At Press Time

Medicare Fee Fix Remains in Limbo

Senate Must Now Act to Avoid 21% Reduction.

■ After the Democrat leadership in Congress failed in an attempt to provide $250 billion for a 10-year program to fund Medicare physician fees, lawmakers will have to come up with another solution before year-end or see doctors' fees reduced by 21%.

The "fee fix" measure was voted down in the Senate as enough Democrats joined with all of the Republicans to defeat what was seen as a maneuver to separate the $250 billion from overall healthcare reform legislation. The Senate will now have to take up a new $210 million fix passed by the Democratdominated House on Nov. 19.

Any long-term fix that is not part of the overall healthcare reform package would dramatically add to the deficit, which is what concerns lawmakers who oppose such measures.

The root of the potential 21% fee reduction is a complex formula called the "Sustainable Growth Rate," which is supposed to set Medicare fees each year. However, because the fees have been seen as inadequate, Congress has passed endof-the-year fixes in seven of the past eight years. The fixes have had the effect of borrowing from future Medicare fees, leaving the possibility of the 21% fee reduction beginning in January if Congress does not act. Despite this, another one-year bipartisan fix remains a possibility.

Democrat leaders in Congress have vowed that something will be done to provide adequate Medicare payment before the 21% reduction goes into effect. The nature and length of the fix is now the issue.

Physician organizations have warned that a major reimbursement reduction would make it harder for Medicare patients to find doctors who are willing to treat them.

The fix "can be one year, two years, four years, 10 years, I don't know. That's got to be worked out," said Senate Finance Committee Chairman Max Baucus, (D-Mont.). "The main point is there will not be a reduction in doctors' reimbursement."

For Dry Eye, Drug Approvals Are Difficult

FDA Has Required Confirmatory Studies.

By Jerry Helzner, Senior Editor

■ As company after company announces it is in the process of developing new therapies for dry eye, enthusiasm regarding the potential availability of innovative treatments must be tempered by the fact that the FDA has been particularly demanding in supervising the approval process for investigational dry eye drugs.

Given the FDA's past record, future dry eye therapies are likely to require confirmatory studies even after phase 3 trials have been completed. The reason for the additional scrutiny is the subjective nature of some trial data. The biggest difficulty is obtaining qualitative results when the signs don't match the symptoms.

Among the many companies with dry eye drugs in their pipelines at various stages of development are Inspire Pharmaceuticals, MacuSight, Ista Pharmaceuticals, Sirion Therapeutics, Alcon, Regenerx, Acucela, Eyegate, Lux Biosciences and Opko Health — and that's just to name a few.

Even Allergan's Restasis (cyclosporine ophthalmic emulsion 0.05%), the only prescription drug to be so far approved for dry eye, had a long, hard road before being approved in December of 2002.

The FDA mandated a confirmatory trial that added more than two years to the approval process despite the fact that the pivotal phase 3 trial confirmed that application of Restasis led to statistically and clinically relevant increases in tear production for patients with chronic dry eye disease, This increased tear production wasn't demonstrated in patients who were taking anti-inflammatory drugs or using punctal plugs.

Another, more recent example: Inspire Pharmaceuticals has encountered delays in the approval process for its dry eye drug Prolacria (diquafosol tetrasodium). The drug received two "approvable letters" and is now in another (confirmatory) clinical trial after consultation with the FDA.

The fault is not with the drug companies. Inspire has proven in the past that it can successfully navigate the FDA process. The company's drug for ocular itching, Elestat, had a relatively smooth path to approval. Inspire was unable to discuss Prolacria's journey through the FDA approval process because the drug is still in clinical trials. However, its experience is not unique. Industry experts agree that obtaining approval for any prescription dry eye treatment is difficult.

"Allergan received two or three approvable letters for Restasis before it conducted a confirmatory trial and was finally approved," said one industry source. "The problem is that the symptom data for dry eye can be very subjective and often depend on how a patient feels on a particular day."

Retina Roundup

Timely and Important Retina News of Interest to All Ophthalmologists

Compiled by Jerry Helzner, Senior Editor

► VEGF Trap extension study. VEGF Trap-Eye demonstrated a durable response and a good safety profile in an extension study presented at the recent AAO meeting.

David S. Boyer, MD, who followed 117 patients from the phase 2 CLEAR-IT study for a second year, reported that 50% of the patients who received VEGF Trap on an asneeded basis required less than four additional doses of the drug in 21 months after receiving three monthly "loading" doses.

Dr. Boyer said that the average vision gain under this regimen was 8.4 letters at 12 months, 7.1 letters at 18 months and 6.1 letters at 24 months.

► Sustained-release planned for Lucentis. SurModics, Inc., a provider of drug-delivery and surface-modification technologies to the healthcare industry, has signed an exclusive license and development agreement with Roche and Genentech to use SurModics' proprietary biodegradable microparticles drug-delivery system to develop and commercialize a sustained-release drug-delivery formulation of Lucentis.

Though anti-VEGF Lucentis has quickly become the accepted standard of care for wet AMD and is being widely used off-label to treat other retinal diseases, the need for intravitreal injections every four to eight weeks has created great interest in finding an alternative delivery method.

► CMS had planned $7 Avastin reimbursement. CMS was set to reduce reimbursement to ophthalmologists for an intravitreal injection of Avastin from $50 to $7 before numerous complaints caused it to reverse its decision. CMS says the planned reduction came as a result of a statutory requirement to provide a new code for the cost of the actual amount of Avastin used in an ophthalmic procedure.

The reduction drew the immediate ire of the American Academy of Ophthalmology and most of the ophthalmology community, which views Avastin as comparable to the much more expensive Lucentis in terms of efficacy and safety.

In the event that the reduction in Avastin payment to $7 had been upheld, the result would most likely have been greater use of Lucentis, which could have cost CMS an estimated $500 million a year in additional Lucentis reimbursement.

► Alcon puts new focus on retinal disease. Alcon recently signed its third deal for retinal disease drug-development in as many months. The agreement provides Alcon with a license to develop Potentia's leading drug candidate, POT-4, for the treatment of both wet and dry AMD. The agreement also provides for Alcon to acquire the shares of privately held Potentia if milestones are achieved.

POT-4 was the first complement inhibitor to enter the clinic for ophthalmic use. Potentia has completed a phase 1 trial for POT-4 in patients with wet AMD. The trial was designed to determine the safety and tolerability of an intravitreal injection of POT-4, as well as its stability and depotforming properties. In the study, investigators observed only minimal and mild local adverse events related to the injection with no serious adverse events related the drug. The study also found that POT-4 deposits form at doses of 450 micrograms and greater and that the higher the concentration the longer the deposits lasted.

► Major new progress against LCA. Years of intensive research into using gene-replacement therapy for patients afflicted with Leber's congenital amaurosis (LCA) is showing stunning results.

Studies that began with successful restoration of vision to blind puppies and continued with young adults have now advanced to the achievement of meaningful vision gains in adults and children.

Researchers at the University of Pennsylvania and Children's Hospital of Philadelphia reported in Lancet that they successfully replaced a defective gene that contributes to LCA with the correct gene in a phase 1 trial of 12 patients. The patients, ranging in age from eight to 44, were injected with the correct RPE65 gene contained in a "safe" virus in their worse eye. All patients showed subjective and objective improvement in major measurements of vision, including, dark adaptometry, pupillometry, electroretinography, nystagmus and ambulatory behavior. The greatest improvement was noted in children, all of whom gained ambulatory vision.

► AMD may predict heart disease. A large study found strong evidence that older people who have AMD are at increased risk for coronary heart disease, although not for stroke. This result adds to mounting evidence that AMD and cardiovascular disease may share some risk factors — smoking, high blood pressure, inflammatory indicators, genetic variants such as complement factor H — and disease mechanisms.

The Cardiovascular Health Study (CHS) followed 1,786 white or African-American participants, who were free of cardiovascular disease or stroke at the study's outset, for about seven years. The incidence of heart disease was 25.76% in patients with AMD, compared with 18.9% in those without AMD. The association between AMD and heart disease was somewhat stronger in people age 69 to 78 than age 79 and up. Data were adjusted to counter potentially confounding factors like hypertension, diabetes and smoking.

► DR shows sharp increase. Continuing an increase that has gone on for more than two decades, diabetic retinopathy now affects more than a third of all diabetes patients, according to the latest nationally representative estimate.

The prevalence of the condition appeared to increase across racial and ethnic groups between the 1988-1994 and 2005-2006 iterations of the National Health and Nutrition Examination Survey.

Research Digest

New & Noteworthy Journal Articles

Compiled by Andrew E. Mathis, PhD, Medical Editor

► Antibiotics and phaco. A pair of articles present data indicating possible future trends for antibiotic use in cataract surgery. In a study in the Journal of Cataract & Refractive Surgery, researchers found that patients undergoing phacoemulsification who were treated one day preop with moxifloxacin were more likely to have an increase in fluoroquinolone-resistant bacteria following surgery. Two older antibiotics were also rendered ineffective. This finding could have a significant effect on the prevention of postoperative endophthalmitis.

Regarding endophthalmitis prevention, an article in Ophthalmology showed that cefuroxine was the most cost-effective drug to use to prevent the complication. The C/E ratio for cefuroxine was $1,403 per case of endophthalmitis prevented. Ciprofloxacin, by comparison, would need to be eight times more effective to be comparable in cost-effectiveness. Other, more expensive fluoroquinolones would have to be even more effective than that.

The likely conclusion: provided that previous pretreatment with moxifloxacin has not rendered the patient unable to fight further bacterial infection, cefuroxime may be the drug of choice for cost-conscious doctors.

► Race and glaucoma. Glaucoma is the leading cause of vision loss among African Americans. A recent article in the American Journal of Ophthalmology may provide some reasons for this.

Using baseline data, the African Descent and Glaucoma Evaluation Study (ADAGES) group came to several conclusions relevant to the correlation between glaucoma and race. First, the group found that individuals of African descent have thinner corneas across all diagnostic groups. A less surprising finding in the baseline data is that African Americans are more likely to have diabetes mellitus and high blood pressure, and both these factors affect glaucoma rates. The third finding is that people of African descent have worse pattern standard deviation for standard automated perimetry fields, both overall and within normal limits, than individuals of European descent. One measurement in the report, mean IOP, was not statistically significant.

Longitudinal data from the ADAGES trial is still forthcoming and will be combined with the baseline data.

► Avastin in corneal neovascularization. Subconjuntival injections of bevacizumab have a positive effect on corneal neovascularization, according to a team of Korean ophthalmologists who conducted a 29-patient trial and published their findings in Acta Ophthalmologica.

The team injected 29 eyes with varying doses of bevacizumab: 1.25 mg/0.05 ml in seven eyes; 2.5 mg/0.1 ml in 15 eyes; and 5 mg/0.2 ml in seven eyes. Follow-up was at one week, one month and three months after a single injection. In the eyes treated with 2.5 mg and 5.0 mg, reduction in neovascularized corneal area was seen at week one, and while the affected areas increased in these two groups by the three-month follow-up, they were still smaller than at baseline. No significant changes were seen in eyes injected with 1.25 mg.

Retinal physicians have been using Avastin for wet AMD since Philip J. Rosenfeld, MD, published his findings in 2005. Dr. Rosenfeld proved that using bevacizumab would safely inhibit angiogenesis and choroidal neovascularization. Now, increasing studies are looking at anti-VEGF agents to prevent neovascularization in other parts of the eye.

► Anti-glaucoma meds and low birthweight. A consistent concern of ophthalmologists prescribing and patients taking anti-glaucoma medications is the possibility of a link between these drugs and low birthweight in infants born to mothers on these drugs. An essay published in the October 2009 issue of the British Journal of Ophthalmology may dispel these concerns.

Research conducted in Taiwan on 244 pregnant women who had used topical beta blockers for glaucoma also encompassed a control group of 1,952 pregnant women matched to the test group for age, year of delivery, maternal hypertension and gestational diabetes. There was no statistically significant difference in birthweights between the two groups.

The authors of the study were careful to note, however, that there were significant rates of low birthweight in women using anti-glaucoma drugs other than beta blockers. That point notwithstanding, beta blockers seem to be a safe category of drugs for glaucoma during pregnancy.

► Riboflavin and UV light against infection. Postoperative infection is a common complication, usually treated with antibiotics. However, antibiotics have their own inherent problems, not the least of which are infection and resistance, so a group of surgeons from the Harkness Eye Institute at Columbia University have tried combinations of ultraviolet light and riboflavin (vitamin B2) against three common ocular bacilli: Staphylococcus aureus, MRSA, and Pseudomonas aeruginosa.

The team found that riboflavin in combination with UV light — a combination frequently used to treat infectious corneal ulcers — effectively eradicated all three bacteria in vitro in every test plate, whereas UV light alone was only marginally successful and riboflavin alone killed no bacteria at all.

The findings of this study, published in the September 2009 issue of the Journal of Refractive Surgery, indicate that antibiotics may not always be necessary for the treatment or prevention of ocular infection, although in vivo studies still need to be conducted.

Fabry Disease: A Rare but Key Diagnosis

Ophthalmologists Can Identify This Serious Disease.

By Jerry Helzner, Senior Editor

■ A practicing ophthalmologist can go for years without ever seeing a patient with a rare lysomal disorder called Fabry disease. However, an ophthalmologist who is knowledgeable about the signs and symptoms of this rare disease can diagnose it and save a life, or at a minimum provide a longer and better quality of life to a patient. This is because a recently developed treatment for Fabry disease has proved effective.

Fabry disease occurs in one of 40,000 males and in a smaller percentage of females. It is an X-linked genetic disorder caused when an enzyme known as alpha-GAL is faulty or missing. The alpha-GAL enzyme is responsible for removing a fatty substance known as GL-3 from cells throughout the body. Without enough of this important enzyme, the GL-3 substance builds up in cells and can cause severe health problems.

Fabry is difficult to diagnose because signs and symptoms can vary widely among patients. Because one of the most common symptoms of the disease affects the cornea, ophthalmologists may be among the very first treatment professionals to be positioned to identify people living with Fabry. Many people with Fabry disease demonstrate ophthalmic manifestations in the cornea, the conjunctival vasculature or lens opacities. The most common corneal involvement, which occurs in 90% of Fabry patients, is corneal whorling, where dense bronze to cream-colored rays radiate from the center of the cornea. Although patients on anti-arrhythmic drugs such as amiodarone, indo methacin, chloroquine or chlorpromazine may present whorl-like opacities that mimic Fabry disease, they usually experience problems with vision. It has been widely reported that visual acuity is not affected by the corneal changes found in Fabry disease.

"Eyecare professionals can be among the first specialists to identify patients with this disease because the cornea changes in the eyes are diagnostically the earliest quantitative sign that points to Fabry," says Leonid Skorin, Jr. DO, OD, FAAO, FAOCO, of the Mayo Clinic.

Conjunctival vasculature abnormalities also occur frequently (in as many as 60% of patients) and early in the disease process. The small blood vessels of the conjunctiva take on a sausage-like appearance that can appear anywhere on the mucus membrane. Two types of lens opacities have been documented in Fabry disease: the anterior capsular cataract and the posterior subcapsular or "Fabry cataract." The anterior capsular cataract develops more rarely than the Fabry cataract, which typically has a whitish, dendritic-like presentation.

"If optometrists and ophthalmologists can recognize these symptoms, we may be able to help patients identify the disease earlier and get treatment earlier," says Dr. Skorin.

Effective treatment for Fabry is relatively new and involves enzyme replacement therapy, where the missing enzyme is replaced by infusion. Clinical research has shown that treatment with recombinant human a-GAL replacement therapy may reduce the GL-3 levels in certain cells.

High-Tech Solutions Improve Outcomes

Selected highlights of product announcements from this year's AAO.

► Topcon augmented its popular EyeRoute image management platform with an iPhone application, allowing mobile access to patient records, and an operating room module. The latter enables video recording of surgical procedures that can then be streamed to a computer terminal for case review and patient education at any location, eliminating the need for DVD burning. The company also released the 3D OCT-2000, a successor to its 3D OCT-1000 that offers enhancements in imaging and visualization, easier connectivity, improved workflow and new clinical modules.

Other new Topcon devices that debuted at the AAO included the TRC-NW7SF MK II camera that combines both mydriatic and non-mydriatic imaging, the CA-200 corneal analyzer, and the MicroSlot illuminator for use in DSAEK procedures.

► Lensar. This new entrant into the industry is one of three companies developing technology that could allow for "laser cataract surgery" that uses a femtosecond laser to perform clear corneal incisions, capsulorhexis, lens fragmentation and limbal relaxing incisions. Proponents say better outcomes will result, such as more precise centration of premium IOLs and less trauma to the posterior segment.

The company presented data from 100 cases performed in Mexico City. US trials are planned, the company says.

► Carl Zeiss Meditec debuted its new data connectivity and management platform, called Forum, which integrates diagnostic results from many disparate devices into one centralized database accessible anywhere, and connects to a number of EMR systems. The goal is to streamline day-to-day workflow, improve efficiency, and aid clinical analysis of diagnostic data, thus providing busy ophthalmologists with "real answers in real time," CZM says.

► Wavetec Vision announced that its next-generation ORange system has been used to calculate the refractive power of over 100 aphakic eyes at six sites in the US. Results validate the system's ability to perform IOL power calculation following lens removal, and is especially useful in eyes with prior refractive surgery for which such calculations are difficult. This application of ORange allows for true measurement of the optical power of an aphakic eye, in hopes of avoiding residual refractive error by confirming or changing the preop IOL power calculation in the aphakic state.

The ORange system, introduced earlier this year, uses intraoperative wavefront aberrometry to identify patients requiring limbal relaxing incisions and to improve positioning of toric IOLs.

► Ellex showcased the latest model of the Eye Cubed ultrasound system, which performs A- and B-scans at 25 frames per second — fast enough, the company says, for real-time visualization of dynamic processes such as blood flow within a tumor and membrane behavior.

Enhancements in the newest model include a 24-inch widescreen monitor, a more user-friendly interface, improved import/export functions, a DVD burner and a high-capacity hard-drive. A forthcoming update will add DICOM compatibility.

► Clarity Medical Systems highlighted the utility of its RetCam digital imaging system for initial screening of retinopathy of prematurity. Digital imaging enables screenings to take place at remote sites that lack access to an onsite pediatric retina specialist and offers more accurate documentation of exam results than binocular indirect ophthalmoscopy. The RetCam is being used for imaging and documentation in two ongoing clinical trials, BEAT-ROP and BLOCK-ROP.

Clarity says it plans to expand beyond pediatric retina in the near future, offering imaging applications in cataract, refractive, glaucoma and adult retinal disorders.

► Reichert acquired the Foresee Preferential Hyperacuity Perimeter (PHP) from Notal Vision. The PHP device aids in early detection of conversion from dry to wet AMD. Reichert will distribute the device to eyecare professionals; a home-based version of the PHP being developed by Notal Vision will be distributed by Sightpath Medical; FDA approval of the home device is expected early next year.

► Iridex introduced a dual-port green laser, the IQ 532. The dual output ports allow two energy delivery devices to be attached simultaneously for greater ease of use. The laser also includes a user-friendly interface that stores preset treatment protocols to save time.

Also at the AAO, Iridex introduced a modular multi-wavelength solution that offers yellow (577 nm) and infrared (810 nm) wavelengths in a single unit.

► Compulink updated its suite of offerings with a new ASC module that simplifies inventory management and improves connectivity with patient records, a web portal that patients can use to schedule visits and update their records from home (thus relieving the practice of some administrative tasks) and several other scheduling and practice management enhancements. The company's white paper, "Guide to Implementing EHR," contains advice on best practices to follow when making the transition to electronic records.

► Endo Optiks introduced a new endoscope for use in ECP that offers a higher resolution and wider field of view than earlier models. Resolution increased from 10,000 to 17,000 pixels and field of view expanded from 110 to 160 degrees.