncorrected distance visual acuity from baseline at 12 months.

She also questioned the findings on refractive stability, a secondary endpoint defined by at least 95% of subjects having no more than a 1 diopter change in manifest refractive spherical equivalent between 2 consecutive visits. That target was not met at 30 to 36 months in the pivotal trial, although it was met at all points in the confirmatory trial, using the 6 × 6 technique.

The percentage of subjects with greater than 1.0 diopter of "hyperopic shift," when the manifest refractive spherical equivalent "shifts" toward the positive direction, from baseline reached a maximum of 16.6% at 6 months and was 10.6% at 36 months in the pivotal trial, but there appeared to be an upward trend. Several panel members expressed concern over what might happen beyond the 36-month point.

FDA officials also faulted AcuFocus' pivotal study for excessive protocol deviations, over-enrolment leading to potential bias (400 had been the original target), and flaws in its patient satisfaction survey, noting that the way patients were questioned could have biased their responses.

The committee was asked to provide input on all these issues as well as to make recommendations about endpoints for a planned 5-year postmarketing study should the FDA approve the inlay.

Struggling to Measure Benefit

On the questions of safety, efficacy, and benefit outweighing risk, panel member Alvin Eisner, PhD, reviewing editor of Current Eye Research, Portland, Oregon, said he voted no on the safety question primarily because of concerns about the outcome of explanted patients over time, the uncertainty regarding hyperopic shift, and potential interference of the device with ophthalmologic examinations, such as for diabetic retinopathy.

However, he said he came down positively for the question of benefit outweighing risk, in deference to "risk benefit considerations that the individual might make as opposed to what we might make for a population of people."

Alice Y. Matoba, MD, associate professor of ophthalmology at Baylor College of Medicine, Houston, Texas, voted yes for safety but no to the other 2 questions. "From a clinical standpoint, I don't have concerns about the safety. Most of the adverse events were minor, I think." She said she would have voted yes for the other 2 questions if the word "emmetropic" had been included in the proposed indication.

Scott R. Evans, PhD, senior research scientist in the Department of Biostatistics at the Harvard School of Public Health, Boston, Massachusetts, said his "no" vote on the question of benefit outweighing risk was influenced by Dr. Rorer's assessment pitting the gain in uncorrected near visual acuity against the loss in uncorrected distance visual acuity. "Eight of 10 met primary endpoint for effectiveness, but only 6 of 10 got benefit when you consider the totality of what's happening to patients. I think that's a key issue to be thinking about, particularly when you potentially have a $2 alternative [ie, drugstore reading glasses]."

Sam S. Dahr, MD, an ophthalmologist who practices in Oklahoma City, was the one who abstained on the question of benefit outweighing risk. He explained his rationale this way: "When we do a study of wet [macular degeneration] or retinal detachment, we're treating a disease, and our outcome data gives us a pretty good sense of the benefit to the patient. In the refractive sphere, it's much more difficult. There's tremendous variability from individual to individual in terms of the perceived benefit. A patient may have the procedure and actually meet the outcome of 20/40 uncorrected at near, but be very unhappy despite meeting the outcome because they may have dryness or halos or what have you. Another patient may have the intervention and not meet the outcome of 20/40 at near, but actually be very happy because they have a 2- or 3-line improvement. This is a very difficult area to measure benefit, and that's why I abstained."

FDA advisory panel members are vetted for conflicts of interest and waivers are granted for participation if necessary. No waivers were granted for this meeting. Dr. Tarantino is an employee of AcuFocus, Inc, and Dr. Vukich, Dr. Pepose, and Dr. Durrie are paid consultants to the company. Dr. Rorer has disclosed no relevant financial relationships.


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