Addressing Safety Concerns with Phakic IOLs
Postmarketing studies of corneal endothelial cell density will be conducted for both lenses awaiting final approval.
BY KEITH CROES

It's one thing to implant an IOL after removing a cataract. It's another to implant one solely to correct refractive errors when extraocular approaches to refractive correction are safe and widely available.

The concept of intraocular approaches to refractive correction has occupied ophthalmologists since the early days of IOL implantation. The approval in 1998 of the small-incision Array multifocal IOL intensified the discussion, as the lens can be used off-label primarily to correct refractive error in people who have little or no cataract , and provide a depth of field not possible with monofocal IOLs. Well-known Austin, Texas, ophthalmologist Guy Knolle, former president of the American Society of Cataract and Refractive Surgery, received bilateral Array lenses precisely for that reason: He disliked his trifocals and his presbyopia, and trusted phacoemulsification and the Array, enough to give it a try. And he's not the only ophthalmologist to prefer an IOL to an extraocular approach.

Long-Term Effects Unknown

Now, two phakic IOLs, whose express purpose is to correct myopia, have reached a regulatory milestone: In separate meetings Oct. 3 and Feb. 5, the FDA's Ophthalmic Devices Advisory Panel voted "approvable" status, with conditions, for the ICL (STAAR Surgical Co.) and the Verisyse (Ophtec/AMO). (See accompanying table.)

The main concerns of the FDA panel reflected the longtime ophthalmic debate on the issue: What effects will a phakic IOL have on corneal endothelial cell density, pigment dispersion (and subsequent risk of glaucoma), and cataractogenesis, all of which are aggravated by inflammation and touch. The clinical studies of both lenses addressed these risks, albeit in slightly different ways. In the end, the FDA panel was most concerned with the corneal endothelium, where the long-term effects, which might be most relevant to younger patients who must live with the lenses for many years, are simply unknown. How deep should the anterior chamber be to minimize the risk of touch? How much cell loss was seen in the clinical study patients, and how much inflammation? How does the rate of cell loss compare with the cell loss normally seen with aging?

The good news is that both lenses provide refractive correction that appears accurate and stable enough to warrant approval, according to the FDA panel. In the case of the ICL, the panel recommended a change in the proposed labeling such that the lens is indicated for the "correction" of myopia in patients with preoperative refractions of ­3D to ­15D, and the "reduction" of myopia in patients with preoperative refractions of ­15D to ­20D. In the ICL study (preoperative myopia ranging from ­3D to ­20D, mean ­10.1D), 95% achieved uncorrected 20/40-or-better visual acuity; 57% had uncorrected visual acuities equal to or better than their best-corrected preoperative visual acuity; and 99% were "very, extremely, or moderately satisfied with the surgical outcome" (n=478).

Preoperative myopia in the Verisyse study ranged from ­4.6D to ­21.9D (mean ­12.3D, n=684 patients, 478 implanted bilaterally); 100% of eyes had a best-corrected visual acuity (BCVA) of 20/40 or better at 2 and 3 years after surgery; and 49% of eyes at 3 years gained BCVA compared with preoperative levels.

According to Roger Kash of STAAR Surgical, the company considers the FDA's conditions "reasonable." In addition to the ICL labeling change described above, STAAR must conduct a postmarketing study of endothelial cell density and cataract formation rates 4 and 5 years after implantation. STAAR also may be required to discontinue using the word "contact" as part of the name of the ICL. According to Kash, the company is ready to substitute "contact" for "Collamer," the latter term being a trademark for the collagen polymer material of which the ICL is made.

Although STAAR is addressing all conditions the FDA has passed along regarding the ICL, the company is distracted by an FDA audit primarily related to STAAR's core IOL business. Kash noted that, despite delays that may stem from this review, approval of the ICL may come by the end of the year.

The Verisyse lens, manufactured by Ophtec BV, based in Groningen, Netherlands, is marketed by Ophtec as the Artisan lens outside the United States. Under an exclusive distribution agreement with Ophtec, AMO will use the Verisyse brand in the United States after approval.

Rick McCarley, president and CEO of Ophtec USA, noted that Ophtec has addressed all conditions set forth by the FDA. The Verisyse labeling will include a chart showing the minimum preoperative endothelial cell counts, by decade of patient age, required for implantation of the lens. The FDA also has asked Ophtec to conduct a 2-year postmarketing study of endothelial cell counts.

Cell Loss Appears Related to the Surgery Itself

Minneapolis surgeon David Hardten, M.D., a Verisyse investigator, noted that he begins to consider using the phakic IOL in patients with 6D or 7D of myopia, especially in those patients with thin corneas who may not be suitable candidates for LASIK or PRK. He pointed out that, except in pathologic states, corneal thickness does not necessarily correlate with corneal endothelial cell density. "You can have patients with 440-micron corneas who have a normal cell density, and patients with 750-micron corneas who have normal cell density," he said.

Iris-fixated IOLs have a checkered history in ophthalmology, with early designs precipitating cataract, glaucoma, and corneal endothelial cell loss. At least in the mind of Dr. Hardten, the Verisyse lens, based on the design of Jan Worst, a renowned ophthalmologist from the Netherlands, is well on the way to resolving the issue of long-term safety. "Before I started implanting the Verisyse, I was concerned enough that I went over to Holland and examined some of Jan Worst's patients, who were out 7 years. I found those eyes very quiet," Dr. Hardten said.

For both phakic lenses, the maximum amount of endothelial cell loss and inflammation emerges in the immediate postoperative period and appears to be related mainly to the surgical intervention itself, and likely the skill of the surgeon. For that reason, the manufacturers of both lenses will offer intensive training. According to Kash, STAAR, which offers a monthly "minifellowship" on ICL implantation, the company has noted "a huge interest among ophthalmologists. We get a lot of cataract surgeons who aren't doing refractive surgery right now or are not doing many [refractive procedures]. We've been surprised at the acceptance [of the ICL] in that group," he said.

Both companies indicate that inflammation does not appear to be a factor after the early postoperative period. Furthermore, the rate of endothelial cell loss at the end of the clinical studies does not appear to differ significantly from what might be expected in the general population, although the FDA will require longer-term follow-up to demonstrate that point.

Both lenses likely will be associated with a recommendation that patients have at least a "normal" corneal endothelial cell count: somewhere over 2,000 cells/mm², perhaps age-adjusted. Neither glaucoma nor cataract appears poised to derail the future of either lens.

Patients to be Closely Monitored

All this may be good news for the millions of myopic Americans who may be candidates for these lenses. As the FDA panel's conditions demonstrate, the agency will be closely monitoring the corneal endothelial health of the early recipients of these landmark intraocular devices.