Tuesday, February 24, 2015

By Richard Smith

          As with many regulatory proceedings, a Food and Drug Administration hearing today will have effects reaching far beyond its official topic. An FDA scientific advisory panel is gathering to consider a new treatment for keratoconus, a rare but potentially disabling eye disorder. How the FDA responds could launch a new phase of the Lasik eye surgery boom–with an add-on technology that’s marketed as enhancing patient safety but that in fact greatly increases patient risk.

          First, the basics: Keratoconus affects about 174,000 Americans, with roughly 6,400 new cases a year.^[1] An afflicted eye loses structural integrity, and the cornea bulges forward under the eyeball’s internal pressure. Vision may deteriorate severely as the eye gets more and more distorted.

          The procedure under review, corneal crosslinking, is simple compared to many ophthalmologic treatments. The eye is doused with a solution of riboflavin (Vitamin B2) and then exposed to ultraviolet light. This stiffens eye tissues containing collagen. (I imagine damp shoe-leather baking in harsh sunlight.)

          The idea is to help the eye hold its shape, but for minorities of patients the treatment causes problems, including significant loss of corrected distance vision in 2.9 percent; significant scarring, up to 8.6 percent; and corneal ulcers, 7.6 percent.^[2] Long-term risks are unknown, but because crosslinking uses a range of ultraviolet light known to alter DNA,^[3] there’s a chance it could trigger cancer.

          Such risks aren’t trivial. But the benefits may be substantial: halting the disease’s progression, which can lead to legal blindness, and avoiding corneal transplant, a frequent treatment for severe cases that is nobody’s idea of a picnic.

          But there’s more to the story. Crosslinking is being evaluated as a treatment not just for keratoconus but also for corneal ectasia. Ectasia is a kind of cousin, with the same basic symptoms and course, but unlike keratoconus its cause is known: the laser vision-correction surgery known as Lasik–a medical intervention widely touted as safe and effective.

          How can Lasik lead to ectasia? Refractive surgeries aim to improve vision by reshaping the eyeball so light focuses properly on the retina. Before Lasik, the laser was applied to the eye’s surface. Recovery was slow and painful. Lasik emerged as an easier sell: a thin flap of cornea is shaved and folded aside, underlying tissue is lasered, and the flap is flipped back into place, creating a natural bandage over the wound. Less pain, fast vision improvement–the so-called Lasik “wow!” effect.

          But the cornea doesn’t heal like most body tissues. In fact, the Lasik flap never really heals. In one study, the edge of the flap retained only 28.1 percent of its original tensile strength–and the central area only 2.4 percent.^[4] That’s why, years after Lasik, a blow to the eye can knock the flap loose, like an unlatched door, and a surgeon “retouching” your Lasik can simply relift the original flap, like scraping an egg off a griddle.

          The flap’s failure to heal also leaves the cornea weaker–less resistant to the eye’s internal pressure. Sometimes the eye’s shape shifts enough to start undoing Lasik’s correction of vision. Worse corneal bulging can cause ectasia.

          How often this happens isn’t clear, as estimates vary and, as malpractice attorneys have found, some cases are hushed up.^[5] Current statistics put the incidence below one percent.^[6] That’s less frequent than some of Lasik’s other downsides, such as glare, halos, starbursts, ghosting, and dry eye.^[7] But because such symptoms are classified by the FDA as less severe than ectasia, they’ve received less official attention and surgeons have been less concerned with them than with downplaying or even denying the risk of ectasia.^[8]

          Now, however, with corneal crosslinking on the horizon, ectasia is back on their radar. In fact, some surgeons and industry leaders advocate adding crosslinking to Lasik as insurance against future deterioration. Avedro, whose procedure comes for FDA review today, is conducting a clinical trial of Lasik and corneal cross-linking performed simultaneously–a double-header already approved in Europe, where Avedro markets it under the trade name Lasik Xtra. Another company, CXLUSA, is running a trial of a Lasik-crosslinking combo for patients known to be at higher risk of ectasia.

          So let’s get this straight. The risk of ectasia after Lasik is less than one percent–way less, surgeons have insisted. But surgeons propose tacking on crosslinking, with risks several times greater than that of ectasia. And the risks of crosslinking would load on top of the known risks of Lasik. These risks have been hotly debated, but one review of FDA documents found that, across studies, 15 percent of Lasik patients had worse or significantly worse night vision than before surgery. Twenty percent had worse or significantly worse dry eye.^[9] These outcomes can be far more disabling than they sound–for instance, when a Lasik patient driving at night must try to peer through streetlight starbursts that span the whole road, or when Lasik-induced dry eye hurts so much a person wants to gouge his eyes out.

          The Hippocratic Oath advises doctors, “First, do no harm.” Given that Lasik is medically unnecessary, maybe the simpler solution is not to do it in the first place.

          To make a case for Lasik plus crosslinking, surgeons have had to stop minimizing ectasia’s risks, instead maintaining that those risks justify adding crosslinking. Whatever net effect crosslinking brings to Lasik patients, it also gives crosslinking tech companies and Lasik surgeons a new option they can add to bills for some 600,000 Lasik customers a year. Big money isn’t in treating kerataconus but in promoting Lasik with crosslinking.

          That procedure will come up for FDA approval within the next few years. But if today’s advisory panel recommends approval for crosslinking, doctors could start slapping the procedure onto Lasik even before the safety and efficacy of the combo platter has been adequately studied. Doctors could claim a right to perform the procedure in what’s called an “off-label” use–that is, for purposes other than those officially sanctioned.

          The FDA regulates drugs and medical devices, not the practice of medicine,so it couldn’t stop off-label uses altogether. But what the agency can do is stipulate that crosslinking, if approved, can be marketed only for the approved purposes–treating keratoconus and ectasia. It could forbid doctors to promote crosslinking as a way to make Lasik safer. Such claims would constitute “misbranding”–essentially, misleading advertising that amounts to fraud. That might give the agency a chance to make a meaningful yes-or-no decision when Lasik Xtra and its competitors come up for approval. Otherwise, Lasik-plus-crosslinking could become so commonplace that future FDA approval would be a foregone conclusion.

          That’s how the Lasik boom got its start two decades ago. In the 1990s, Lasik became what its critics regard as a runaway train when lasers were FDA-approved for an earlier method of eye surgery, and surgeons began using them for Lasik as well–before anyone adequately studied Lasik’s safety and effectiveness. According to Morris Waxler, then branch chief of the FDA’s Center for Devices and Radiological Health, the agency got worried that Lasik was spreading without safety studies or rules, risking not only patients’ eyes but also the FDA’s reputation. So the agency tried to rush Lasik surgeons into the corral of government oversight.^[10]

           Predictably, this rushed job was a botched job. For one thing, according to Waxler, the FDA allowed industry too much say in establishing official definitions of safety and effectiveness. Many of the ways Lasik can damage vision and eye health got downgraded from adverse event to complication or side effect–and thus didn’t affect Lasik’s official safety profile.

          The FDA advisory committees reviewing Lasik in the 1990s tried to slow things down. The first one voted the application under consideration nonapprovable–largely because the reported percentage of patients returning for followup evaluation was so low that the data looked cherry-picked. Nonetheless, the agency approved it, fearing a battle with the applicant’s formidable attorney (a former FDA chief counsel).^[11]

          During the next round of hearings, NIH ophthalmologist Frederick Ferris acknowledged it was bizarre to see the FDA debating approval of a surgery already in widespread use: “…driving in here I heard a number of advertisements for this procedure…. I thought to myself, Well, people little note nor long remember what we do here because, as near as I know, this train is moving.”^[12]

          Now another train is lurching into motion. The FDA needs to hit the brakes.