"White Paper on Sculpting" page 1 September 15, 1989 THE EVOLUTION AND PROSPECTS FOR LASER REFRACTIVE KERATOPLASTY IRVING J. ARONS ARTHUR D. LITTLE I. Overview The American public spends more than $16 billion annually for vision care. More than 60 million eye examinations are given annually and nearly 60 million pairs of eyeglasses and 3 to 4 million pairs of contact lenses are dispensed. In addition, more than 1 million surgical procedures are performed to correct vision deficiencies or for therapeutic reasons. The laser has and continues to play an important role in the treatment of eye disease. Soon after the laser's discovery, ophthalmologists were putting this unique tool to use in stopping retinal bleeding and repairing retinal tears. Today, more than 90% of all ophthalmologists own or have access to a laser for performing a myriad of treatments including retinal photocoagulation, retinal reattachment, punching holes through the trabecular network to alleviate glaucomas, clearing vitreous strands and membranes, treating senile macular degeneration, and clearing clouded posterior capsules or "secondary cataracts". Procedures under investigation include "White Paper on Sculpting" page 2 September 15, 1989 photophacoemulsification (softening or fragmenting the lens prior to cataract surgery), thermal sclerotomy, and treatment of ocular cancers either through tumor vaporization or use of photo dynamic therapy (PDT), among others. One of the most important new procedures, if it can be shown to be safe and efficacious, will be the use of a laser to reshape the front surface of the eye, or as I have coined the term, "corneal sculpting". (The more formal designations are laser refractive keratoplasty or laser refractive keratectomy, or LRK for short, and photorefractive keratectomy or PRK.) The surgical potential of the use of ultraviolet radiation was first reported by scientists in both the health sciences field (Taboada and colleagues) and in the materials and electronics industries (Rhodes; Ruderman; and Srinivasan). Dr. Rahgaswamy "Srini" Srinivasan of IBM's Watson Research Center reported in 1982 and 1983 that the excimer laser could make precise cuts in organic plastic materials for use in the electronics industry, or in human tissue such as hair. Subsequently, two researchers began to exploit the use of excimer lasers in the field of ophthalmology. Dr. Stephen Trokel, an ophthalmologist at Columbia- Presbytarian Medical Center in New York, heard about Srinivasan's experiments and arranged to observe the procedure. This led to Dr. Trokel's first experiments in Dr. Srinivasan's "White Paper on Sculpting" page 3 September 15, 1989 laboratories on bovine eyes in 1983. The work was originally done in the hopes of using the laser to make more precise cuts in the cornea in a radial keratotomy-type procedure, then coming into vogue for correcting myopia. At about the same time, an associate of Dr. Trokel's, Dr. Francis L'Esperance, a pioneer in the use of lasers in ophthalmology, saw a wider application for the excimer laser to ablate the front surface of the cornea, "corneal sculpting", and began efforts to develop both the technology and the medical research to exploit it1. Today, at least three companies in the United States, and several more in Europe and Japan are funding research in an attempt to commercialize this procedure. Almost all of the work is being done with the argon fluoride (ArF) excimer laser, operating at 193nm, since experiments have shown that this wavelength appears to provide the "cleanest" cuts in corneal tissue, removing cellular matter by breaking molecular bonds one cell at a time, in a cold ablation or photodecomposition process without damaging adjacent tissue. The 193nm wavelength also appears to have non-mutagenic effects on corneal tissue. 1 At this time, 9 U.S. patents on methods and apparatus for accomplishing corneal sculpting have been issued to Dr. L'Esperance and assigned to Taunton Technologies. Dr. Trokel claims to be the original inventor of the concept and through his affiliated company, Visx, has filed an interference action with the U.S. Patent Office. In addition, a patent has issued to Dr. Srinivasan and his co-workers at IBM, covering the use of ultrviolet energy below 200nm to selectively remove organic biological material. So, to say the least, a confusing picture of ownership of technology exists that will most likely be resolved by the courts, unless a mutually satisfactory agreement can be reached between the involved parties. "White Paper on Sculpting" page 4 September 15, 1989 In the procedure, which is being performed under FDA investigational device exemption (IDE) protocols, a corneal surface scan or refractive data is fed into a computer and the computer program determines how much corneal stroma material must be removed (usually only about 10 to 15% of the corneal thickness in selected sectors) to form a contact lens-like reshaping of the corneal contour. The laser procedure takes about 30 seconds, with the total procedure taking about 30 minutes. The epithelium, or top surface layer of the cornea, regenerates in about 48 hours. Thus, the eye must be bandaged for one or two days before the healing is completed. Using the procedure, or modifications of it, nearsightedness, farsightedness and astigmatism can all be corrected, replacing the need for eyeglasses or contact lenses for the majority of people who elect the procedure once it becomes generally available. The problems seen to date are involved with the healing of the cornea. In some animal studies and early clinical trials, several of the corneas treated have become cloudy (hazy) and taken months to clear. It is felt that this is a matter of technique. With shallower, smoother cuts, less haze has been seen in later patients. With improved techniques, and perhaps in combination with the newly developed epithelial growth factors that speed corneal healing, it is believed that it is only a matter of time before this problem is resolved. A second early complication has been regression, or thickening of the epithelium during regrowth. Again, with "White Paper on Sculpting" page 5 September 15, 1989 smoother, shallower ablations, the amount of regression or corneal epithelium thickening is appreciably reduced. In an earlier study done in March 1986 for Dr. L'Esperance's group, your author forecast that within five years after commercial introduction (following FDA marketing approval), a minimum of 800 systems would be sold annually in the U.S., more than 2000 would be in use, and 4 to 5 million procedures performed annually. Thus, we forecast that the successful introduction of this procedure could have a marked impact on the increased use of lasers in ophthalmology. This forecast was based on very preliminary information, before any of the three companies now involved had built their laser systems. In our latest study, completed in August 1989, after more careful consideration of the clinical work now underway and the attitudes of the ophthalmic community, we believe that fewer systems will be sold annually in the U.S., because of slower adoption by the medical community, and that closer to 2 million sculpting procedures will be performed annually after about five years following FDA marketing approval. However, we remain confident that the successful introduction of this revolutionary technology into ophthalmic practices will change the way vision is corrected forever. Further, the new technique will eventually change the way ophthalmologists practice and result in an increase in dispensing of glasses and "White Paper on Sculpting" page 6 September 15, 1989 contact lenses by the remainder of the optical professions, as ophthalmologists find it more lucrative to become involved in laser refractive surgery than in simple refractions and the dispensing of eyewear. II. Other Medical Applications of the Excimer Laser The major application for the excimer laser in ophthalmology is for refractive correction, including the correction of myopia, hyperopia and low to moderate degrees of astigmatism. The latter is being approached in two ways; with the use of "T" cuts, similar to the way RK correction of astigmatism was done, and with the use of selected area ablation. The former technique has been successfully demonstrated both by U.S. clinicians and in West Germany by Theo Seiler, using the Summit Technology ExciMed UV200 laser. The latter technique, using area ablation to correct astigmatism, is under clinical investigation with the Taunton Technologies LV2000 laser. (And we believe this technique could also be incorporated into the Visx Twenty/Twenty Excimer Laser system.)2 Besides the "cosmetic" refractive corrections, several therapeutic applications are under clinical study. Superficial 2 For more information about the U.S. and foreign companies involved in the development of both excimer and other laser technologies for corneal sculpting, see the section following on The Participants. "White Paper on Sculpting" page 7 September 15, 1989 keratectomy or excimer laser smoothing of the cornea is being investigated by all three of the companies noted above. In some cases, the use of a viscous liquid, methylcellulose, is used to fill in the irregularities, and then the filled in surface is smoothed without duplicating the irregularities originally present. The laser is also used to remove calcium deposits, known as band keratopathies, and for the removal of wedge-shaped growths known as pterygiums. Corneal scars are also being removed with the restoration of normal sight to some patients in the clinical studies. One company, Summit Technology, is investigating the use of their laser for treatment of glaucoma through the formation of a partial window or filtration bleb, in a process known as partial excimer trabeculectomy. Apparently, the process is self limiting, as the escaping fluids prevents further tissue penetration. In addition to the ophthalmic applications noted above, the excimer laser is under investigation in several other medical specialties. Probably the largest potential is in laser angioplasty, or the clearing of peripheral and coronary arteries obstructed with plaque. Summit Technology, as well as at least seven other companies, is experimenting with excimer lasers, and is among the more than two dozen companies seeking a laser solution to the clearance of clogged arteries. "White Paper on Sculpting" page 8 September 15, 1989 Other potential medical applications for excimer laser technology include arthroscopy and dentistry. In arthroscopy the laser may be used for the removal of both tissue and bone fragments in endoscopic procedures, while in dentistry, the laser may be used in penetrating enamel for access to caries (dental decay), which can then be removed with a pulsed YAG laser in "painless/drilless dentistry". III. The Participants In the United States, there are three companies currently developing excimer laser systems for use in corneal sculpting, and at least two others experimenting with competing technologies. In Europe and Japan, another three or four companies are developing excimers and perhaps working on other technologies as well. U.S. Companies Involved in Excimer Laser Development Summit Technology -- Watertown, MA Summit has developed and built a compact ophthalmic excimer laser system, the ExciMed UV200, that is under study in both the U.S. and in Europe. The unit has a built-in operating microscope and computer for controlling the "White Paper on Sculpting" page 9 September 15, 1989 sculpting and therapeutic procedures. Its lasers are also sold in Japan through a distribution agreement with Canon Sales. The company presently has four IDEs for clinical trials in ophthalmology and at least one for clinical investigation in coronary artery disease. The four ophthalmic IDEs include: 1) Superficial Keratectomy; 2) Photorefractive Keratectomy; 3) Partial Excimer Trabeculectomy for Glaucoma; and, 4) T-Excisions for Astigmatism. Some of the principal investigators3 include: John Hunkler - Kansas City, KS Robert Fenzyl - Garden Grove, CA Theo Seiler - Berlin, West Germany John Marshall - London, United Kingdom Roger Steinert - Boston, MA George Waring - Atlanta, GA Taunton Technologies -- Monroe, CT Taunton has developed a sophisticated, integrated, 3 According to the company, clinical trials are underway at 16 sites in the U.S. and Europe. For further information contact the company directly. "White Paper on Sculpting" page 10 September 15, 1989 diagnostic/ therapeutic advanced technology excimer laser system, the LV2000, that incorporates a digital keratoscope and Zeiss operating microscope into the laser system. Colored displays of the dioptric power of the cornea guide the surgeon in computing the changes to be made. Taunton holds IDEs for both refractive corrections, including correction of both myopia and hyperopia and removal of superficial scars, and for selected area ablation correction of astigmatism. Taunton has an agreement with Alcon Laboratories to handle worldwide marketing to the ophthalmic community. Principle investigators include: Jim Rowsy - Oklahoma City, OK Richard Lindstrom - Minneapolis, MN Visx -- Sunnyvale, CA Visx has taken over the former CooperVision excimer laser program. This system is perhaps the largest of the three and incorporates a high resolution observation/alignment operating microscope and video display, along with a mobile computer-controlled workstation for guiding the operator through the procedure and storing the patient data. A "White Paper on Sculpting" page 11 September 15, 1989 modified version of an autorefractor can be used for both pre-op and post-op patient diagnostics. The company holds at least two IDEs for both refractive and therapeutic corrections. Principle investigators include: Herb Kaufman and Marguerite McDonald - New Orleans, LA Walter Stark - Baltimore, MD Non-Excimer Laser U.S. Companies Phoenix Laser Systems -- San Francisco, CA Phoenix is a newly public company (August 10, 1989) developing a pulsed doubled YAG, which they claim operates in a photodisruptive (plasma) mode to selectively remove corneal tissue. As far as is known, no IDEs have yet been obtained to begin clinical trials. Intelligent Surgical Lasers -- San Diego, CA "White Paper on Sculpting" page 12 September 15, 1989 This private company is developing a fast pulsed, variable wavelength, solid state laser system for working on the eye. According to their issued patent, the laser is a diode-pumped Er:YAG or Ho:YAG that can produce multiple wavelengths from a dispersion line device for spreading the wavelengths in each pulse. The laser can also contain a frequency doubler to split the beam into components of different wavelengths. Excimer Laser Development Work Underway Outside the U.S. Aesculap-Meditec (West Germany) has reported on masked excisions for making RK-type cuts and for making corneal transplant cuts. Lumonics (Canada) had been funding university research on the use of its excimer laser in surgical correction of the eye, but no recent references have been noted. Nidek (Japan) is reported to be investigating the use of excimer lasers in the treatment of ocular disease and in correcting vision. Attempts to obtain more definitive information have as yet been unsuccessful. Synthelabo (France) showed an excimer laser at the 1988 Academy of Ophthalmology Meeting in Dallas and is "White Paper on Sculpting" page 13 September 15, 1989 supposedly completing the development of its system. They recently reported on animal eye studies but not as yet on humans. IV. Results of the ADL/ORC Survey As part of the recently completed study of the prospects for "corneal sculpting", Arthur D. Little and its subsidiary, Opinion Research Corporation, collaborated in seeking the knowledge level and interest in corneal sculpting of the ophthalmic community. One thousand randomly selected ophthalmologists, located in metropolitan areas, were sent a comprehensive questionnaire that attempted to determine how they felt about becoming involved in corneal sculpting once FDA marketing approval was obtained. One hundred and eighty nine responses (19%) were received, of which 163 were included in the tabulation of results, having been received before the cut- off date. The general findings are reported below. o Of the 163 tabulated respondents, 55% were in solo practice, 15% in partnerships and 25% participated in group practices. The overwhelming majority, 72%, considered themselves "general ophthalmologists" as opposed to specialists, and they were fairly evenly split in terms of years in practice and location around the country. "White Paper on Sculpting" page 14 September 15, 1989 o Knowledge of our respondents regarding corneal sculpting was on the low side. Eight percent knew little or nothing about it, and only 9% considered themselves very knowledgeable. The remainder had either attended a seminar (13%), had heard about it (33%), or read about it (59%). Their impressions about the ophthalmic community's knowledge of sculpting was decidedly on the low side, with their belief that 76% of their colleagues had only slight to no knowledge about the technique. They felt that only 2% of their peers had a great deal of knowledge about the process, and only 21% were moderately knowledgeable. o In terms of interest in learning more on the subject, 67% of those surveyed were moderately to extremely interested in participating in the technology once it receives FDA marketing approval. Ten percent were undecided and 9% were not interested. o Our respondents felt that the most important ophthalmic application for the excimer laser was for sculpting to correct myopia (65%), while 55% were in favor of ablating for correction of astigmatism, as compared to 37% in favor of T-cuts. Correction of hyperopia and removal of scars was favored by 45%, while glaucoma filtration got a 51% favorable rating. "White Paper on Sculpting" page 15 September 15, 1989 o Most of the doctors (57%) would accept 1/2 diopters of correction for myopia and/or hyperopia, while an additional 30% would accept 3/4 to 1 diopter accuracy. o Fifty-two percent said that they would charge between $1000 to $1500 per eye, and an additional 29% claimed to be able to charge more than $1500. On a weighted basis, a mean charge of $1360 would be charged, with a higher $1510 fee in the Northeast, and a lower fee of $1270 in the West. o The mean number of procedures that would be done per week was 4.9. Only 28% expected to do 5 or more procedures per week, while 30% expected to do 2 to 4, and 21% thought that they would do one or less. o Acceptance of the procedure will only happen after it is reported on by their peers (27%), and/or in common practice (47%). Only 15% reported that they would get involved either before general release (8%) or soon thereafter (7%).
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