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FDA panels say yes to HydroView, LASIK; no to Hyperion, Restasis
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GAITHERSBURG, Md. — July was a busy month for Food and Drug Administration (FDA) advisory panels, which were reviewing ophthalmic premarket approval applications (PMAs). When it was all over, Visx and Summit received recommendations for a laser in situ keratomileusis (LASIK) indication for their excimer lasers and Bausch & Lomb received a recommendation for its HydroView IOL. Those not receiving recommendations were Allergan’s Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan) for keratoconjunctivitis sicca (KCS) and Sunrise Technologies for its holmium laser for treating hyperopia. The manufacturers are still awaiting the final word from the FDA.
Visx, Summit lasers recommended
The FDA’s Ophthalmic Devices Panel recommended that the agency approve LASIK as an additional indication for both the Visx Star and Summit Apex Plus excimer lasers.
Although the approvals would go to Visx and Summit, both approvals stem from the study started and conducted by CRS-USA, a private corporation formed by ophthalmologists and headed by Charles Casebeer, MD, of Scottsdale, Ariz.
The panel recommended approval of the Visx Star for up to 12 D of myopic LASIK correction and up to 4 D of cylinder. The panel also recommended that the labeling indicate that poorer outcomes result in patients with more than 10 D of myopia and that stability is poorer in cases above 7 D.
The Summit Apex Plus is recommended by the panel for up to 14 D of myopic correction and 5 D of cylinder. The panel also recommended that labeling include cautions that outcomes are less predictable at higher correction and that adverse visual symptoms occur in patients with larger pupils.
Visx results from 11 study centers
Clinical results from the Visx data presented to the panel came from researchers at 11 study centers; 1,276 eyes were enrolled and 723 were included in the premarket approval cohort. Some surgeons filed incomplete data, so only 76.3% of the original study patients were included in the final data analysis.
FDA effectiveness endpoints for refractive surgery require that 95% of patients have stability of mean refractive spherical equivalent (MRSE) within ±1 D and that 85% have an uncorrected visual acuity of 20/40 or better. Half need an MRSE within 0.5 D of attempted and 75% need MRSE within 1 D of attempted.
Guy Kezirian, MD, who presented the data for CRS-USA, said that mean refractive changes after 1 month were minimal.
Eyes that required less than 7 D of correction achieved 20/40 vision 98% of the time at 6 months, while eyes with more than 7 D of correction achieved 20/40 vision 86% of the time.
Panelist Mark J. Manus, MD, FACS, a primary reviewer of the data, said that because there was a clear dividing line at 7 D in safety and efficacy it should be reflected in the labeling for the Visx Star. He added that patients requiring more than 10 D of correction could experience many more complications that were not revealed by the cohort presented to the panel. Safety was not questioned with the Visx Star, however.
Among the safety endpoints, the FDA safety criteria state that fewer than 5% of patients should lose two or more lines of best spectacle-corrected visual acuity (BSCVA), that fewer than 1% should have worse than 20/40 vision and that fewer than 1% should lose more than two lines of vision because of haze. Dr. Manus added that the data certainly suggested safety and efficacy.
Among the CRS results for the Visx Star among patients with more than 7 D of attempted correction, 1.4% exceeded this rate at 3 months and 0.7% had lost two or more lines at 6 months. Patients with more than 7 D of attempted correction also experienced worse visual acuity. In the cohort, 1.9% had BSCVA worse than 20/40 at 3 months and 1.5% had BSCVA worse than 20/40 at 6 months.
Summit results from 1,013 eyes
Summit data was reported for a total of 1,685 eyes, from which a cohort of 1,013 eyes was presented. Account ability was more acceptable to the panel, as surgeons reported an 84% account ability rate at 6 months among the cohort and 81.3% accountability for the entire study.
In the Summit study, the mean age was 38.8 years old, with a range of 18 years to 64 years. The average attempted corrections were: spherical 6.1 D, spherical equivalent 4.5 D and cylinder 1.83 D, Dr. Kezirian said.
Patients needing correction less than 7 D sphere achieved 20/40 in all eyes and 20/20 vision in 90% of eyes. Patients needing more than 7 D sphere achieved 20/40 in 99% of eyes and 20/20 in 96% of eyes.
The Summit data met all of the safety guidelines required by the FDA, Dr. Kezirian said. No study group exceeded 5% with loss of more than two lines of visual acuity at 6 months. All types of adverse events occurred in less than 1% of patients.
HydroView receives recommendation
The panel also unanimously recommended for approval Bausch & Lomb’s HydroView IOL, a composite one-piece lens that has already been sold in more than 30 countries and implanted in nearly 500,000 eyes.
Douglas Koch, MD, who presented the clinical study data to the panel, reported that 96.4% of eyes implanted with the lens achieved 20/40 or better best-corrected visual acuity.
Of the overall study group of 387 patients, 52.6% of eyes achieved 20/20 or better vision and 38.4% achieved 20/30 or better vision, he said. All persistent adverse effects fell within the “FDA grid” criteria that the agency uses to assess IOL safety and efficacy.
No recommendation for Restasis
In other deliberations, the FDA Ophthalmic Drugs Subcommittee advisory panel unanimously recommended not to approve Allergan’s Restasis for KCS after concluding that clinical trials did not show efficacy. Soon after the meeting, Allergan announced that it stood behind the drug and would continue to pursue approval.
Allergan supplied phase 2 and phase 3 study data in its PMA application. Wiley A. Chambers, MD, Deputy Director, Division of Anti-inflammatory, Analgesic and Ophthalmologic Drug Products of the FDA, opened the meeting by asking the panel whether the data were sufficient to show efficacy of Restasis, even though all parts of the study did not replicate each other. By the end of the day the panel had decided that the trials showed no significant difference between treatment and control groups and that proof of the drug’s efficacy would require further study.
The phase 3 study was divided into two groups, identified as 002 (405 patients) and 003 (472 patients). Both groups underwent the same randomized, double-masked multicenter study, but pharmacokinetic evaluation was performed only in patients in group 003. Of the 877 patients in the phase 3 trial, 671 completed a 6-month vehicle-controlled, double-masked study in which they instilled one drop twice a day of 0.05% cyclosporine concentration, 0.1% concentration or vehicle alone. Only data from this 6-month study was evaluated to decide upon drug efficacy.
Biopsy data showed specifically that Restasis reduced the inflammatory response, said Brenda Reis, PhD, Allergan’s director of clinical research.
According to study data, several differences were apparent between the two phase 3 study arms. Al though the magnitude of improvement from baseline was greater in the 003 arm than the 002 group, statistically significant differences favoring cyclosporine over the vehicle alone were more often demonstrated in the 002 arm than in 003.
Allergan wrote in a briefing document that, “This was due to the relatively strong vehicle response in 003, which was evident as early as month 1 and persisted throughout the treatment period.”
According to Allergan’s briefing document, baseline entry data differed between the two arms of the study. The second arm of the phase 3 study had a greater proportion of less severe dry eye patients than the first arm, as shown by corneal staining scores.
“The mildest corneal staining score allowed at study entry was grade 2, which occurred in 53% of patients in (the second arm) compared with 42% of patients in (the first arm),” according to the document. “Thus, the difference between the studies in patients with the lowest allowed grade of corneal staining was approximately 10 percentage points.”
The difference was evident in the vehicle control group, where 61% of patients entered with grade 2 staining in the second study arm but 41% of the patients entered with grade 2 in the first arm, a difference of 20%.
Schirmer’s test results did not correlate, however, as was expected among a study group of dry eye patients in whom no one endpoint can describe all the symptoms that characterize the disease.
Allergan still seeks approval
Lester Kaplan, PhD, Allergan’s corporate vice president for research and development, said after the meeting that the company will discuss with the FDA how to move forward toward approval for Restasis. The company could include additional analysis of the data set, such as long-term results, or conduct more studies.
“This is pioneering work,” Dr. Kaplan said. “There has never been a large, well controlled drug study in this area. We still believe that our studies were adequate to show the safety and efficacy of this product. It’s an important product for a very underserved market.”
John R. Gibson, MD, Allergan’s senior vice president of research and development, had earlier told the panel members that no previous controlled clinical trials had been conducted in this area.
“Allergan had to break new research ground,” he said. “This was not a routine matter. It was challenging.”
Allegan: Restasis restores cornea
Allergan researcher Michael E. Stern, PhD, told the panel that Restasis administered twice daily restores a clinically normal cornea to KCS patients. The drug decreases inflammation and the apoptosis that results in corneal irregularities.
He added that Restasis works because its active ingredient, cyclosporine, indirectly facilitates lymphocytic apoptosis while directly preventing epithelial cell apoptosis. Both mechanisms restore a smooth cornea and a crisp ocular reflex.
The vehicle for Restasis is itself palliative and soothing. Because it remains in the eye much longer than artificial tears, patients can reduce drug administration to twice daily from as often as every 15 minutes.
Cyclosporine is delivered ocularly in much lower concentrations than the systemic formulas, which helps its safety profiles. And cyclosporine does not penetrate large molecules but rather prefers lipids and tissue, said Allergan’s director of pharmacokinetics and drug metabolism Diane D-S. Tang-Liu, PhD.
Panel on Hyperion: too much regression
Additionally, the devices panel unanimously recommended that the agency not approve Sunrise’s Hyperion holmium laser treatment to correct between 0.75 D and 2.5 D of hyperopia because the clinical results showed too much regression.
Panel reviewers and FDA staff said 6-month follow-up data showed that the refractive correction provided by the procedure was not sufficiently predictable. They recommended delaying approval until more long-term follow-up and data analysis are available. At question is the tendency for refractive results to regress.
The company reacted as aggressively to the panel vote as they have to recent attacks by stock market analysts and an accusatory story in The Wall Street Journal. Sunrise argues that the results with the Hyperion meet or exceed the refractive laser surgery standards set for the approval of photorefractive keratectomy, so they will persevere in obtaining FDA approval regardless of the panel recommendation. And despite rumors to the contrary, Sunrise says, the company is solvent and will see their product to market.
Although the panel did not dispute the safety of the Hyperion, they did challenge the device’s efficacy. Two primary panel reviewers said the device was not approvable. The panel’s discussion of questions submitted by the FDA was concise.
The panel decided to focus on the data analysis that excluded early cases in which a Weck-cel sponge was used to dry the cornea. Because they were among the patients with the longest follow-up, however, the lack of data from those cases made the panel leery about recommending that the FDA approve the product.
The panel agreed that data should be resubmitted when follow-up of at least 24 months can be obtained in 90% of a group of 300 enrolled patients.
Hyperion: After the vote
In a conference call for stock analysts held the morning after the advisory pan el meeting, R. Doyle Stulting, MD, said, “The process that occurred yesterday was not a good one, at least in my opinion. During the discussion, the panel selectively quoted data and quoted data that was in accurate. They ignored data that they had in their hands as part of the discussion.”
Now, the company will work directly with the FDA staff on how to further seek approval for its laser, based upon the panel’s input. This will allow Sunrise a chance to address the panel’s concerns.
“Fortunately, the concerns and requirements are relatively easy to address and perhaps even easier to address than some of the conditions that may be attached to the approval recommendation,” Dr. Stulting said.
In these talks, the FDA staff will recognize the unfairness of some of the panel’s judgments, he added.
Sunrise consultant Donald Sanders, MD, PhD, director of the Center for Clinical Research, said in the same conference call that the drift seen after laser thermokeratoplasty with the Hyperion is virtually identical to that demonstrated by the excimer lasers made by six other companies.
“What [the panel] chose to ignore is all the other available technology has the identical issue to deal with. The FDA in a past submission with Visx chose to accept substantially less data with the same drift issue. They essentially set up a double standard for two competing technologies. That I believe the FDA has to address because they have repeatedly said that with new technologies they believe that it’s important to have what they call a level playing field.”
NASDAQ suspended trading of Sunrise stock at the close of the market on July 22, although many on-line information services showed a false jump of the share price early the next afternoon to $32.375. In fact, the share price did not move until the opening of the market Friday morning.
And move it did. By the end of the day Friday, Sunrise stock had fallen from $15 to $3.7188 as 27 million shares were traded.