Hedging bets on laser refractive surgery
Excimer-laser surgery to correct vision is among the more intriguing medical applications to emerge in the last decade, but it`s been slow to gain approval in the USA. The reasons for the delay are complex and go far beyond the usual complaints of bureaucratic foot-dragging by the Food and Drug Administration. They stem from rapid technical advances, the nature of the surgery, and trends affecting the whole eye-care industry.
The idea of excimer-laser surgery on the cornea grew from 1982-1983 experiments in which R. Srinivasan of the IBM Watson Research Center (Yorktown Heights, NY) found that excimer-laser pulses could vaporize polymers. Other researchers soon showed that excimer pulses could remove material from the cornea, the thin transparent membrane covering the eye. The cornea provides much of the eye`s refractive power, so reshaping it could compensate for refractive defects that leave light out of focus on the retina. The major interest was myopia or nearsightedness, in which light focuses in front of the retina. This can be corrected by thinning the center of the cornea to reduce the eye`s focusing power.
A few American ophthalmologists already had been experimenting with radial keratotomy (RK), a procedure developed in the former Soviet Union in which eight radial slits are cut in the cornea. As the cuts heal, the central cornea thins, reducing its refractive power. Early American researchers followed the Soviet practice of using scalpels, a delicate operation which requires cutting through u¥to 90% of the cornea. The first laser experiments were aimed at replacing knives, in the hope of making more precise cuts.
Soon, however, eye specialists shifted to an approach they considered less risky. Instead of indirectly reshaping the cornea by relying on healing of the cuts, they directly ablated material from the central corneal surface with excimer laser pulses, a process called photorefractive keratectomy or PRK (see Laser Focus World, March 1992, p. 53). Early animal tests yielded promising results, and entrepreneurs soon started developing surgical excimer lasers. After a series of legal battles over patents, two companies emerged as the prime American movers in PRK: Summit Technology Inc. (Waltham, MA) and VISX (Santa Clara, CA).
FDA applies the brakes
While laser ablation of thin layers from the cornea may sound safer than radial keratotomy, federal regulations treat them differently. The FDA lacks authority to regulate how doctors use conventional instruments such as scalpels, even for new procedures like RK. However, it must verify the safety and efficacy of new instruments such as surgical lasers, an extension of its original charter to assure the safety of foods and drugs. As a result, radial keratotomy has been performed clinically in the USA since the early 1980s, while laser treatment has remained experimental.
Lasers were not used on sighted eyes until 1988, notes industry analyst Irving Arons, senior editor of Medical Laser Report. It took time after that for researchers to refine the process and collect data, especially the two years of follow-u¥observations on hundreds of treated eyes required by the FDA protocol. Most other developed countries have less stringent restrictions, so excimer-laser systems made by companies from America and elsewhere, notably Germany and Japan, are already in general use for refractive surgery in Europe, Canada, and Pacific Rim countries.
Laser PRK has largely replaced radial keratotomy in countries where the laser systems are available for clinical use, but radial keratotomy remains the only refractive surgery in wide use in the United States. Data from a 10-year controlled study of early RK patients were published in the October 15, 1994, Archives of Ophthalmology. The study, funded by the National Eye Institute (NEI), yielded mixed results. The absence of severe side effects was reassuring. Only 3% of patients lost some visual acuity with corrective lenses, and all of them retained at least 20/40 vision, usually shar¥enough to qualify for a driving license.
The surgical correction has not been stable, probably because it depends on healing of the cornea. More than 40% of treated eyes continued to shift slowly toward farsightedness years after the operation. Study cochairman Peter J. McDonnell of the University of Southern California says those results indicate that some people initially pleased with the operation "may change [their minds] five, ten, or fifteen years down the road." Patients who had thrown away their glasses immediately after the surgery could well need a new pair (albeit with less correction) later.
Just days after the NEI study was published, Summit`s application to market its excimer system for PRK came before the FDA`s Ophthalmic Devices advisory panel and only narrowly survived its first review. After a long and sometimes heated debate, the panel asked Summit to supply more data and meet 17 conditions for FDA approval. The panel requested data to show that, after surgery, 75% of patients have vision of 20/25 or better without glasses and to prove that no less than 5% suffer any vision loss. Summit was to submit that data by February of 1995. FDA staff must analyze the results and make the final decision on approval of the laser system for clinical use.
The FDA panel did not display the same reservations in March 1994 when it voted to approve sale of the Summit system for Phototherapeutic keratectomy (PTK), the treatment of scars and other corneal lesions. Within three months, the FDA told Summit that the system was "approvable." Final approval has not yet come through, however.
Lasers for the two procedures differ only in software programming. The important difference is in the purpose of the surgery. PTK treats corneal lesions that are hard to repair in other ways and which might otherwise require corneal transplants. In contrast, corrective lenses can easily correct most myopia; PRK and other refractive surgery is primarily cosmetic, and no one will go blind if it is delayed.
Weighing the pros and cons
The panel`s action on Summit`s PRK application reflects a debate among American ophthalmologists over the relative advantages of radial keratotomy vs. laser PRK. "The volume and length of experience both favor RK," which has improved since the start of the NEI study, says McDonnell, who served on the FDA panel as well as the NEI study group. On the other hand, he says, laser surgery works better than RK did at the same stage of development. The computer-controlled laser systems require less surgical skill, and the outcome is more predictable because it relies less on healing response. The laser also can correct more-severe vision defects. Where both procedures are available outside the USA, McDonnell says both doctors and patients tend to prefer the laser to the knife.
However, the newness of the laser procedure has led to some problems. Steady improvements in PRK techniques and instruments pose problems for the FDA approval cycle. Recent studies show laser treatment works best on a 6- to 7-mm spot in the center of the cornea, an approach Summit now uses in its European systems. But Summit presented the FDA with two years of follow-u¥data on 700 eyes where only 5-mm spots were treated with an older system. That didn`t satisfy some members of the FDA advisory panel, who complained that the new instruments differ enough from the old ones to require a new study.
Nor is the technology standing still. Summit and others are working on holmium-laser systems that would reshape the cornea by a process called laser thermokeratoplasty (LTK). Water absorbs the 2-µm output of the holmium laser strongly, causing controlled shrinkage of collagen and thereby reshaping the cornea. Developers believe that this approach can treat astigmatism and farsightedness, conditions not amenable to PRK, as well as nearsightedness. The possibility of better instruments raises a regulatory dilemma--should the FDA approve current excimer systems or wait for a new generation of instruments that may be much more effective?
Reading closer between the lines reveals other complications, many involving money. The major developers of lasers for refractive surgery are betting their futures entirely on the technology. They have to pay for clinical trials, but lack the dee¥pockets of big drug companies--and anxious investors are far more likely to complain about FDA delays. Summit and VISX both sell lasers overseas, where they can be used clinically, but the United States is considered a bigger market.
Meanwhile, a new cadre of firms has appeared, most targeting what they consider the more lucrative market for surgical services. Some have started operation in Canada or Europe but are eager to enter the US market. They, too, have a strong economic interest in early approval of lasers for refractive surgery.
Many ophthalmologists also hope to cash in on refractive surgery. Recent cuts in federal Medicare payments for cataract surgery on elderly patients have hurt their income, and a few already heavily advertise radial keratotomy. Laser surgery requires more equipment but demands less surgical skill. Moreover, as with other cosmetic surgery, physicians would bill patients directly, at $1000 to $1500 per eye. That lucrative prospect has some providers veritably rubbing their hands in glee. The January 1995 Review of Ophthalmology pointed to 63 million nearsighted people in the USA alone and projected potential surgical revenue of $9 billion through 2000.
In part, the FDA and its ophthalmic advisors may be going slow to counter the gold-rush mentality, as well as wild claims that eyeglasses will be museum pieces in five years. Members of the panel argued for more long-term follow-u¥to be sure vision remained stable after surgery. Some want to delay approval until better results can be demonstrated, complaining that Summit submitted results for a laser it no longer offers commercially.
Specialists do not yet understand why some patients suffer cloudy vision after laser surgery, a problem not present after RK. Some worry about long-term effects of exposure to UV excimer-laser pulses, although no damage has yet been documented. The central problem--balancing the benefits of approving the laser systems now against the risks of long-term hazards going undetected and better technology going undeveloped--has no easy answer. n