Avastin/Lucentis Update 11: A White Paper on Why Avastin vs Lucentis Matters
This paper is reproduced with permission of the authors.
Avastin versus Lucentis: Why It Matters
Although Lucentis is a remarkably safe and effective treatment for exudative macular degeneration, it could cost our health care system billions of dollars annually, which will be a significant burden on our strained health care system. Fortunately, it appears that Avastin is roughly equal to Lucentis in safety and efficacy, and Avastin’s far lower cost makes it an attractive alternative. We encourage wider use of Avastin, which can help sustain the health care system that has benefited our patients medically and ourselves professionally.
Growing health care expenses (to which rapidly rising drug costs have contributed heavily) are unsustainable. In response to these growing costs, Medicare has been attempting to reduce all physician fees, a move Congress blocked at the last minute in 2006. Right now, ophthalmology faces annual cuts of 1% for four years, a 3% cut in 2007 for certain commonly used ophthalmology codes, and the prospect of further Medicare cuts in the future. Just as legislators targeted cataract fees as a way to reduce health care expenditures, it cannot serve ophthalmology well if huge pharmaceutical expenses result in an explosive growth in federal expenses for ophthalmic care. Fortunately, there are things all ophthalmologists can do to address these challenges.
How Might Lucentis Affect Physician Compensation?
Medicare Part B pays for physician services as well as drugs delivered in offices. In ophthalmology, Visudyne and Macugen have caused sharp increases in Medicare Part B expenses, and the impact of Lucentis is likely to far exceed that of Visudyne and Macugen combined. There are more than 200,000 new cases of exudative age-related macular degeneration (AMD) in the U.S. each year, (1) and we estimate that about 85% are treatable. The cost of Lucentis is about $2257 per injection, (2) and the MARINA study (3) showed benefit from monthly Lucentis injections for two years. Therefore, after one year of full market implementation, Lucentis costs in the U.S. could, in theory, exceed $9 billion.(4)
Several factors temper this figure, and, based on Lucentis sales data, it appears reasonable to anticipate at least $2-3 billion in annual U.S. sales under current conditions. Some patients require less than 24 treatments, and some retinal specialists use the PIER or PrONTO protocols. (5) Also, many providers currently treat exudative AMD primarily with Avastin. On the other hand, exudative AMD appears to be a recurrent condition, so many successfully treated patients may need additional rounds of therapy, just as many of our PDT patients have developed recurrences after initial closure of the choroidal neovascular membrane (CNVM).
To put this $2-3 billion figure in perspective, in 2006 the total Medicare Allowed Charges for all of ophthalmology was $4.77 billion. That total covers physician fees, practice expenses, malpractice Relative Value Units, and imaging. In 2004, total spending for all Medicare Part B drugs for all medical fields was about $12 billion. Compare the approximate $54,168 cost of treating one eye with Lucentis monthly for two years to the $46,326 median annual household income in the U.S. in 2005.
In contrast to Lucentis’ cost, the drug cost for Avastin is only about $50 per dose. Further, many treating physicians have noted that Avastin seems to be longer-acting than Lucentis, perhaps because Avastin’s larger size impedes clearance from the eye. Consequently, many clinicians use a less frequent dosing regimen with Avastin than Lucentis.
Why Would Ophthalmologists Use Lucentis?
Although Avastin is a safe, effective, inexpensive treatment of exudative AMD, some ophthalmologists have offered the following reasons to use Lucentis:
1. Lucentis is FDA-approved for this indication.
2. Unlike Avastin, Lucentis has been studied with a randomized clinical trial, and the data for Lucentis are more long-term data than those of Avastin.
3. Lucentis may be safer than Avastin.
4. Lucentis has greater activity in vitro and Lucentis is a smaller molecule designed for better retinal penetration.
5. Physicians receive substantially more income by using Lucentis.
We’ll address each of these reasons in turn. First, most prescriptions written in the U.S. are for off-label uses. There is compelling evidence of Avastin’s safety and efficacy for CNVM in AMD based on published reports (6) and current widespread clinical use. Consequently, the federal Medicare program offers coverage for intraocular Avastin for this indication.
Second, Avastin and Lucentis are structurally very similar, and ophthalmologists’ collective short-term experience with Avastin has shown results comparable to those with Lucentis. The planned two-year National Eye Institute head-to-head study should clarify this issue.
Third, after thousands of applications, the ocular safety of both Lucentis and Avastin has been well demonstrated. In terms of systemic safety, thromboembolic events (such as angina, heart attacks, and strokes) have been the main concern. Preliminary long-term data indicate that Lucentis in the ocular dose of .5 mg (as currently prescribed) has a four-fold increased risk of stroke compared to a .3 mg dose, and this risk seems to involve primarily people with a history of prior stroke. (7) There is less long-term data on ocular use of Avastin. Among patients using Avastin systemically for metastatic colon cancer, 4.4% who had Avastin in combination with other colon cancer chemotherapies had thromboembolic events, compared to 1.9% who received various colon cancer chemotherapies and no Avastin. However, this finding is of doubtful relevance to ocular use of Avastin. The ocular dose (1.25 mg) is about 1/300th of the systemic dose (5 mg/kg) used to treat metastatic colon cancer. Colon cancer patients receive treatment every two weeks, while intraocular injections of Avastin are generally at least 6 weeks apart. Therefore, ocular Avastin results in approximately 1/1000th of the systemic exposure compared to intravenous use. The increased risk of thromboembolic events occurred only in colon cancer patients who concurrently used other chemotherapies, so the increased risk may reflect drug interactions. Finally, colon cancer often leads to a hypercoagulable state, which predisposes the patient to thromboembolic events. As a smaller molecule, Lucentis has a shorter systemic half-life than Avastin, but it is unknown whether Lucentis has less systemic toxicity. (8)
Fourth, in practice Lucentis does not appear to be more effective than Avastin. It may be that the 1.25 mg Avastin dose effectively blocks all VEGF receptors, and any additional potency of Lucentis does not confer additional effect. Lucentis’ smaller size may turn out to be a drawback, because Lucentis may clear the eye too quickly to work as well as, or as long as, Avastin.
Fifth, Medicare reimburses ophthalmologists 6% over the Average Wholesale Cost of Lucentis. Consequently, ophthalmologists who pay $1950 for Lucentis receive $2067 from Medicare, for a profit of $117 per dose given. In contrast, there is little, if any, profit generated by the $50 Medicare reimbursement for Avastin. A retinal specialist treating only 72 patients with monthly Lucentis injections, rather than treating these same patients with Avastin, will be paid an additional $100,000/yr by Medicare for the Lucentis drug. Further, retina specialist treating monthly with Lucentis, rather than treating patients with Avastin every 6-12 weeks, will likely generate additional income through injection fees.
Retinal specialists typically treat hundreds of exudative macular degeneration patients per year. While there are strong financial incentives to use Lucentis, we don’t know whether these incentives influence treatment recommendations. We do know that, for every $100,000 of “profit” paid to ophthalmologists by the 6% “margin” from Lucentis sales, the cost of the drug to Medicare, insurers, and patients is $1.76 million. The 80% Medicare portion of this $1.76 million comes from the same Medicare Part B “pot” that also pays for physicians’ medical services.
Are Medicolegal Concerns with Avastin Reasonable?
We see no reason to infer that ocular use of Avastin poses significant risk of systemic toxicity or more such risk than other anti-VEGF ocular drugs. While some providers avoid Avastin in patients with a recent thromboembolic event, (9) ocular Avastin has become a standard of care for most exudative AMD patients. A January 2007 Internet survey of the American Society of Retinal Specialists (ASRS) with 276 respondents found that 58.76% usually recommend Avastin for patients with subfoveal CNVM due to AMD when these patients have both Medicare and secondary insurance coverage (9.97% of these recommend Avastin plus PDT for such patients). For patients without secondary coverage, for whom the co-payment on Lucentis treatment is substantial, 79.20% of ASRS respondents usually recommend Avastin (2.77% of these recommend Avastin plus PDT).
What Other Factors Influence Pharmaceutical Use?
Pharmaceutical companies have always been eager to court “opinion-shapers,” academic clinicians whom their colleagues trust to offer informed recommendations. The companies readily sponsor research by these academicians, hire them as consultants, and pay them for speaking engagements. These people deny that their objectivity has been compromised, but a general review of industry-sponsored research showed a bias in favor of the sponsoring company’s products. (10) Of course, many academicians do speak their minds, regardless of corporate relationships.
Who Is Paying for Lucentis?
For many years, growth in government expenditures for health care has exceeded the rate of inflation. Such growth is not sustainable. In an attempt to control rising costs, there are federally mandated restrictions on Medicare cost increases, effectively putting health care providers in direct economic competition with drug companies for limited Medicare Part B dollars. If we cannot control pharmaceutical costs, our patients will suffer, and we physicians will likely suffer as well. While it may be more politically expedient in the short term for Medicare to cut reimbursement to physicians than to reduce benefits, rising health care costs will eventually result in larger patient premiums, increased co-payments, or reduced access to care. Ultimately, our patients will suffer to the degree that the health care system is financially crippled.
What about Patients Who Demand Lucentis?
Genentech’s media blitz has encouraged many people to request Lucentis. We tell patients that Avastin appears roughly equal in safety and effectiveness. One reason we prefer Avastin is that it may require less frequent injections, which would help reduce the risks of anti-VEGF treatment. We also note that, for people without secondary insurance, the out-of-pocket cost of Lucentis is much higher. Then we leave the choice to our patients. When using Lucentis, we generally follow the PrONTO study guidelines. That protocol often results in significantly fewer than 24 treatments for each CNVM episode.
What Do We Recommend?
1. We think it is reasonable for general ophthalmologists to ask retinal specialists who use primarily Lucentis why they choose to do so.
2. Until the NEI’s study of Avastin versus Lucentis is completed (not before 2009), we need to carefully monitor outcomes.
3. As professionals, we have obligations to society-at-large as well as to our patients. In this new era of extremely (we think outrageously) expensive drugs for macular degeneration, we should be mindful of the public-health consequences of our practice patterns.
4) As public health advocates, we should encourage legislators and regulators to remove financial incentives that might encourage physicians to treat patients with more expensive drugs.
1. Postgrad Med 1998;103(5):153-64.
2. $1950 (wholesale cost) + $117 (Average Wholesale Cost mark-up) + $190 (approximate injection fee).
3. New Eng J Med 2006;355:1419-31.
4. After one year, there could be 170,000 eyes receiving monthly treatments and another 170,000 added in the second year. Each eye would receive 12 treatments per year at $2257 per treatment.
5. Ophthalmol Clin North Am 2006;19(3):361-72.
6. Ophthalmol 2006;113:363-72; Am J Ophthalmol 2006;142:1-9; Retina 2006;26:383-90.
7. Genentech “Dear Health Care Provider” [physician advisory] 1/24/07.
8. New Eng J Med 2006;355:1409-12.
9. Ophthalmol 2006;113:363-72.
10. JAMA 2006;296:996-8; Br Med J 2006;333:782-6; Br Med J 2003;326:1167-70.
Authors (All authors are retinal specialists):
February 9, 2007
Leon A. Bynoe, MD, Fort Lauderdale, FL
Randy Dhaliwal, MD, FRCSC, FACS, Augusta, GA
Joel D. Eichler, MD, Belleville, NJ
Matthew E. Farber, MD, Ft. Wayne, IN
Steve Friedlander, MD, FACS, Reno, NV
Timothy Holekamp, MD, Columbia, MO
Stephen R. Kaufman, MD, Cleveland, OH
Mike Lahey, MD, Hayward, CA
Jeffrey M. Lehmer, MD, Union City, CA
James G. Randall, MD, Missoula, MT
Scott C. Richards, MD, Ogden, UT
J. Gregory Rosenthal, MD, Toledo, OH
J. Sebag, MD, FACS, FRCOphth, Huntington Beach, CA
Avastin versus Lucentis: Why It Matters
Physicians for Clinical Responsibility
P.O. Box 201791