MicroLight Gains First FDA Biostim Approval

This article, written by Kathy Kincade the editor of MLR, was published in Medical Laser Report in March 2002. It is a fitting conclusion to our series on biostimulation.

MicroLight Gains First FDA Biostim Approval

Kathy Kincade
Editor, Medical Laser Report

It took 11 years and more than $4 million, but Michael Barbour has finally seen his low-energy therapeutic laser technology make it to “the show.” The FDA granted clearance to MicroLight (Missouri City, TX), Barbour’s latest commercial venture to market the ML830 diode-laser instrument for the treatment of carpal tunnel syndrome (CTS). This is the first time the FDA has given the “thumbs up” to a laser based device for low-level laser therapy (LLLT), also known as “biostimulation.”

The 830-nm ML830 is battery operated and comprise three laser diodes, each delivering 30 mW of energy peripherally located around a red light-emitting diode. Barbour first began pursuing the technology for non-surgical treatment of CTS in the early 1990s when he was head of a company called Lasermedics. In 1993, Lasermedics sponsored a preliminary clinical study involving 100 employees at General Motors and found that those individuals treated with the laser showed significant improvement in certain hand functions, compared to those treated with a dummy laser or with physiotherapy. A subsequent randomized double-blind trial involving 173 patients at Baylor College of Medicine (Houston, TX) and two other sites showed an 80% success rate and further demonstrated the efficacy of the device in relieving pain and improving functionality for individuals suffering from CTS.

In 1997, Lasermedics was revamped and renamed Henley Healthcare, with the intention of expanding its product portfolio into nonlaser products and accessories used to control acute and chronic pain. Barbour continued to serve as president and CEO, and in mid-1999, the company began submitting preliminary clinical data from the MicroLight trials to the FDA in support of its anticipated premarket approval application. But one year later, Barbour was gone, and in April 2001, Henley terminated all of its U.S. employees following foreclosure by creditors on Henley’s U.S. assets. Those assets – including the MicroLight technology – were subsequently sold to a third party in Seattle for $900,000 as part of the company’s efforts to repay some of its debts. That’s when Barbour decided to try his hand again with MicroLight.

“I was able to purchase the technology at a reasonable price and was willing to invest the time, energy, and money necessary to see it through the FDA process,” said Barbour, who founded MicroLight in October 2001, and serves as president of the two-man operation.

Barbour expects the first MicroLight CTS device to be on the market by mid-year. The product is currently being assembled by an OEM supplier in Denmark, but Barbour’s strategy is to join forces with a much larger medical-device company that can handle volume manufacturing and move the ML830 into the U.S. marketplace through a well-established sales and distribution network. In addition, MicroLight holds a method patent that covers the use of this technology in soft tissue “from head to toe,” according to Barbour.

Market Potential

Having the first FDA-approved biostimulation product — and a method patent covering use of the technology in soft tissue “from head to toe,” according to Barbour – should make MicroLight very attractive to any number of large medical-device companies. According to Irving Arons of Spectrum Consulting (Peabody, MA), the market for the ML830 in the treatment of CTS alone could reach $480 million to $600 million in the United States over the next few years. This projection represents the sale of 60,000-100,000 laser biostimulation devices selling at an initial average price of $8000-$10,000. The potential market for CTS treatment alone includes physical therapists, anestheologists, neurosurgeons, orthopedic surgeons, and hand surgeons. More than 1 million Americans develop CTS symptoms each year, and more than 200,000 surgical procedures are performed to treat CTS at an annual cost of more than $10 billion.

But CTS is only the first of what should be a broad spectrum of applications for the ML830 and similar devices. Ongoing research in LLLT covers a wide range of applications, including dentistry, where studies in Switzerland and Russia have shown that LLLT encourages wound healing in the mouth; pain alleviation and modulation, with studies in Ireland indicating that there may be a way to determine LLLT’s effect on pain receptors; and bone and nerve regeneration. Other studies have focused on the interaction of light with biological systems and determining the molecular mechanisms underlying the anecdotal and clinical results that have been reported.

“What we know about this technology is that it is using light in a non-heat fashion to have an anti-inflammatory response in tissue,” Barbour said. “Clinicians say they see applications in arthritis, wound healing, and other soft-tissue indications – even, in the next few years, internal anti-inflammatory responses via an endoscope.”

Eventually, Barbour envisions the technology making its way into any number of consumer-based applications where it functions in a more autonomous capacity. “When someone goes to put a tennis-elbow brace or a knee brace on, the brace could have an anti-inflammatory sensor in it,” he said. “This technology could probably go where magnets have gone, but with clearer science behind it.”

Editorial Comment -- The Lasermedics Press Conference – "The Rest of the Story"

This editorial comment was prepared for publication in the October 1994 issue of Medical Laser Report, but was not published. (The editors of the newsletter chickened out!)

Editorial Comment -- The Lasermedics Press Conference – "The Rest of the Story"

Irving J. Arons
Managing Director
Spectrum Consulting

Last month, our front page feature story was about the release of the results from the General Motors carpel tunnel syndrome (CTS) study. I was the only media person allowed to attend the symposium held by Lasermedics, as GM pulled the plug on all publicity about the event two days before it occurred (on August 31). I was allowed to remain in the room when the study results were presented, only because I had agreed to allow GM to see, comment, and have some editorial control on what I wrote. This is not my usual custom, although I sometimes send drafts to the companies or people about whom I am writing for their comments and corrections in order to accurately report about the subject on which I am commenting.

In this case, GM was extremely concerned about the release of the information from the symposium for several reasons: the "implied" endorsement of the Lasermedic's laser; the effect of the "good" results on their ongoing negotiations with their labor union and the effect this "benefit" might have on those negotiations; and the release of data before their in-house scientists could prepare the information for publication in a scientific journal. For these reasons, the national and local media were excluded from the proceedings. I was able to "negotiate" my presence only on the terms noted above.

The original draft that I prepared was scrutinized carefully by GM personnel at the highest levels within the organization, and after lengthy negotiations, the "sanitized" version, which was published, was reluctantly approved by GM.

However, now that the "cat is out of the bag", I would like to fill you in on "the rest of the story", or what was "altered" or omitted. According to the Bureau of Labor Statistics, as noted in the Wall Street Journal of July 14, 1994, approximately 9% of auto manufacturing workers are afflicted with repetitive stress injuries, including carpel tunnel syndrome. And according to my sources, that percentage holds true for GM assembly workers as well.

As for the double blind clinical study conducted at eight GM plants, 116 out-of-work employees volunteered to take part in the study. All were chronic CTS sufferers, some out of work as long as three years because of their disability. Eighty-six completed the five week program and, of those, 46% of both groups (47% of those that had physical therapy alone [and treatment with a "sham" laser -- having the aiming LED light active but the laser inactive] and 45% of those that had both physical therapy and laser treatment), were able to return to work. However, this number is misleading because many more of those treated would have been able to return to work if appropriate jobs had been available or if seniority allowed. Thus the 46% is just a baseline, as the percentage would have been considerably higher if jobs had been available.

More importantly, I was told by a plant manager that the laser continued to be used in the eight GM plants (the study concluded last fall) and that thousands of workers complaining of CTS symptoms, i.e., in the early stages of CTS development, were being treated, with a success rate of between 85% to 90% of alleviating the symptoms and allowing the workers to return to their jobs!

I believe this information is important and should have been presented, and that is the reason for this editorial.

Low Level Light Therapy – Can Laser Biostimulation Be Taken Seriously?

This article, discussing laser biostimulation in general, was also published in the September 1994 issue of Medical Laser Report.

Low Level Light Therapy – Can Laser Biostimulation Be Taken Seriously?

Irving J. Arons
Managing Director
Spectrum Consulting

The therapeutic effects of laser light on tissue -- as opposed to the surgical effects of cutting, ablating or otherwise removing tissue -- include both photodynamic therapy (light activated fluorescence for detection and diagnosis, and photoactivation or excitation of chromophores to act on the host cell) and biostimulation. In biostimulation, low powered (less than 60 mW) laser energy is absorbed by tissue or cells and is believed to cause the release of enzymes or the transformation of prostaglandins to have a therapeutic effect on the target tissue to which the laser has been applied.

For the past twenty to twenty five years, from the experimentation in 1968 by Professor Endre Mester of Hungary, the grandfather of biostimulation, low energy laser therapy, also referred to as low level laser therapy, produced by helium neon (HeNe), gallium arsenide diodes (GaAs), and yttrium aluminum garnet (YAG) lasers, have been used primarily in Europe and in Japan for the acceleration of healing of open wounds and ulcers and to alleviate the pain of swollen or arthritic joints, both in humans and in race horses and other animals.

The lasers used, defined as "soft lasers" because they produce little to no thermal effects, have been found to "heal" non-healing or slow-to-heal chronic ulcers which remained resistant to conventional therapeutic methodologies, and to stimulate nerves and the lymphatic system to speed up the healing process and reduce pain and swelling of injured tissue. These low powered lasers are believed to increase the production of collagen which provides healing for non-healing tissues, and to stimulate the production of enzymes which remove or reduce the by products of tissue inflammation and thereby reduce swelling, leading to the alleviation of pain in swollen or arthritic joints.

The various lasers, HeNe at 635 nm; diodes at between 820 to 904 nm; and the YAG at 1064 nm, are used either in CW or pulsed modes at between 15 to 60 mW levels. They are usually applied for a few minutes at each treatment, and are repeated on a daily or weekly basis until relief from the symptoms is achieved. In Asian countries, biostimulation lasers are used in place of needles to perform a form of laser acupuncture to replace the use of anaesthesia.

In a trip to the former Soviet Union with a group of medical laser specialists in the summer of 1990, we observed biostimulation lasers being used to treat angina by scanning a HeNe laser across a patient's chest, and for treating heart disease through the insertion of a HeNe laser catheter into the arteries of other patients to "cleanse their blood".

A question often asked is, why lasers rather than chromatic light? The reason is that even a milliwatt laser system can penetrate deeper into tissue that the light of a 100 W bulb. The laser's monochromatic light and coherent beam (with all of its photons being unidirectional) has a considerably higher photon density resulting in the deeper penetration and the ability to reach and act on the target tissue.

Market Potential

If the claims made about biostimulation can be shown efficacious to the satisfaction of the US FDA, we estimate that a market of between $150 to $300 million would develop within 5 years of approval, representing the sale of 60,000 to 100,000 of laser biostimulation systems at an average selling price of between $2500 to $5000. Thousands of these lasers are in use in other world areas, with annual sales of an estimated $40 million in 1994.

Over the years, a number of US companies have attempted to gain FDA marketing approval, most recently (in the late 1980s) Physio Technology (North Park, IL) and Dynatronics (Salt Lake City, UT). The latter's PMA application was rejected by the FDA in 1988 on the grounds that the clinical work submitted did not prove the effectiveness of the device in the alleviation of pain associated with rheumatoid arthritis.

The last time I looked at the companies active in biostimulation (in my medical laser report, "The Outlook for Medical Lasers: The New Technologies", published by Arthue D. Little's Decision Resources in December 1988), there were at least 6 firms operating in North America; nearly 20 in Europe; and about 6 in Japan. I am sure there are at least that many -- although probably not the same ones -- still operating around the world. The implication of an impending FDA approval should spur even greater marketing efforts and could entice additional laser companies to produce and sell systems for this lucrative market.

Now it appears that there may be hope for the approval of a "soft", biostimulation laser. Lasermedics (Stafford, TX) has conducted double-blind tests on workers afflicted with carpel tunnel syndrome at General Motors plants in Detroit, and according to the just released study data -- see the lead article on page 1 -- those people treated with the Lasermedics Microlight 830 laser showed significantly improved results compared to both those treated with a placebo and those treated by physical therapy. The company has applied for a 510 (k) exemption to market its battery-operated therapeutic laser to apply infrared light to alleviate pain in soft tissue, and is supposedly in line for FDA review of its application. With the results of the GM study, and the added work on the effects of 830 nm laser light on median nerve function done at the Mayo Clinic (Rochester, MN), the company may be poised for a breakthrough in the use of biostimulation lasers in the US.

GM Releases Carpal Tunnel Test Results

The General Motors/Lasermedics press conference to release the results of the in-house study of carpal tunnel syndrome treated using the Lasermedics ML830 diode laser, was postponed from June 1994 until August. I was invited to attend this press briefing (the only outsider allowed) and reported on what I learned at the press briefing in this report, published in the September 1994 issue of Medical Laser Report.

GM Releases Carpal Tunnel Test Results

Irving J. Arons
Managing Director
Spectrum Consulting

Carpal tunnel syndrome (CTS), one of the repetitive stress injuries that strikes between 30% to 50% of workers involved in industries which have repetitive motion jobs (meat packing plants, automotive manufacturing, etc. -- see the Wall Street Journal of 7/14/94), is reportedly responsible for an estimated annual $29,000 per worker in lost job time for those workers so inflicted, according to the Bureau of Labor Statistics.

In an attempt to better understand the problem and to enable affected workers to return to work, General Motors Flint Assembly Plant, in 1989, began a program to deal with the approximately 10% of its work force getting CTS. What began as a means to track the injuries and redesign the work environment to alleviate the problem, turned into an 8 Phase program that has spread to an additional 7 GM assembly plants.

The study was coordinated by Dr. Wayne Good, medical director of the GM Flint plant and included a team of medical experts from various fields who studied the participants tool usage, designed physical therapy treatments to relieve the problem, and studied hand and wrist strength, motion, and blood flow, and the effects of low level laser light therapy in relieving the CTS symptoms.

Carpal tunnel syndrome is caused by a swelling or inflammation of the tendons leading to the thumb and first three fingers caused by repetitive motion, and the subsequent pressure and possible injury to the median nerve which are all contained in a tunnel-like structure (the carpal retinaculum) in the wrist area. In the later stages of the disease, the hands become wracked with pain, the fingers become numb, and the patient loses his/her ability to work with the afflicted hand (or hands).

About three years ago, Dr. Bryan Shumaker, director of the laser center at St. Joseph Mercy Hospital in Pontiac, MI, who had been working with Dr. Good on the GM CTS project, came across the biostimulation laser under development by Lasermedics (Stafford, TX) and suggested that perhaps this modality could be added to the GM project as a means of alleviating CTS. The laser therapy became Phase 8 of the program.

In conjunction with Lasermedics personnel, the GM CTS study group designed a double-blind study to evaluate the effects of physical therapy (PT) and physical therapy plus low level laser therapy on chronic CTS sufferers. The study included 116 out of work with CTS GM workers, who volunteered to undergo 5 weeks of treatment and testing. Half of the group were randomly assigned to receive physical therapy plus laser treatment, while the other half received PT and the use of a "sham" laser. (The Lasermedics Microlight 830 biostimulation laser has 3 diode lasers each delivering 30 mW of 830 nm infrared laser energy, which are peripherally located around a red emitting LED in the center of the battery-operated, hand-held device. In the "sham" laser, only the LED was operational, and since the infrared laser causes no discernable heating or sensation in use, neither the subjects nor the attending technicians delivering the laser treatment knew which coded device was real or the sham.)

The subjects were treated on a weekly basis for the five weeks of the program (which took place in late 1993), with the laser applied for a 33 second duty cycle to three spots on the wrist around the carpal tunnel. A baseline of blood flow, tactile sensation, and objective strength, grip, and motion measurements were taken, and also determined following the five week treatment program. 116 subjects were initially enrolled, but 17 dropped out during the screening process and an additional 10 dropped out during the program, leaving 89 subjects completing the testing (132 hands were treated). The median age of the subjects was 44, and slightly more females than males (54% vs. 46%) took part. About half of the subjects had previously had carpal tunnel release surgery, but the symptoms had re-occurred.

In the test results reported at the medical symposium sponsored by Lasermedics in Detroit on August 31, Dr. Tom Anderson, the GM spokesman for the study, revealed that there was improvement in almost every category of sensory perception, grip strength, and wrist motion for both the physical therapy alone and the PT plus laser treatment groups, with the only statistically significant improvement for those that received the laser treatment being in several categories of grip strength and in one category of range of wrist motion. More importantly, about 45% of both groups were able to return to work. However, this percentage is somewhat misleading and should be considered a bare minimum, because many more of those treated could have gone back to work if appropriate jobs had been available or if seniority allowed. Also, most of the subjects had been out of work because of CTS for more than three years and represented the worst case scenario, being chronic sufferers.

All of the research team agreed that the laser therapy was beneficial and could have been more so if used at an earlier stage of CTS development. In fact, according to one of the GM plant supervisors, the laser treatment continues to be used in all eight GM plants and to date several thousand workers who complain of CTS symptoms are regularly treated with the Lasermedics' laser alone, with a claimed success rate in alleviating the CTS symptoms of better than 85%!

It should also be noted that the cost savings of low level laser therapy compared to either open or endoscopic CTS release surgery can be substantial. Dr. Tracy Standridge of Owasso, OK, one of the Lasermedic clinical investigators for the Microlight 830 laser, supplied the information shown in the table below, based on data provided him by the Oklahoma Workman's Compensation Board, and what a CTS laser treatment program would cost in his office. As shown, including the costs of surgery and bringing another worker on board to replace the individual effected with RSI or CTS in those industries where it is prevalent, the difference could amount to as much as $20,000 more per worker to replace the surgery patient compared to the patient who receives laser treatment and can return to productive work.

Biostimulation: An Application Whose Time May Have Come

This article was published in the May 1994 issue of Medical Laser Report.

Biostimulation: An Application Whose Time May Have Come

Irving J. Arons
Managing Director
Spectrum Consulting

Biostimulation -- the use of low energy lasers to treat inflammatory conditions of the joints – and the FDA’s stance on this application, were the subject of a discussion by Richard Felton of the FDA during one of the morning sessions at this year's ASLMS meeting.

Felton defined biostimulation as the use of a low energy laser to produce physiological changes, either directly or indirectly, by non-thermal interaction of mono-chromatic radiation with a target site. Although this use of lasers provides a non-significant risk, the FDA's position is that specific applications will require the IDE/PMA route to marketing clearance. Felton went on to state that although a body of scientific evidence was being produced to show that low energy lasers do have a bio-effect on tissue, much of the evidence remains contradictive. Much of the human testing has been inconclusive, and further testing will be required to show reproducible endpoints and significant improvements/differences over conventional treatment modalities. He believes that 510 (k) clearance is problematical, with the need to show equivalence to pre-1976 devices. Thus, he believes that multi-center trials (at least three sites) with valid sample sizes will be required.

With this being said, however, we have learned that at least one company claims to have received a 510(k) approval for the use of infrared energy to provide therapeutic effects, and a second company, Lasermedics (Stafford, TX), who will participate in a medical symposium on June 15th in conjunction with General Motors, to announce the results of its controlled, double-blind program to treat carpal tunnel syndrome with its diode-laser based MicroLight 830 biostimulation laser, which the company hopes will lead to a 510(k) approval for the use of its device. Lasermedics reports that it obtained Canadian government approval for use of its device on humans in February. According to company officials, in the GM program the target group treated with the Microlight 830 laser showed significant improvements over those receiving the blinded non-laser treatment and those getting standard physical therapy normally used to treat the problem.

We will report on the results of the General Motors test program in our July issue.

Menu – Part 6: A Primer on Biostimulation and Biostimulation Lasers

In 1994, I wrote a series of three articles (and an editorial comment) on low level laser treatment (LLLT), especially for the treatment of carpel tunnel syndrome (CTS) for Medical Laser Report. Here are those articles, along with one written by my friend Kathy Kincade, the editor of MLR, following the FDA approval of the biostimulation laser that was the subject of most of my writing. Her article appeared in the March 2002 issue of the newsletter.

1. Biostimulation: An Application Whose Time May Have Come

This first article appeared in the May 1994 issue of MLR. It followed a presentation by an FDA official at that year’s ASLMS meeting in Toronto, that discussed the FDA’s position about biostimulation and the possibility of at least one laser company, Lasermedics of Stafford, TX, achieving FDA marketing approval. It also mentioned an upcoming press conference that was to be held at General Motors in June, about a biostimulation study being conducted at the company in conjunction with Lasermedics.

2. GM Releases Carpal Tunnel Test Results

This second article, published in the September 1994 issue of MLR (because the press conference referred to above was postponed until August). It discusses the results of the double-blind study conducted on GM workers with carpal tunnel syndrome.

3. Low Level Light Therapy – Can Laser Biostimulation Be Taken Seriously?

This third article in the series was also published in the September 1994 issue of MLR. It discusses some of the history of low level laser treatment and the market potential in the United States for biostimulation lasers, if they ever are approved for marketing by the FDA.

4. Editorial Comment -- The Lasermedics Press Conference – "The Rest of the Story"

This editorial, telling the real story behind my writeup of the GM/Lasermedics press conference, was supposed to be published in the October 1994 issue of MLR, but was not – the reason is given in the writeup.

5. MicroLight Gains First FDA Biostim Approval

Just to conclude this series, I thought I would present the writeup that Kathy Kincade wrote in March 2002, following the FDA marketing approval for the MicroLight ML830 biostimulation laser. In it, she explains the trials and travails that the Michael Barbour had to go through to finally get his laser to market.

The Wonderful World of Computers – A Personal Journey

The Wonderful World of Computers – A Personal Journey

Irving J. Arons

Since starting my Web Journal last December, I have joined the North Shore Computer Society and started writing for their monthly newsletter. This personal journey through the world of computers will be published in the June issue of the newsletter, News@Northshore.org, in an abbreviated version.

1966-1967

My first exposure to using a computer was in 1966 or 1967. I was working at the Exploratory Development Lab of United Carr, Inc. in Kendal Square, Cambridge, and the head of the lab decided that we needed a computer to work out the solutions to the experiments we were running. He bought and had installed a Mathatronics Mathatron (see Figure 1). This computer, invented by a couple of local guys from Waltham, was really a glorified programmable calculator, with a tape output. We learned how to program this computer and used it for calculating the results of our sometimes complex experiments.

(Courtesy of the Old Calculator Web Museum)

At the time, I was the secretary for the Temple Beth Shalom bowling league, and wrote a simple program that used the Mathatron to update the weekly bowling averages of the bowling league members. This was my first exposure to a working computer.

1969-1986

I next came into touch with a computer at my next job, as a consultant on the staff of Arthur D. Little, the world-wide technology and business consulting firm. I joined in March of 1969 and until the early 1980s, the secretaries used typewriters to prepare our proposals and reports from handwritten copy. I recall them using IBM Selectronics (with the moving ball instead of individual type keys). In 1981-1982, the secretaries got the first desktop IBM Personal Computers, the IBM PC (Figure 2), which made their jobs much easier, and provided us with much cleaner copies of proposals and reports.


It wasn’t until several years later, probably 1986, that the company started providing the professional staff with computers. My first computer was the so-called Compaq Portable II (Figure 3), an IBM-compatible computer. I’m not sure how a 30-pound computer could be called “portable”, but it was what it was and somehow I managed to lug it between the office and home when necessary. As I recall, the computer (with a small 9" green monochrome screen) used IBM DisplayWrite as its word processing program and also had Lotus 1-2-3 as a spread sheet.

1980-1981

Prior to getting the Compaq, I saw an ad in Popular Science in 1980 or 1981, for the Sinclair ZX 81 personal computer (Figure 4) available for about $150. This was really a toy, having a tiny membrane keyboard, a 1 kilobyte memory, expandible to 16 K with an add-on module, and using a TV monitor as its screen. It was programmed with “basic” and the programs could be saved using a recorder and played back into the computer the same way. It came with a “cookbook” of basic programs, but with the tiny keyboard, you could only build the program and run the computer one finger at a time. It ran real simple programs, like for converting F to C, etc. But, it was fun to be able to say that you owned and used a “computer” at the time.

1989-1990

Then about 1989 or 1990, ADL switched the staff over to the Compaq Laptop (Figure 5), the model SLT/286. This machine ran the Intel 80286 chip, had a decent 9 inch monochrome screen ( I also got a separate 15" color monitor that I could attach to the laptop for working in my office) and was loaded with Word Perfect 5.1 for DOS and Lotus 1-2-3. Word Perfect 5.1 was and remains the best word processing program I ever used. It has a feature called the “reveal” function, which shows the formatting coding associated with each word or line of type. This allows you to easily change (or correct) the format as you go.

March 1994

In March 1994, I retired after 25 years at ADL, and as my going-away gift, asked for and received my Compaq Laptop. As I was starting my own consulting company, I wanted the computer primarily to take advantage of the many proposal and report templates that ADL had created and loaded onto my computer. Since I wanted and needed a full time computer and more realistic screen at home for the new business, I splurged and got a custom-built desktop designed to my specifications by PC Warehouse in Waltham, MA. This computer was a 486x33, with a 250 MB hard drive and a built-in 14.4K modem. I also bought a 15" NEC color monitor and an HP laser printer, for a total price of $3500 (which, I thought was a good price at the time). I had the computer technicians at PC Warehouse copy my ADL DOS operating system from my Compaq Laptop into my new desktop.

November 1997

I soon outgrew this first desktop and went back to PC Warehouse in November 1997 for an upgrade. This time, the desktop was a Pentium 586x166 with a 3 GB hard drive and had a 33.6K modem (later upgraded to a 56K model). The cost just for the computer – I kept my old monitor and printer – was $1168. I had the good people at PC Warehouse, again install my old DOS operating system but, it also operated Windows 3.1. I had the hard drive partitioned, so that I could switch between the DOS mode, using my Word Perfect 5.1 and Lotus 1-2-3 programs, or into Windows 3.1 from the C:/ prompt. This way I could still operate in either DOS or Windows 3.1 – but at a much faster rate. The Windows side also had a version of Word Perfect (Word Perfect for Windows) and Lotus, but neither was as easy to use as the DOS versions.

January 2001

Finally, in January 2001, I gave in to my family and friends that kept telling my that I was operating in the dark ages with DOS and Win 3.1, and broke down and got a Gateway V933 PC, operating Windows 98. It came with Office 2000 installed, which contained Word, Excel, and PowerPoint (for presentations), and I bought and installed a newer version of Word Perfect (Version 7.1), along with Quattro Pro (the updated version of Lotus 1-2-3). This computer also had a read/write CD drive, a 20 GB hard drive, and a 16" flat screen monitor, at a cost of $1700. (I also bought an Epson Stylus 880 color inkjet printer for an additional $150.)

However, last July, the CD drive on the Gateway stopped working and I took the computer to a local repair shop (The Computer Store) to have it replaced. Somehow, they managed to screw up the operating system while replacing the CD drive and the new/replacement Windows 98 OS never worked as well as the original set up, causing me all kinds of aggravation.

September 2005 - Present

I decided it was time, to once again upgrade. This time I bought a Dell Dimension 3000 system, with an 80 GB hard drive and a 17" LCD monitor, operating with Windows XP. It came with Word Perfect 12 and Quattro Pro 12 installed. This system, bought in September 2005 was only $940, and works like a charm. (I did install my copy of Office 2000 on the computer as well, so that I can work with either Word or Word Perfect.)

(I also had my old Gateway refurbished, having Windows 2000 installed. That way I would have a workable back up system if my new Dell ever crashed. But, the Gateway takes forever to boot up, as long as 5-6 minutes, compared to the 1 to 2 minutes that Dell XP takes.)

So, in a rather long-winded way, you have my journey through the world of computers. From my early days of calculating bowling league averages on the Mathatronic, to today, when I use my Dell to stay in touch with the world via the world wide web and publish my blog – putting a lot of what I’ve written over the past twenty years into the public (and accessible) record.

ENTERING THE PATENT ZONE, PART 3: Optical Feedback Patents Discovered

This column was originally published in the August 1994 issue of Medical Laser Report.

ENTERING THE PATENT ZONE: PART 3

Optical Feedback Patents Discovered

Industry Update

Irving J. Arons
Managing Director
Spectrum Consulting

As a wrap up to this three part trilogy on medical lasers and patents, or "welcome to the patent zone", I would like to tell you about a patent, and the story behind it, that few of you probably know about yet. But which many of you may wish to know about, as I believe it may play an important role in the future of medical lasers.

While wearing my other hat as a consultant to the medical laser industry, I am in the process of preparing a report on the potential for a laser-based diagnostic system to determine the thickness of severe burns. While doing a literature search on the subject, I came across an obscure reference to a company called Silicon Surgical, which was supposedly developing a closed-loop laser system for imaging the depth of a burn and removing the necrotic eschar down to viable tissue. In trying to contact the company, I was told by the people at the medical newsletter where I had seen the notice that the company "hadn't made it and was no longer in existence". Not one to give up that easily, I made further inquiries, and thanks to Dr. Norm Nishioka of Mass General's Wellman Laboratories, I was able to contact the founder and guiding spirit behind Silicon Surgical, Dr. Paul Lovoi.

It turned out that Dr. Lovoi was coming to Boston on business and agreed to meet with me and tell me his story. We met on my back porch in mid-July, and over a glass of lemonade, I learned the background of how Paul came to be the patent holder of a basic patent for the use of optical feedback to perform surgery with lasers.

It seems that Paul and his partner, Len Reed, left ILC Technology in 1978 to start a business using a pulsed flashlamp light to remove paint from airplanes and other structures for the military. When the flashlamp source proved inadequate for the task, they turned to lasers, and under a 1981 contract for the Navy, came up with the concept of using optical feedback to determine when the laser's energy had removed the paint down to the underlying primer (or any underlying layer with a distinguishing signature). It seems that different materials have different spectral signatures, and by using an optical (spectroscopy) feedback system, they could stop the laser before damaging the underlying primer, or other layer. Understanding the importance of patents in business, Paul and Alan Frank, of Lawrence Livermore Labs, applied for and received a patent for this application, U.S. Patent #4,588,885, "Method and Apparatus for the Removal of Paint and the LIke from a Substrate", issued May 13, 1986. Later in 1986, the team thought about the need for a feedback system to control laser energy in surgery, and in May 1986 filed their patent application which resulted in U.S. Patent #4,737,628, "Method and System for Controlled and Selective Removal of Material", issued April 12, 1988. The patent describes both the method and apparatus for the controlled removal of tissue using spectral reflectance of optical radiation to control the action of the surgical laser, for example, in the selective removal of a tumor without damaging adjacent tissue.

And now, like Paul Harvey says, "For the rest of the story!"

About the time of the issuance of the optical feedback patent, at least two companies were attempting to use similar systems to remove plaque in occluded arteries. MCM, and its "smart laser", was using spectroscopic feedback to direct the laser energy only against the plaque, allegedly leaving the arterial wall unaffected. That approach never really got off the ground, but another company, GV Medical (now called SpectraScience), in conjunction with a license to the work of Dr. Michael Feld of MIT, was also attempting to use optical feedback in conjunction with its LASTAC balloon catheter. This group was using laser-induced fluorescence for the discovery of plaque and ablating only the plaque attached to arterial walls. In filing for its own patents on the use of optical feedback, MIT came across the Lovoi patent, and claiming prior art, filed an interference action, trying to split the Lovoi patent into two parts; the base patent and one covering its use in angioplasty. That attempt failed, and MIT withdrew its interference action. This is perhaps why SpectraScience is no longer involved in diagnosis and therapy, but only developing the diagnostic portion of their technology!

This gets us back to Silicon Surgical. Paul Lovoi, president and CEO of INTA, the laser-based paint stripping company in Santa Clara, CA, would still like to get Silicon Surgical up and running. He is seeking a CEO for the firm and is in the process of licensing the combined burn diagnosis and therapy system under development at Wellman Labs. When the development is completed, he would like to bring it to market under the aegis of Silicon Surgical. Paul is also looking at developing and marketing other laser-based systems potentially useful for solving medical problems that could involve the use of optical feedback coupled to laser therapy, including the treatment of skin tumors and surface cancers.

So this is to put all of you involved in using lasers in combined optical feedback and therapy on notice (see Jeff Manni's article, "Feedback Devices Increase Surgical Precision" in last month's MLR). You might want to contact Dr. Lovoi and discuss his patent. He has told me that he is willing to grant non-exclusive licenses at reasonable royalties, so that both the system developer and he can make some money from his idea. Paul can be reached at 408-748-9955 (fax 408-727-3027).

ENTERING THE PATENT ZONE, PART 2: SAMPLING OF THE MEDICAL LASER PATENTS ISSUED IN 1993/1994

This column was originally published in the July 1994 issue of Medical Laser Report.

ENTERING THE PATENT ZONE, PART 2

SAMPLING OF THE MEDICAL LASER PATENTS ISSUED IN 1993/1994

Industry Update

Irving J. Arons
Managing Director
Spectrum Consulting

An interesting potpourri of patents were issued to companies and individuals involved in the medical laser industry over the past 18 months. As the industry becomes more application oriented, more patents seem to be aimed at meeting the needs of the identified niches. In a rough count of the 50 plus patents reviewed, 4 were involved with delivery catheters for angioplasty; 13 were directed at dental applications, including the use of dual wavelengths to treat both hard and soft tissue and special handpieces for hard to reach areas of the teeth; about a dozen were aimed at corneal sculpting -- or the alleviation of some of its problems; more than a dozen concerned catheters for delivering laser energy within the body -- either directly at a tissue or at some divergent angle; several patents dealt with multiple wavelength outputs, control of laser pulses or dosimetry; and another half a dozen or so involved better control of the lasing process itself.

Here then is a sampling of some of the more interesting medical laser patents issued last year and for the first several months of 1994.

Advanced Interventional Systems

● US 5,188,632 (2/23/93) -- A waveguide for ablating lesions in blood vessels, incorporating an expanding lens at the distal end of the laser fiber to provide a larger ablation area -- one of a series of ablation catheter tips assigned to AIS.

American Dental Technologies (7 patents issued during the period)

● US 5,275,564 (1/4/94) -- A pulsed holmium dental laser for welding of enamel and hydroxyapatite.

● US 5,257,935 (11/2/93) -- A laser for removing dental enamel, dentin, and soft tissue using a wavelength between 1.5 and 3.5 microns.

● US 5,232,367 (8/3/93) -- A method for sterilizing or reducing bacteria in accessory canals or closing same with a pulsed laser output of between 0.1 mj and 5 joules per pulse.

● US 5,207,576 (5/4/93) -- A dual wavelength dental laser with one laser having a pulsed output between 0.2 to 2.0 microns, and the second pulsed laser having an output between 2.0 and 5.0 microns.

Candela Laser

● US 5,287,380 (2/15/94) -- A method of generating long pulses (greater than 500 ms) from a flashlamp-excited laser, using a ramp pulse having an amplitude increasing with time.

Intelligent Surgical Laser (2 patents issued in the period)

● US 5,246,435 (9/21/93) -- A method of using an ophthalmic laser to remove cataractous tissue from within the capsule.

Laser Medical Technology (6 patents issued during the period)

● US 5,292,253 (3/8/94) -- A method of repairing an opening in a bone or tooth by applying a laser beam to weld a calcium containing protein gel to the bone or tooth tissue without harming the bone or tooth tissue.

● US 5,290,274 (3/1/94) -- An apparatus comprising two laser sources operating at different wavelengths and power levels, capable of cutting a given organic tissue, simultaneously applying the two laser wavelengths to a single body region and directing a cooling fluid at the tissue while applying the radiation.

● US 5232,366 (8/3/93) -- A tunable laser capable of producing at least 2 wavelengths for use in the mouth for cutting physiological tissue, used in conjunction with a cooling fluid.

Laserscope (10 patents issued during the period)

● US 5,281,214 (1/25/94) -- A disposable surgical probe that can deliver laser energy either forward or deflected. When a curved optical fiber is retained within a sheath, the laser energy is directed forward; when the fiber is pushed out of the sheath, the fiber curves, deflecting the energy.

● US 5,257,991 (11/2/93) -- A side firing laser fiber having a beveled end contained within a cylindrical probe, having a cutout in the side of the probe.

● US 5,249,192 (9/28/93) -- A multiple frequency medical laser having outputs at 1.06, 1.44, and .532 microns.

● US 5,242,434 (9/7/93) -- An apparatus consisting of an elongated tube for inserting and guiding a laser beam for performing a discectomy of the herniated nucleus of a herniated disc.

● US 5,201,729 (4/13/93) -- Performing percutaneous discectomy with a 1.44 micron YAG laser.

● US 5,178,617 (1/12/93) -- A scanner system for distributing laser energy in a treatment pattern using a bundle of optical fibers, with a scanner configuration at the fiber input, and a treatment configuration at the output end.

Massachusetts Institute of Technology

● US 5,290,275 (3/1/94) -- Use of a transparent protective shield at the distal end of a multifiber catheter for mechanically displacing intravascular blood and protecting the fibers from the fluid. The shield also protects the patient in the event of fiber failure.

Premier Laser (4 patents issued during period)

● US 5,267,856 (12/7/93) -- A method of ablating a selected area of a material with a laser by adding a laser energy absorbable liquid to the area that enters the material via surface pores or is chemically bonded to the material. Application of the liquid is done either directly prior to or during each laser pulse, until desired amount of tissue/material is removed.

Summit Technology (4 patents issued during period)

● US 5,230,334 (7/27/93) -- The use of ultrasound for controlled localized hyperthermia, useful for inducing controlled collagen shrinkage in corneal tissue.

● US 5,214,071 (5/25/93) -- The use of topically applied aliphatic alcohols to reduce discomfort and inflammation, and to promote corneal wound healing and epithelial regrowth over a reprofiled corneal surface.

Sunrise Technology

● US 5,304,169 (4/19/94) -- A method for shrinkage of collagen by application of laser energy, wherein the threshold shrinkage temperature is substantially reduced by application of a reagent, such as lysozyme, to the tissue prior to heating. This allows the use of substantially lower energy levels.

Trimedyne (5 patents issued during period)

● US 5,242,438 (9/7/93) -- The means for deflecting laser energy circumferentially by reflecting the laser energy off of a cone placed in the path of the beam transmitted out of a fiber, within a catheter.

● US 5,242,437 (9/7/93) -- A medical device to apply heat to a site within a patient's body by using both irradiation and conduction to locally treat a tissue such as the endometrium. At the operative end of the device, some of the laser energy is absorbed, delivering heat omnidirectionally, while another portion is transmitted through an aperture for localized and intense heating and destruction of the target tissue.

ENTERING THE PATENT ZONE: The Volatile History of Medical Laser Patents

This column was originally published in the June 1994 issue of Medical Laser Report.

ENTERING THE PATENT ZONE

The Volatile History of Medical Laser Patents

Industry Update

Irving J. Arons
Managing Director
Spectrum Consulting

A U.S. Patent conveys the rights to an inventor (or his/her assignee) to prevent others from making, selling, or licensing a process, method, or material invention, as described in the claims of a letter patent, for 17 years from the time of issue. And, as it is in every other field of endeavor, so it is in the laser field -- where wars have been fought and battles won or lost over patents. Thus we introduce a regular feature to appear occasionally in our column, describing some of the battles and patents issued and fought over in the medical laser field.

In this initial look, we will introduce you to Patlex, Pillco, and Pillar Point Partners -- as well as to Dr. R. Srinivasan of IBM. We will tell you about some of the past battles, and those yet to be fought. And in doing so, tell you about some of the pertinent patents in the field and those issued over the past 18 months.

So sit back and get ready for an exciting ride through the "Patent Zone".

Gordon Gould and Patlex

The Gordon Gould story is an interesting one. While a graduate student in physics at Columbia University, studying under Charles Townes (the inventor of the "maser"), in November 1957 he conceived of the idea for making a laser, wrote his idea into a notebook and had the pages notarized. However, mistakenly believing that he had to have a working model before filing for a patent, he failed to do so at the time. He was beaten to the patent office with a laser patent application by his professor, Dr. Townes and Townes' brother-in-law Arthur Schawlow, then working for IBM. In 1975, Gould turned to patent attorney Richard Samuel, who after studying the situation for about a year, decided to take on the case, and formed Patlex to fight for the Gould patents.

Several months later, in October 1977, the first patent was issued to Gordon Gould. And then the fight began, as Samuels and his partners at Patlex began to license the Gould patents (with Gould retaining a 20% interest in all royalties). Over the years, four laser patents were issued to Gould, and assigned to Patlex for licensing. The four patents were the "gas discharge" patent (U.S. 4,704,583) issued in 1987 and covering most gas lasers -- HeNe, CO2, Ar, and Kr; the "optically pumped amplifier" patent (U.S. 4,053,845) issued in 1977 and covering most YAG, ruby and dye lasers; the "use" patent (U.S. 4,161,436) issued in 1979 and covering the applications of lasers to materials; and the "brewster angle window" patent (U.S. 4,746,201) issued in 1988 and covering the use of a brewster angle window in lasers. To date, more than 200 laser users and manufacturers have signed on to license one or more of the patents, with patent royalties exceeding $60 to $65 million, making Gordon Gould a millionaire several times over. What was most fortuitous was the delay in getting the patents through the patent office in the face of the "first filed" Townes and Schawlow patent. By the several years delay, when the Gould patents finally issued in 1977, 1979, 1987, and 1988, they were worth considerably more than if they had issued in 1959 or 1960, as the laser field was by then a mature business!

Ken Fox, Arthur Coster and Pillco Limited Partners

Sensing the opportunity represented by Patlex and the Gould patents, Ken Fox and Arthur Coster tried to follow suit with a series of four patents that issued to them in 1988, 1989 and 1991. Their patents concern the method and apparatus of using pulsed laser energy within a body lumen to remove tissue. They formed Laser Research Associates (later renamed Pillco Limited Partnership) to "manage" their four patents (U.S. 4,784,132 (11/15/88); U.S. 4,800,876 (1/31/89); U.S. 4,848,336 (7/18/89); and U.S. 5,041,108 (8/20/91)). Pillco then took aim at the various laser companies that it believed infringed their patents. These included the companies producing lasers used in lithotripsy for breaking up stones, and those used for cardio-revascularization. Among the laser companies to accede to royalty demands were Candela, Technomed, and after a court battle, Advanced Interventional Systems. In addition Spectranetics and Laser Photonics have also signed on. The company has now licensed the above five firms and is in negotiation with several others.

Summit Technology, VISX, and Pillar Point Partners

It started with the patents issued to Fran L'Esperance, assigned to Taunton Technologies. It continued with patents issued to Steve Trokel and Charles Munnerlyn, assigned to Visx. Rather than a prolonged fight in the courts over these patents having to do with the methods and means for performing removal of corneal tissue to correct various eye ailments, Taunton acquired Visx, with the new entity renamed Visx, under the management of the former Visx management team. Enter David Muller and Summit Technology. Summit had its own patents for photorefractive keratectomy (PRK), and rather than going through the vagaries of another potential lengthy court battle, the management of both firms met over a game of golf at the Pillar Point Inn in South San Francisco. There they worked out the initial details to form Pillar Point Partnership, an entity that would be the exclusive licensee of the key patents from both firms and would have the right to sub-license the technology and collect a royalty from the distributors and/or manufacturers using the patented technology, i.e., the two firms selling equipment based on the patents, while charging a "per use fee" to each licensee on each use of the equipment that fell within the protected technology, for performing PRK (or PTK).

Alan McMillen (Visx CEO) and David Muller (Summit CEO) are co-managing directors of Pillar Point, with earnings of the company distributed to Summit and Visx according to a complicated formula. Twelve Visx (and Taunton) patents and four Summit patents make up the technology bank, with both companies describing the partnership as a win-win relationship for each. However, time will tell if the ophthalmic community will accept the payment of an additional $100 to $300 per-procedure fee for the right to operate the lasers (to kick in upon one of the Company's lasers receiving FDA marketing approval) after paying such a high price ($400,000 to $450,000) for the equipment.

Dr. R. Srinivasan and "Big Blue" (IBM)

While all the wrangling between Summit and VISX noted above was going on, Dr. Rangaswamy Srinivasan and two associates at IBM quietly were issued a patent (U.S. 4,784,135 -- 11/15/88), covering the basic use of ultraviolet energy to ablate tissue. Those of you familiar with the history of "corneal sculpting" will recall that the first experiments using an excimer laser to attempt to reshape an eye were done in 1983 by Stephen Trokel and Dr. Srinivasan in Srinivasan's laboratory at IBM. Dr. Srinivasan had been experimenting with the excimer laser as a tool to trim plastic materials (e.g.Kapton), and had also conducted experiments to show the precise cuts that could be made on human aortic tissue and hair. This had attracted Stephen Trokel’s attention and led to the first ablation experiments on bovine eyes as mentioned above. Since the issuance of the IBM patent, just about all excimer laser (and solid-state laser) companies operating in the UV on tissue have taken a license to the IBM patent.


With this introduction to the "Patent Zone", next month we will tell you about some of the more interesting medical laser patents of the 50 plus issued in 1993, and the 14 issued in first few months of 1994. Then, periodically, we will update you on significant patents (and patent battles) in the medical laser field.

ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD

ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD

Michael Lachman of Lachman Consulting LLC issued his EyeQ Report #6 on May 8th, a summary of the ARVO 2006 meeting recently held in Sarasota, FL, with an emphasis on the latest clinical trial results with Genentech’s Lucentis – the two-year efficacy and safety results for the MARINA trial, a 76-patient randomized controlled Phase III study of Lucentis for minimally classic or occult neovascular wet AMD.

In addition, Michael also reported on the early clinical experience with off-label intravitreal Avastin, Genentech’s already FDA approved drug (for colorectal cancer), but being used off-label as a low cost and low dosage intravitreal treatment for neovascular AMD.

In both cases, the results did not disappoint the physician attendees. Here are some excerpts (with permission from the author) from Michael Lachman’s EyeQ Report #6:

Lucentis Update

On May 2, Jeffrey S. Heier, MD of Boston reported impressive two-year efficacy results from the MARINA trial. “Compliance at 24 months was good, with 89% of treated patients and 80% of sham patients available for 24-month examination. Treated patients received an average of 22 injections out of a possible 24. As shown in Table 1 below, Lucentis continued to perform exceptionally well during the second year of treatment on all visual acuity metrics, further distancing itself from sham treatment. With regard to “response rate,” or the relative increase in the percentage of patients “maintaining” vision in-line with the primary endpoint, Lucentis improved from 53% to 72% during the second year. In terms of mean change in visual acuity versus sham treatment, the Lucentis-treated eyes gained an additional 3-4 letters during the second year, for a net treatment effect of 20-21 letters (four lines) after two years.”

“During MARINA, investigators were allowed to offer Visudyne photodynamic therapy (PDT) or Macugen to patients at their discretion if they met certain criteria regarding disease progression. Interestingly, over the two year study period, PDT or Macugen was administered to 21% of sham patients but to only 0.4% of Lucentis patients.”

On May 3, Joan W. Miller, MD of Harvard Medical School reported satisfactory two-year safety results from MARINA. On key safety metrics, Lucentis was no worse than the sham treatment, and the two Lucentis dosages were similar to each other. With regard to serious ocular adverse events, endophthalmitis occurred in 1.0% of patients through 24 months, and uveitis occurred in 1.3% of patients. These are cumulative rates per patient over 22 injections, not rates per injection; as such, it is not surprising that these complication rates were roughly double the cumulative rates at 12 months.

Importantly, the two-year MARINA safety data is very favorable with respect to key non-ocular adverse events, particularly cardiovascular. In the previously reported 12 month results of MARINA, the rate of arterial thromboembolic events was higher in the two Lucentis groups (1.7% for 0.3mg and 2.1% for 0.5mg) than in the sham group (0.8%). Recall that when Genentech announced the results of the ANCHOR study in January, the company reported that the combined rate of stroke and myocardial infarction in both ANCHOR and MARINA with monthly dosing was similar in the control and the 0.3 mg Lucentis arms (1.3% and 1.6% respectively) and slightly higher in the 0.5 mg Lucentis arm (2.9%). At that time, Genentech seemed to be leaning toward submitting for FDA approval of the 0.3mg dose, because it was only slightly less efficacious than the 0.5mg dose and would avoid many of the questions regarding cardiovascular safety. At the same time, Pfizer/ OSI/Eyetech’s competitive marketing strategy for Macugen seemed to be hanging by the thin thread of Lucentis cardiovascular risk. At ARVO 2006, this thin thread broke.

David M. Brown, MD of Houston reported on a subgroup analysis of the 12-month results of the ANCHOR trial, which compared Lucentis to PDT. According to Dr. Brown, this analysis was used to determine if there is a subgroup of patients for which PDT “has a chance” to outperform Lucentis. There was not such a subgroup identified; Lucentis outperformed PDT in all subgroups based on age, baseline visual acuity, CNV lesion size, and lesion type.

Less Frequent Dosing of Lucentis Appears Very Promising

Philip Rosenfeld, MD, PhD presented the initial experience with less frequent Lucentis dosing from the single-site (Bascom Palmer), open-label PrONTO study. During the Phase I/II extension studies of Lucentis, it was observed that once the scheduled monthly injections stopped, the need for re-injection varied from patient to patient. It was also observed that cysts were visible on optical coherence tomography (OCT) before leakage became evident on fluorescein angiography (FA) or vision declined. In PrONTO, three initial monthly injections of Lucentis (0.5mg) were administered, followed by additional injections based on specific criteria (increase in retinal thickness, visual decline, new CNV leakage, or fluid observed on OCT). During the study, OCT examination was the primary driver of additional injections, as opposed to FA or visual exam. As Dr. Rosenfeld put it, one of the lessons of PrONTO is that “little cysts become big cysts if not treated.”

Visual outcomes in PrONTO were consistent with the MARINA and ANCHOR studies. By month 12, patients had gained an average of 9.3 letters of vision, in-line with the 7-11 letter gain reported at 12 months in MARINA and ANCHOR for the 0.5mg dose. Three or more lines of visual improvement was noted in 35% of patients, and only 18% lost letters of vision. Central retinal thickness decreased by an average of 178μm. There was complete resolution of retinal cysts and sub-retinal fluid in 72% of eyes after one month and 95% by three months.

Avastin Update

Last spring, Philip J. Rosenfeld, MD, PhD and his colleagues at Bascom Palmer looked at the encouraging preliminary outcomes for systemic Avastin and for intravitreal Lucentis, recognized the commercial availability of Avastin and the 400x lower dose if administered intravitreally versus systemically, and took a leap of faith. They started injecting Avastin intravitreally (and very much off-label) for neovascular AMD, and reported their very favorable early clinical experience at the ASRS meeting last July in Montreal. (For more on the results reported at that meeting, see my original report, published earlier on this web site, Avastin: A New Hope for Treating AMD.) The low cost of the drug, about $17-50 per injection in quantities appropriate for intravitreal use, lowered barriers to adoption in the US and internationally. By the winter, intravitreal Avastin had become the global de facto standard of care for wet AMD.

Last week at ARVO 2006, Dr. Rosenfeld summarized the excellent outcomes seen so far with intravitreal Avastin in neovascular AMD patients: average visual acuity from about 20/200 to 20/100, 44% of patients gaining 3 or more lines of visual acuity, and decrease of retinal thickness of about 100μm. As with Lucentis, the duration of effect is variable. Regarding the medical-legal aspects of off-label Avastin use, Rosenfeld argued that it is legal, ethical, and the logical application of scientific and clinical knowledge to patient care. Another prominent retina specialist pointed out that, given all of the investigator-sponsored research that is being conducted and reported for Avastin in retinal diseases other than AMD (see more on this below), Lucentis will be “more off-label” than Avastin for these non-AMD applications.

With off-label use of Avastin growing and FDA approval of Lucentis likely less than two months away, hot topics of discussion at ARVO were various pricing scenarios for Lucentis and what would happen to Avastin use following FDA approval of Lucentis:

Key Question #1: How will Lucentis be priced in the US?

Eyetech set a high bar with its $995 per dose pricing of Macugen, resulting in an annual cost of about $6,000 per year based on six injections (or about $8,000 per year based on the labeled six-week interval). Lucentis has proven to be significantly more effective, and should be able to command a higher price. Although the pivotal MARINA and ANCHOR studies of Lucentis featured monthly dosing, Bascom Palmer’s PrONTO study strongly suggests that less frequent dosing (5-6 injections per year instead of 12-13) is equally effective. Results from Genentech’s Phase IIIb PIER study, which examines a less frequent dosing regimen of Lucentis that also results in six injections during the first year of treatment, should be available to the FDA this month, in advance of the June 30 FDA action date. As such, it is possible that this less frequent dosing regimen could be incorporated into the Lucentis label. The significance of this from a pricing standpoint is that Genentech would be able to support per-dose pricing for Lucentis based upon an average of six treatments during the first year, not 13.

Lachman also heard at ARVO that Genentech is pursuing the 0.5mg dose for Lucentis in the US, instead of the 0.3mg dose. After Genentech reported ANCHOR trial results in January, which raised the possibility of elevated cardiovascular risk for the higher dose, comments from management suggested a bias toward the lower dose despite its somewhat lower efficacy. This would have been the more conservative path, one that the company characterized as having a “low likelihood of being wrong.” We have heard that since that time, the company and the FDA have gotten comfortable with the safety profile of the more efficacious 0.5mg dose, a conclusion supported by the recently announced and very favorable two-year safety results from MARINA
Given the superior efficacy versus Macugen, an average of six treatments per year, and high dose formulation, we would not be surprised to see Lucentis priced in the US in a range of $2,000-$3,000 per dose. Pricing below $1,500 per dose seems highly unlikely.

Key Question #2: What Will Happen to Avastin Use Once Lucentis is FDA-Approved?

Because Avastin is formulated and priced for intravenous infusion for the treatment of colorectal cancer, it is very inexpensive in the small quantities used for intravitreal retinal injection (25-30 syringes per vial of Avastin, costing $50 or less per dose). The fact that Medicare is not currently providing reimbursement for the off-label drug is a relatively small annoyance to retina specialists; the lack of reimbursement for the injection, which would normally be over $200, is a bigger deal. In some cases, private insurance is covering the Avastin injections or patients are paying out-of- pocket (generally $300-500 for the drug and injection). In other cases, retina specialists are “eating” the cost, in the name of providing the best available therapy for their neovascular AMD patients.

Once FDA-approved, despite its inevitably much higher cost, Lucentis (drug and injection) will be reimbursed by Medicare for the treatment of neovascular AMD. Because of reimbursement, as well as the medical-legal benefits of using an on-label drug when possible, Lucentis will likely be used for patients that are fully insured (either private insurance or Medicare plus supplemental insurance to cover the 20% co-pay). Avastin will likely still be used for uninsured or partially-insured AMD patients in the US that cannot afford Lucentis, as well as for the many off-label indications that are being treated with intravitreal Avastin (see Table 2 below).

Internationally, where healthcare spending is more tightly constrained, Avastin will be much more difficult to displace. Longer term, it is likely that organizations such as CMS and NIH will initiate randomized, controlled studies to validate the safety and efficacy of intravitreal Avastin, given the enormous potential savings to the Medicare system.

Other Uses for Avastin

Avastin is now being used experimentally for a wide variety of retinal conditions. Reports from around the world describing these initial clinical experiences with Avastin dominated the scientific program at ARVO 2006. Our search of the ARVO abstract database turned up 86 posters and papers referencing Avastin/bevacizumab, versus just 14 last year, all 14 of which described systemic use (see the chart on Page 3 of the EyeQ Report). Some of the ocular conditions for which experience with Avastin was reported at ARVO 2006, and the countries of origin for this research, are listed in Table 2 below. To detail all of these research results here is beyond the scope of this report, but with few exceptions, intravitreal Avastin led to one or more of the following outcomes: (1) improved visual acuity, (2) decreased central retinal thickness and vascular leakage, and (3) favorable safety profile.

Finally, although clinical experience with intravitreal Avastin is clearly in its earliest stages, there appears to be no “red flag” or “smoking gun” that would suggest an underlying issue regarding safety or efficacy. Over the past several years, intravitreal Kenalog (triamcinolone) has become the default “wonder drug” used to treat a variety of retinal conditions, including AMD (in combination with PDT), macular edema, and retinal vein occlusion, despite known risks of cataract formation and elevated IOP. Avastin has quickly taken over this role from triamcinolone, with apparent advantages in both safety and efficacy.

(With much thanks to Michael Lachman for allowing me to reproduce excerpts from his report. For more detailed information, I urge you to read his full report at the link provided herein.)

Author’s Note on Avastin

Since the original posting on January 31st, I have added five updates on this important drug for treating age-related macular degeneration. In addition to the posting you are reading, here is a listing (with links) to the others:

Avastin: A New Hope for Treating AMD

Avastin Update: Medicare not Likely to Cover its Use

Avistin Update II: AAO supports Medicare Coverage for Off-label Avistan Use

Also, on June 30, 2006, Lucentis was approved by the FDA. Here is the link:

Avastin/Lucentis Update 4: FDA Approves Lucentis for Treating Wet AMD

Avastin Update 5: NIH Considers Comparing Lucentis and Avastin (August 2006)

Custom Ablation #9: Questions......and Answers

Irving J. Arons
Spectrum Consulting

Since the last time I wrote about refractive surgery, following the AAO meeting of 2002, a lot of questions raised at the time have been answered. At that time (see An AAO 2002 Update: Classic vs. Custom LASIK — the Battle Continues, OSN, January 1, 2003), the major question was, is customized ablation that much better than conventional LASIK? I reported that the results being obtained with customized LASIK (as reported during the 2002 AAO meeting) were, in general 10% - 15% better than that obtained with conventional LASIK. But, because customized ablation treated higher order aberrations (coma, tilt, and spherical aberrations), in addition to the lower orders of sphere, cylinder and defocus, that the quality of vision (contrast sensitivity and especially night vision – the lack of halos) was dramatically improved.

Now, in a series of articles presented in a supplement to the April 2006 issue of Cataract & Refractive Surgery Today entitled, “Piecing Together the Laser Vision Correction Puzzle” (provided as an unrestricted educational grant from Advanced Medical Optics), I believe the answers to my original questions are now quite clear. Wavefront-guided LASIK (custom ablation) is better that either wavefront-optimized LASIK (wherein wavefront measurements are used to provide optimized ablation algorithm – but not used directly to guide the laser) and standard or conventional non-waveguide LASIK.

Richard Lindstrom introduced the supplement (“Next-Generation Laser Vision Correction) and put it best; “The current generation of wavefront-guided ablations provide significant advantages over and above simply adding an aberrometer to the process. Wavefront-guided platforms, such as the VISX CustomVue, have made at least six meaningful advances that have enhanced clinical outcomes since their original FDA approvals. These exciting advances include: (1) the use of Fourier analysis (over Zernike polynomials); (2) Variable Spot Scanning (VSS—with improved algorithms, which include a nomogram boost and correction for a “cosine effect”—the current lasers are faster, spare more tissue, and generate a smoother surface); (3) options for enlarged optical zones; (4) improved blend zones; (5) iris registration; and (6) compensation for pupil centroid shift. In short, the current generation of the VISX S4 excimer laser includes many more benefits than just the addition of a wavefront analyzer. These added elements allow surgeons to give patients the best possible outcomes for laser vision correction today.”

The only thing he left out was the improved, smooth corneal bed provided by using the femtosecond laser (IntraLase) to provide the flap.

In a panel discussion – “Wavefront-Optimized or Wavefront-Guided?, Andrew Holzman, Sao (John) Liu, Jeffrey Machat, and Mark Whitten concluded that the new technological laser platform improvements are driving wavefront-guided results to the top. This is probably best shown in the retreatment results reported by three of the participants (shown below in Figure 1.), whereby retreat rates using the new VISX Star S4 CustomVue platform has dramatically dropped by at least half over the generally good results obtained with the WaveLight Allegretto wavefront-optimized algorithm.

Figure 1. Retreatment rates improve when moving from wavefront-optimized to wavefront-guided ablations.

Source: “Wavefront-Optimized or Wavefront-Guided?”; pg 5 of the April 2006 supplement “Piecing Together the Laser Vision Correction Puzzle”; CRS Today; supported by an unrestricted educational grant from Advanced Medical Optics and used with permission of CRS Today.

Perry Binder is currently running a private-practice comparison (to be published later this year) between patients treated for sphere only and spherocylinders using conventional LASIK on both a Star S4 and an Alcon LadarVision 4000, VISX Star S4 CustomVue, Alcon Custom Cornea, and the WaveLight Allegretto (wavefront-optimized). Dr. Binder agrees with his colleagues, “All of the lasers performed well—that is, they all improved patients’ UCVA and BCVA and produced very predictable refractive changes. The Star S4 wavefront-guided ablations produced the best visual acuity results in eyes with a spherical refraction and no astigmatism (spheres), whereas eyes with myopia and astigmatism (spherocylinders) achieved their best acuity results with either the Allegretto laser or the VISX CustomVue. The LadarVision 4000 laser performed better than any other in reducing cylinder, regardless of whether the procedure was conventional or wavefront-guided. Overall, the Star S4 wavefront-guided ablations produced better results compared with conventional VISX treatments. The LadarVision’s wavefront-guided ablations did not improve on its conventional results.”

Mark Whitten, in a separate article, “Look to Wavefront-Guided Surgery to Reduce Enhancement Rates”, reported on his results using conventional ablation and wavefront-optimized LASIK versus the VISX CustomVue with just the Fourier upgrade and with both the Fourier upgrade and the Iris-registration upgrade. As shown in Figure 2, he has reduced his retreatment rates with the CustomVue with Fourier and Iris registration to below 5%, from the 20%-25% it was with conventional LASIK!

Figure 2. Advancements in the CustomVue platform, including the Fourier upgrade and Iris Registration, have reduced retreatment rates.

Source: “Look to Wavefront-Guided Surgery to Reduce Enhancement Rates”; Mark E. Whitten, MD; pg 10 of the April 2006 supplement “Piecing Together the Laser Vision Correction Puzzle”; CRS Today; supported by an unrestricted educational grant from Advanced Medical Optics and used with permission of CRS Today.

And finally, Steven Schallhorn created a model to look at the differences in higher order aberration RMS between conventional LASIK, wavefront-optimizes LASIK, and wavefront-guided LASIK. In his discussion (“Modeling Quality of Vision After Laser Vision Correction”) he showed that going to wavefront-guided ablation, regardless of the type of eyes treated, that this type of LASIK predicted the lowest mean change in HOA RMS (see Figure 3). Further, the odds of inducing significant higher order aberrations were also lower with wavefront-guided ablation than with either wavefront-optimized or with conventional LASIK.

Figure 3. The model shows that wavefront-guided LASIK provides a dramatic improvement in results over both conventional and wavefront-optimized ablations.

Source: “Modeling Quality of Vision After Laser Vision Correction”; Captain Steven C. Shallhorn, MD; pg 12 of the April 2006 supplement “Piecing Together the Laser Vision Correction Puzzle”; CRS Today; supported by an unrestricted educational grant from Advanced Medical Optics and used with permission of CRS Today.

So, as the pendulum (and laser platform technology) moves forward toward vastly improved results, it is becoming more apparent that visual outcomes are greatly improving as ophthalmology moves toward wavefront-guided ablation.