Avastin/Lucentis Update 35: The CMS Does the Full Monty on Code Q2024 for Avastin!

According to an email received yesterday by Jack Mitchell of the Senate Committee on Aging, “Effective immediately, CMS is no longer going to recognize code Q2024 for payment of non-outpatient hospital claims. Practitioners are directed to return to their previous reporting practice for small intraocular doses of Bevacizumab (Avastin®) furnished prior to October 1, 2009.”

“The Medicare claims processing contractors will post the following information on their websites within 5 days to inform providers of this policy: “Effective immediately, the Centers for Medicare & Medicaid Services (CMS) no longer recognizes Healthcare Common Procedure Coding System (HCPCS) Code Q2024 Bevacizumab (Avastin®) for payment of non-outpatient hospital claims. Practitioners shall return to their previous reporting practice for small intraocular doses of Bevacizumab (Avastin®) furnished prior to October 1, 2009. HCPCS Code Q2024 will be deleted as of January 1, 2010, and, therefore, it will be removed from the Average Sales Price (ASP) pricing file effective with the January 2010 Release.”

In addition, the Medicare contractors have been instructed to reprocess any claims from physicians for Avastin administered in their offices that were paid based on the Q2024 code if requested by the physician.

In plain English, this reverses the prior reversal and the policy goes back to the original policy in effect before the reduction in reimbursement took place. Good news for both retinal physicians using Avastin and for patients and Medicare!


According to a spokesperson for the AAO, Dr. William L. Rich, the AAO's Medical Director for Health Policy, "The AAO, all three retinal societies, Congress and our patients are all very thankful for this reversal. It benefits patients, doctors, and taxpayers."

Oraya IRay In-office Stereotactic X-ray Treatment for AMD: A First Report

Another new company with a treatment for wet AMD has come out of “stealth mode”, and presented information on how it’s system works and the results of it’s initial clinical trials. Here is an in-depth presentation of the Oraya IRay radiotherapy system.

Introduction

Over the past few years, several drug-based treatments have been suggested and tried to prevent visual loss due to neovascular age-related macular degeneration. Two anti-VEGF drugs, Avastin and Lucentis are now available to prevent significant vision loss in a majority of wet-AMD patients who are treated. However, it appears that repeated intravascular injections over an indefinite time period are required to keep the disease at bay.

One promising approach to reducing the number of injections needed is the synergistic use of radiation in conjunction with intravascular injections, to prevent the proliferation of vascular tissue and to induce visual acuity gains.

The idea of using radiation as a treatment modality for wet AMD has been around for years, but its use has been limited due to the potential damage that can be done to sensitive tissue within the eye without localization of the radiation beam and treatment area. Two companies now claim to have systems that achieve that aim.

The NeoVista Epi-Rad 90 System

The first of the two new therapy systems is the NeoVista Epi-Rad 90, which involves delivery of a target dose of 24 Gy of beta radiation to the center of the choroid neovascularization (CNV) following a partial vitrectomy for placing the strontium 90 tip close to the choroid. Several controlled clinical trials with this system are currently underway to determine if the combined use of radiation therapy and anti-VEGF injections can result in AMD control with fewer injections, compared to drug use alone.

(For more on the NeoVista Epi-Rad 90 system and the clinical trials underway, please see my four reports already posted on this site – links noted at the end of this writeup.)

The Oraya IRay System

Now, a second, office-based system has been proposed and is in early stages of testing. This is the Oraya IRay system, that uses a table-top source of low-energy X-ray beams, directed through the sclera onto the macula to treat CNV secondary to AMD. Unlike the NeoVista system, the Oraya IRay system delivers three doses of highly localized low energy X-ray radiation to the macula non-invasively, using a robotic positioning system, targeting algorithm and a device, I-Guide, for eye stabilization and motion detection. This office-based procedure can be performed in about 10-20 minutes, under a topical anesthetic. The IRay device delivers three beams of up to 8 Gy each through three different locations on the sclera (roughly at 7 o’clock, 6 o’clock and 5 o’clock), delivering up to 24 Gy to a single spot on the macula.

The unique method of delivering the three beams of radiation to the macula was chosen to avoid other sensitive eye structures such as the lens and optic nerve. In addition, the angle of the beam path minimizes collateral damage to radiosensitive structures, while enabling the delivery of the appropriate dosage of radiation (24 Gy) to the choroidal neovascularization that was found clinically useful in the NeoVista studies.

Details of the System

The IRay system consists of three parts: the robotically-controlled X-ray generation and eye imaging workstation (Figs. 1-3); the I-Guide, which is coupled to the patient’s eye via suction, and aligns and optically connects the eye to the X-ray generator (Figs. 5, 6); and the adjoining shielded operator workstation (Figs.3, 4).

To minimize the effects of eye motion during therapy, the I-Guide is used, which consists of a contact lens coupled to the eye with syringe-generated suction, and attached to a central post. The post is mounted to a stabilizer bar via a ball joint. The purpose of the I-Guide is to steady the eye and act as a target for the imaging system to monitor the eye’s position and gaze angle. During treatment, the automated positioning software continuously evaluates the deviation of the eye from nominal. Motion of the eye already is substantially reduced by the I-Guide and is monitored in real-time using a two-camera imaging system. When necessary, the beam is automatically gated off by an algorithm that incorporates time as well as displacement, allowing brief eye excursions while still maintaining effective targeting. The I-Guide is designed with a breakaway feature that allows emergency exit of the patient from the system.

Targeting is achieved on the basis of a calculated position of the fovea, as determined by the simple geometric relationship of the center of the I-Guide lens to the back of the eye. Oraya determined its targeting algorithm based on extensive pre-clinical studies, mathematical modeling of the eye, and subsequent developmental work. Pre-procedure fundus imaging, obtained via spectral-domain OCT, is used to verify targeting and ensure that patients with “outlier” fundus anatomy are identified.

In performing the procedure, the operator, after protecting the lower lid with a specially designed self-retaining retractor, places the I-Guide on the anesthetized eye. The patient’s head is secured in a chin rest/head restraint, which incorporates a radiation shield.

The operator at the shielded operator workstation obtains a visual lock on the eye and applies the appropriate X-ray dose to the three designated spots on the sclera. The three 3.5 mm collimated X-ray beams are sequentially and automatically delivered to converge onto a single 4 mm target spot on the fovea (Figs. 7-11).

This office-based, low-voltage (100 keV) X-ray radiation therapy is a 10-20 minute procedure with no appreciable external shielding required. For patients, the exposure is comparable to the radiation received in getting an X-ray of the head and neck. For operators, the radiation exposure would be equivalent to ~0.14 mrem/hour or one-quarter of the radiation from a transcontinental airline flight. Each patient would get just one lifetime dose, not repeated exposures. Even though doctors might experiment, after FDA approval, with pulse or repeat dosing at some interval, Oraya is not studying repeat dosing at this time.


The following illustrations show the elements of the system:


Figure 1. The Table-top X-ray Generator System




Figure 2. The 3-Part System Platform




Figure 3. The I-Ray System



Figure 4. The I-Ray System (showing operator station and shielding)




Figure 5. The I-Guide Assembly




Figure 6. The I-Guide in Position




Figure 7. The Robotic System and Spot Distribution




Figure 8. Spot Positioning on the Sclera




Figure 9. The X-Ray Beam Size on Sclera and Macula




Figure 10. X-Ray Beam Distribution within the Eye and Brain




Figure 11. X-Ray Beam Intensity on Fovea

Clinical Trials

Phase I (CLH001)

There are three clinical trials planned. The Phase I Trial (CLH001) has been initiated and is fully recruited with over 60 patients to having been treated at either 16 or 24 Gy.

The Phase I trial is a pilot study to evaluate the safety and tolerability of the IRay stereotactic, radiosurgery system in patients with Choroidal Neovascularization (CNV) secondary to AMD. The study aims to determine safety, preliminary efficacy, and dose evaluation.

The study includes two cohorts: those without previous treatment and those previously treated with anti-VEGF therapy requiring additional treatment due to persistent or recurring disease activity.

Monthly retreatment with additional anti-VEGF drug, if needed, is based on any of the following criteria:

– Increase of >100 microns central subfield thickness using SD-OCT
– Evidence of new macula hemorrhage on clinical exam
– New area of classic CNV on FA
– ≥10 EDTRS letter decrease in BCVA vs. previous visual acuity score, with associated fluid on SD-OCT

The initial results, on 28 patients with up to a year followup, treated in Mexico City, were presented by Dr. Peter Kaiser of the Cleveland Clinic Foundation at the Retina Sub-Specialty pre-meeting held prior to the main 2009 AAO Meeting. Dr. Kaiser reported on patients treated with 16 Gy of radiation plus Lucentis (following two monthly injections) in 15 anti-VEGF-naïve patients and in 13 prior Avastin or Lucentis patients (who had had on average 2.9 injections prior to entry into the study).

There were no device-related serious adverse events and no evidence of radiation-related abnormalities, but there were a few device related adverse events, all superficial keratopathy − which Dr. Kaiser attributed mostly to placement of the I-Guide. These superficial events required no intervention by the physician.

The efficacy results are shown in Figures 12, 13 and 14 below:

Figure 12. CLH001 Efficacy Results after 12 months



Figure 13. CLH001 Efficacy Results for Treatment Naive and Previously Treated Patients


Figure 14. Loss or Gain in Letters


The results of this feasibility study, while meant to evaluate primarily safety and tolerability of the IRay therapy, demonstrated a number of encouraging efficacy signals, including substantial preservation and gain of vision in both the treatment-naïve and previously treated cohorts, as well as low numbers of required anti-VEGF retreatment injections. The rate of the anti-VEGF retreatment injections (following the two mandatory “baseline” doses) was found to be only 0.9 per patient over 10 months, and ~56% of patients needed no additional anti-VEGF injections, while still demonstrating visual acuity preservation and gain at least comparable to that seen in other studies, such as MARINA and PrONTO, with much greater injection burdens.

(For a refresher on the MARINA, PrONTO – and ANCHOR studies, please see my NeoVista Update report of July 11, 2007, linked at the end of this report.)

Anti-VEGF retreatments, as described by Dr. Kaiser, are shown in the following graph:


Figure 15. Anti-VEGF Retreatments

Dr. Kaiser concluded that IRay extends the durability of Lucentis, reduces the number of injections, and appears safe and effective.

The company concluded that its non-invasively delivered, ionizing radiation in combination with Lucentis appears to:

– Extend the durability effect
– Limit the number of anti-VEGF injections
– Work in both treatment n ive and previously treated patients, and,
– Be safe and well tolerated

Phase II Clinical Trial (CLH002)

Oraya expects to enroll the first patients in a multi-center, randomized, masked, sham-controlled European trial before the end of the year, using a 16 Gy dose. (The company continues to evaluate the possibility of adding a higher-dose treatment arm.) It is expected that 8-10 sites in Europe will participate.

Phase III Pivotal (CLH003)

This larger randomized, masked, sham-controlled study is expected to initiate in mid-2010 and plans to enroll approximately 450 patients in 15-20 sites in both the U.S. and Europe


Questions and Answers

During the recent 2009 AAO Meeting in San Francisco, CEO of Oraya, Jim Taylor, was interviewed by Lynne Peterson of Trends-in-Medicine. She asked him the following questions:

Asked about the long-term safety of IRay, Taylor said, “I’d be the last person to say we have absolute certainty we know the outcome (with IRay). The comfort comes from the ample data and research from ocular oncology and from some early work done in radiotherapy for AMD that suggest the incidence of radiation retinopathy is low. Years of study in ocular oncology have given comfort that the doses here (are safe). We know that AMD has an inflammatory component to it, and we know that AMD causes scarring and building of lesions in the eye that don’t respond to anti-VEGF therapy. We also know that radiation is anti-vascularization and antifibrotic as well. Lastly, we know that if you combine an anti-VEGF agent with radiation, you get a synergistic effect”.

Taylor explained that radiation works best on concentrated lesions in an atmosphere of oxygenation. So, stopping leaking capillaries with an anti-VEGF, tends to make the center of the lesion more robust, and a better target for radiotherapy. Oraya has worked with radiation and oncology researchers and experts around the world to determine the dose and the approach. The science looks good. And the radiation is not delivered through the cornea but through the sclera. Taylor said one advantage of IRay over NeoVista’s therapy is that IRay is robotically delivered while NeoVista has a hand-held system. “We have a robot that is a wonderfully designed sniper, shooting low energy in tightly collimated beams with 3 beams going through the sclera at separate points, all converging at the same point on the fovea”. The IRay goal is to deliver either 16 Gy or 24 Gy to a spot centered on the fovea covering approximately 6 mm in diameter.

The three elements of IRay that Taylor highlighted were:

1. Robotic positioning.

2. Continuous tracking and management of eye motion with the I-Guide.

3. Collimation of the beam.

Does IRay make financial sense for retina specialists? Probably, if CMS reimburses for it. There would be an initial machine cost plus a per-procedure disposable cost. Taylor believes the procedure will be cost-effective because it should reduce both diagnostic testing and anti-VEGF injections. IRay is not currently being tested in dry AMD, but that might be an area for research in the future, as drusen formation has been demonstrated to have an inflammatory component which may be amenable to radiotherapy.



References:

1. Office-based External Beam Radiation Therapy for Age-related Macula Degeneration; Hsu, Jason and Regillo, Carl; Retinal Physician, September 2009.

2. Stereotactic Radiotherapy for AMD; Taylor, James; Ophthalmology Innovation Summit, October 2009.

3. Motion Management for a Novel Ophthalmic Stereotactic Radiosurgical Device; Chell, E. et al; AAPM, July 2009.

4. 2009 AAO Meeting; Peterson, Lynne and Woods, Diane; Trends-in-Medicine, November 2009. (Subscribers, only, contact Trends-in-Medicine)


Links to the NeoVista Writeups:

NeoVista Epi-retinal Strontium 90 Treatment for Wet AMD (2-14-07)

NeoVista Epi-retinal Strontium 90 Treatment for AMD Update (7-11-07)

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 2 (11-19-07)

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 3 (10-1-08)

Avastin/Lucentis Update 34: More on the Comparative Studies

In my constant search for new information about AMD treatments, I happened across a blog devoted to all things retina: The Retina Blog. In one posting, following the recent AAO Meeting, author David Khorram reported on Dan Martins talk during the Retina SubSpecialty Day Meetings. Apparently, the Academy sent out an email on its Academy Live network describing Dan’s talk in more detail than I had received.

Anyway, The Retina Blog had the up-to-date details on both the CATT Study and most of the other head-to-head studies – although, news about the Spanish study appears to be missing.

Here, thanks to David Khorram, is the latest information on the comparative studies.


Head-to-head Lucentis vs. Avastin Trials
10-25-09
The Retina Blog – David Khorram, MD

This bit of news just came in from the annual meeting of the American Academy of Ophthalmology, which is being held right now in San Francisco. There is a lot happening in terms of these two drugs. The results will be important, both clinically and economically. Lucentis costs $2,000 per dose. Avastin costs less than 10% per dose. Both drugs are made by Genentech — that’s a whole different story. Here is a list of the current clinical trials as described in the article from the “Academy Live” email of Friday October, 23, 2009, a service of the American Academy of Ophthalmology.

Bevacizumab vs. ranibizumab: Initial results expected in 2011

Bevacizumab (Avastin) and ranibizumab (Lucentis) are competing in a hefty schedule of six head-to-head randomized clinical trials directly comparing their use in AMD patients, said Daniel F. Martin, MD. This year, researchers hope to complete enrollment in the studies, which compare varying doses and treatment schedules of the drugs. Initial study results are expected to be available in early 2011, according to Dr. Martin.

Here’s the status of each of the studies:

* The NEI-sponsored CATT (Comparison of AMD Treatments Trial) study began enrolling an estimated 1,200 wet AMD patients at 44 sites in the United States in February 2008. The four-arm study comparing bevacizumab and ranibizumab on fixed and variable schedules is proceeding well, according to Dr. Martin, with one-year results targeted for 2011.

[Editors Note: According to Dr. Martin, enrollment is expected to be completed by the end of November, at which time enrollment will be closed. For more on the CATT Study, see my CATT Study Update 10.]

* In April 2008, researchers in the United Kingdom began enrolling an anticipated 600 patients at 17 sites in the IVAN (Inhibit VEGF in Age-related choroidal Neovascularization) study. This four-armed study compares monthly bevacizumab 1.25 mg and ranibizumab 0.5 mg injections given over two years with three monthly injections followed by PRN dosing.

* The four-site German VIBERA study started enrolling 360 AMD patients in 2008 to receive three monthly bevacizumab 2.0 mg or ranibizumab 0.5 mg injections and additional injections as needed.

* The Austrian MANTA study began assigning an anticipated 320 AMD patients in June 2008 to three monthly bevacizumab or ranibizumab injections, with additional treatment as needed.

* Researchers in Norway began enrolling an anticipated 450 patients in the 12-site LUCAS study in March. Subjects receive bevacizumab 1.25 mg or ranibizumab 0.5 mg monthly as needed until dry, with intervals between doses decreasing over time.

* French investigators opened enrollment this fall in the 600-patient, 20-site GEFAL study. Subjects are randomized to receive three initial monthly injections of one of the two drugs.

[See my Update 25 for more on the French study.]

David Khorram, MD is the co-founder of Marianas Eye Institute, and the medical director of the Center for Advanced Diabetic Eye Care. A US-trained Board Certified ophthalmologist, he is listed in "Guide to America's Top Ophthalmologists."

Avastin/Lucentis Update 33: The Wording of the CMS Order for Repricing of Avastin

The following note was received this morning by my contact in Senator Kohl’s office, from the director of CMS’ Office of Legislation, along with the wording, shown below, taken from the Federal Register of October 30th.


From the Office of Legislation of CMS:

“The excerpt from the CY 2010 hospital outpatient PPS final rule follows below. I have also attached the relevant page (page 615) from the copy of the rule that went on display at the Federal Register on Friday afternoon.

As requested, I am also checking with our program experts to see if we have any flexibility regarding the timing of this coding change (i.e., whether it can be applied retroactively or whether it can go into effect before January 1). If you have any questions, please let me know. “


From page 615 of the Federal Register, October 30, 2009:

We note that HCPCS code Q2024 (Injection, bevacizumab, 0.25 mg) was implemented effective October 2009 and represents a different dosage descriptor for the same drug described by HCPCS code J9035 (Injection, bevacizumab, 10 mg). Further, HCPCS code Q2024 has been replaced with HCPCS code C9257 (Injection, bevacizumab, 0.25 mg) effective January 1, 2010. In accordance with our CY 2010 policy to make a single packaging determination for a single drug, we are applying the methodology described above to bevacizumab and are assigning the applicable bevacizumab HCPCS codes the same packaging status for CY 2010. HCPCS codes C9257 and J9035 are included in Table 35 below.


In what I read from this in plain English, the reimbursement for the 0.25 mg dosage of Avastin, used in treating AMD, will revert on January 1st to the reimbursement in place before the change over on October 1st, or about $50.00, which I believe is what it was before the change.

Further, both CMS and Senator Kohl’s office, along with several ophthalmic organizations (AAO, ASRS, among others), continue to look into/request that the change in policy be implemented before January 1st.

Menu – Part 14: Some Updates and a Few New Posts

Since the last menu posting on June 12th, I have added two new updates on the CATT Study; eight updates on Avastin vs. Lucentis; and three new postings. The new postings include a writeup on the use of femtosecond lasers in cataract surgery; a review of the history of customized ablation, and a little about an upgraded endoscope for use in ophthalmology (including some history on this device).

First, the CATT Study Updates:

CATT Study Update 9: The CATT Study is On Track

In June I learned that the CATT Study was on track, with 850 of the intended 1200 patients enrolled. I also included a review of the first eight updates (including links).

CATT Study Update 10 – From the 2009 AAO Meeting

In October, I received a report from the AAO meeting that enrollment was nearly completed, and that first results wouldn’t be published until all 1200 enrollees had completed their first year of results.


And, the Avastin/Lucentis Updates:

Avastin/Lucentis Update 25: Comparative Studies Proliferate – France Joins the Fray

In September I learned that France had started a comparative study, to join studies underway in five other countries.

Avastin/Lucentis Update 26: CMS Ups the Ante

In early October, I learned that Medicare was tilting the table towards Lucentis by lowering the reimbursement for Avastin.

Avastin/Lucentis Update 27: Dr. Rosenfeld’s Remarks at Retina Congress 2009

Dr. Phil Rosenfeld gave an interesting presentation about the search for optimal dosing for anti-VEGF drugs at the 2009 Retina Congress.

Avastin/Lucentis Update 28: Sustained Release Lucentis May Eventually Change the Equation

Roche and Genentech announced their licensing and developmental deal with Surmodics for a sustained release/delivery system for Lucentis. I provided a few comments.

Avastin/Lucentis Update 29: Six-Month Results of Controlled Comparison Study Published

The Boston University School of Medicine and the Veterans Administration of Boston announced their six-month results of comparative study of Avastin and Lucentis. This was the first published prospective, double-masked, randomized, controlled comparative study of the two drugs. However, this study only contains 20 subjects!

Avastin/Lucentis Update 30: A Followup to Update 26 – Sen. Herb Kohl Queries CMS

Following the implementation of the reimbursement cut for Avastin to ophthalmologists, and its implication for Medicare, Senator Herb Kohl got into the act, asking CMS why this cut took place and if Genentech had any involvement?

Avastin/Lucentis Update 31: Problems with Pharmacy Compounding of Avastin?

During the 2009 AAO Meeting in San Francisco, one ophthalmologist presented on problems he had experienced with compounded Avastin. (There is, however, one problem with this presentation – the good doctor is a paid consultant for Genentech.)

Avastin/Lucentis Update 32: More on the CMS Repricing of Avastin

Finally, just after posting a good summary of the pricing of Avastin reimbursement, I learned about the CMS reversal of its policy. I posted both the summary and the breaking new information.


Some New Postings on Other Subjects:

Femtosecond Lasers Proposed for Use in Cataract Surgery

In June, I received a writeup from old friend Larry Haimovitch, writing about femtosecond lasers under investigation for cataract surgery, his report from ASCRS 2009. After receiving permission from Larry and the publisher of his piece, Biomedical Business & Technology, I reproduced it in my Journal.

By the way, this is my third writeup on femtosecond lasers.

A Review of the History of Customized Corneal Ablation (Custom LASIK)

In July, I noticed an approval for an iris-tracking laser from Technolas Perfect Vision and decided that it would be a good time to review the history of what I had written about customized corneal ablation, basically, its history. So, I listed the nine articles I had written on this subject, along with links to each piece.

Endoscopy in Ophthalmology: The Latest News and Some History

And, finally, a brief note about an improved ophthalmic endoscopic system from Endo Optiks, and my 1992 writeup about this interesting company and product.

INDEX/SEARCH

INDEX/SEARCH

For your convenience, and because only the last ten posts are shown on the opening page, here is a means for finding all of my posts in an easy-to-use fashion.

Use the Blog Search box in the upper left-hand corner of the header above, enter in "Menu" and click on "search this blog" and menus for all of my 120 or so postings will come up in an easy to search/find method (including short descriptions and live links.)

Avastin/Lucentis Update 32: More on the CMS Repricing of Avastin

During the 2009 AAO Meeting in San Francisco, there was much discussion of the CMS cuts in reimbursement of Avastin beginning at the beginning of October.

Crystal Phend of MedPage Today provided a good summary of what has been transpiring in this controversy, including comments from the AAO. Now we await the results of Sen. Herb Kohl’s meeting with CMS officials.

Late Breaking News: (Courtesy of Dr. John Kitchens of Retina Associates of Kentucky)

According to CMS....

Effective January 1, we will be replacing the temporary HCPCS code, Q2024 (Injection, bevacizumab, 0.25 mg), with a new HCPCS C code with the same descriptor as Q2024. Because the C codes are only used by hospitals to bill for outpatient services, effective January 1, 2010, physicians should return to their billing practices prior to October 1, 2009 for small doses of Avastin, when administered in their offices to treat macular degeneration. If they have any questions, they should contact their local contractor.


AAO: CMS Payment Cuts for Eye Drug Counterproductive, Group Says

By Crystal Phend, Senior Staff Writer, MedPage Today
Published: October 27, 2009

SAN FRANCISCO -- The recent cut in Medicare reimbursement for intravitreal bevacizumab (Avastin) will hurt both patients and taxpayers by forcing a shift to more expensive options, according to American Academy of Ophthalmology officials.

The rule change that went into effect on Oct. 1 created a code to account for the tiny doses used in ophthalmology, requiring practices to bill in 0.25 mg increments at $1.25 each. That dropped reimbursement for the standard 1.25-mg intravitreal dose from about $50 to $6.25.

Reimbursement for its competitor ranibizumab (Lucentis) -- a closely related molecule generally considered to have equal efficacy -- remained unchanged at a whopping $2,039. Since ranibizumab costs under $2,000 for a single dose, ophthalmologists usually make around $120 with each injection.

But even at the prior reimbursement level, they usually didn't profit from choosing bevacizumab. One vial of bevacizumab -- originally developed for cancer treatment -- contains more than one intravitreal dose, but drawing multiple doses from the same container almost doubles the risk of infection. So, compounding pharmacies divide up the drug into individual doses, repackage, and sterilize them -- but at a price that typically pulled even with reimbursement before the Oct. 1 cut.

So the new rule actually creates a disincentive for using the drug that has been estimated to save Medicare $1.5 billion each year in treating macular degeneration alone, said William Rich, MD, the medical director for health policy at the AAO. The AAO and other ophthalmology organizations immediately started negotiating for a change that would reflect compounding charges, he said. One argument for the new rule is that CMS cannot legally pay for pharmacist costs, but that's not true, according to Rich, who said it is allowed for some asthma and pain management treatments.

Early talks were positive but led nowhere except to a Congressional inquiry, according to George Williams, MD, of William Beaumont Hospital in Royal Oak, Mich., and a member of the AAO Health Policy Committee. "We thought we had a solution," he told retinal surgeons at the AAO meeting here. After daily talks with CMS, "we were told two weeks ago it would be fixed. Two weeks have passed, and it is still not fixed."

Sen. Herb Kohl, D-Wis., who chairs the Senate Committee on Aging, has demanded an explanation for the change and questioned the role of Genentech, which manufactures both drugs and would stand to gain financially from greater use of its more expensive product.

The company has denied any part in the CMS decision, according to media reports.

CMS officials are set to meet with the Senate Committee on Aging later today, and Kohl has reportedly asked for a copy of all communication between CMS and Genentech. However, Rich was skeptical that CMS would have a remedy in place soon. "If the current policy is left in place, physicians lose, patients lose, and taxpayers lose," he said.

He has already heard reports of some ophthalmologists switching to the more expensive drug in order to avoid losing money. Because most patients with conditions treated off-label with bevacizumab are on Medicare, their 20% copays have increased dramatically. "Physicians who changed are getting tremendous pushback from patients," Rich said.

He urged a quick solution to avoid the shift in practice patterns from becoming set. As of 2007, bevacizumab held about 60% of the market share. "We're not interested in assigning blame, we just want to get it fixed" Rich said.

Avastin/Lucentis Update 31: Problems with Pharmacy Compounding of Avastin?

A disturbing report from the 2009 AAO Meeting, as described on the OSN Supersite. Dr. Malik Kahook, speaking at the joint meeting, said that he had seen 16 cases of IOP spikes following injection of Avastin in his clinic, and has seen reports of at least 74 additional cases in five states. He went on to say that investigation was ongoing with both Lucentis and Avastin, but that "cases are overwhelmingly in the Avastin corner."

"By no means am I saying that Avastin is doing something to the trabecular meshwork or the eye cells, [but] certain compounding techniques are affecting the components that you're getting in the syringe, whether it's aggregation of proteins, formation of dimers and trimers, or other components that could be as large as 20 μm."

Inflammation and toxicity related to delivery of Avastin have been suggested as potentially causing IOP spikes. However, microflow imaging showed significant differences in total particle number in samples of Avastin drawn directly from a multidose vial, from the vehicle and from a dose supplied by a compounding pharmacy, Dr. Kahook said. The compounding pharmacy was selected because it [had] supplied doses to a Utah clinic that saw 42 post-injection IOP spikes.

This bears further watching.


November 10, 2009: A Update to the original story posted on October 27th.

I just received a copy of an email alert, Academy Alive, sent to Academy of Ophthalmology members during the recent meeting in San Francisco. One of the excerpts referenced the story above that I had originally sourced from Ocular Surgery News.

Here is more on this potentially troubling story:

Investigations continue into reports of IOP spikes following VEGF inhibitor use

Research is ongoing into the causes of cases of IOP spikes following bevacizumab (Avastin) or ranibizumab (Lucentis) use that have been reported around the United States, Malik Y. Kahook, MD, said at Glaucoma Subspecialty Day on Saturday. An active researcher on this topic, Dr. Kahook said he knows of more than 50 cases of IOP spikes after bevacizumab use and a smaller number after ranibizumab use. He said most of these patients don’t experience obvious inflammation, have no previous history of glaucoma or ocular hypertension, and sustain high IOP levels for weeks or months that often require laser therapy or surgery.

In an effort to elucidate the causes of these IOP elevation cases, Dr. Kahook and his colleagues tested bevacizumab samples from multiple compounding pharmacies and found noticeable variability in the concentration of the active monomer IgG, which in many cases was much less than the expected 25 mg/ml. Further investigations showed that some of the particles were much larger than expected.

“We believe that these molecules either plug the outflow pathway or may result in subclinical inflammation in the outflow pathway that then leads to elevation in eye pressure,” Dr. Kahook said during an interview. “We do not think that this is an issue with the active IgG monomer of Avastin, and we are not saying that people should stop using Avastin.”

Dr. Kahook recommends further study of the Avastin compounding and shipping processes to ensure greater product consistency between compounding pharmacies and to decrease the chances that high molecular weight adducts cause aqueous outflow obstruction and subsequent IOP elevation in additional patients. Studies are also being conducted to examine the potential link between IOP spikes and ranibizumab use.


Dr. Kahook has previously received research support from Genentech but has not received funding from Genentech for studies on this topic.



Reproduced from Academy Live, October 25, 2009, an e-mail service of the Academy of Ophthalmology to its members.


Q&A

I contacted Dr. Kahook several times asking him to name the five states that he said had reported at least 74 other occurrences; was there an online reference to these other reports; and who was doing the investigation – the FDA, NIH, or Genentech?

He refused to answer, responding that we would have to “await his further publications”.