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.

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”.

CATT Study Update 10 – From the 2009 AAO Meeting

According to Dr. J. Kitchens, Tweeting from the Retina SubSpecialty Day Session at the 2009 AAO Meeting, Dan Martin, head of the CATT Study, reported this morning that the study is almost finished recruiting. To date, 1130 patients are enrolled and the 44 clinics involved hope to have 1200 patients by the end of next month, at which time the study will be closed.

First one-year results on all enrolled patients expected in Spring of 2011.

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

As reported by Alicia Mundy in a Wall Street Journal Health Blog yesterday evening, Senator Herb Kohl wants to know if Genentech had any input into the CMS decision to reduce the Medicare reimbursement rate for Avastin when used in small doses in the treatment for AMD.

Here is a copy of the WSJ blog and a link to Senator Kohl’s letter to CMS.


WSJ Health Blog
October 13, 2009, 5:41 PM ET

Senator Wants to Know About Medicare Shift on Eye Drugs
By Alicia Mundy

Sen. Herb Kohl wants to know whether Genentech was involved in a recent Medicare shift that could prompt eye doctors to use a more expensive drug. Genentech, which recently became part of Roche, says it wasn’t involved.

As we noted recently, Medicare introduced a new payment code that cut payments to doctors for small doses of Avastin, a cancer drug that many doctors use off-label to treat patients with macular degeneration. That could prompt doctors to switch to Lucentis, a similar but far more expensive drug approved for macular degeneration. (When used to treat the eye, Avastin costs less than $50 per dose; Lucentis costs about $2,000.)

Genentech had “no involvement” in the government’s decision to create a new payment code, a company spokeswoman told the Health Blog

Ophthalmologists are now using Avastin about as much as Lucentis, according to Dr. Philip Rosenfeld, a retina specialist in Florida. Both drugs are sold by Genentech, so its revenues would increase if eye doctors used less Avastin and more Lucentis. Rosenfeld, who was an early proponent of using Avastin in the eye, told us he thinks the change could cost the government nearly $500 million a year, based on estimates of usage he and other eye doctors have compiled.

In a recent letter to CMS, the agency that oversees Medicare, Kohl wrote that he was “disturbed to learn from members of the medical eye care community that Genentech may have communicated directly with CMS officials about this proposed coding change, reportedly suggesting that CMS was over-paying for the small amounts of Avastin being used off-label for intraocular treatments.”

Kohl wants all communication between Genentech and CMS on the matter. CMS says it is currently reviewing the letter and will respond to the senator.

Here is a link to Sen. Kohl’s letter.