The recent windfall in promising therapies for AMD is most welcome. Next comes the job of weighing their relative costs and benefits.
The first treatment option is observation,” said Sharon Fekrat, MD, associate professor of ophthalmology at Duke University.
She was speaking about age-related macular degeneration, and her restraint may set the right pace for assessing the exciting and newly rich spectrum of AMD therapies: the anti-VEGF agents Macugen (pegaptanib), Avastin (bevacizumab) and Lucentis (ranibizumab), as well as combination approaches such as photodynamic therapy (PDT) with Visudyne (verteporfin), PDT with Visudyne plus Kenalog (triamcinolone acetonide), and PDT with Visudyne plus an anti-VEGF treatment. “In some cases,” Dr. Fekrat added, “there’s full macular translocation surgery.”
“I’ve been in practice for 11 years,” said Nancy M. Holekamp, MD, associate professor of clinical ophthalmology at Washington University in St. Louis. “In the past, it was either thermal laser or observation. Now we have choices.”
Choices aren’t always cheap, however, and that’s a shadow hanging over an otherwise bright horizon. In fact, the consensus among some retina specialists is that Avastin and Lucentis, the only treatments shown to prevent vision loss and improve visual acuity, will outshine the others. But the difference in their respective costs is looming over their respective benefits.
Here is the emerging picture on cost-effectiveness for AMD therapy.
The Value of Value?
“Most companies in the business world talk about value,”Dr. Holekamp said. Medicine, on the other hand, talks about outcomes based on the best scientific data available. While Dr. Holekamp agreed that evidence-based medicine is how we need to practice ophthalmology, she said value also matters.
Dr. Holekamp is a proponent of the work of Gary C. Brown, MD, MBA, and Melissa M. Brown, MD, MN, MBA, a husband-and-wife team that hopes to revolutionize the practice of ophthalmology by quantifying the value of particular treatments. They measure total improvement in quality of life from a particular intervention, taking into account efficacy and all the side effects. Value-based analyses identify the best interventions across all fields of health care while integrating the relevant costs.
How it works. First, a “utility” value is assessed. This assessment of value takes into account:
- the visual improvements demonstrated by the treatment in clinical studies,
- the adverse effects of the treatment, and
- the patients’ perspective on how the treatment affects the quality of life.
Extensive research has been done to measure the quality of life of patients at different visual abilities. This may sound elusive, but one approach has been to ask a large number of patients with varying levels of visual acuity how much time of their remaining life they would trade in return for perfect vision. In the case of moderate vision loss, for example, the average patient is typically willing to trade four to 10 years to achieve perfect vision. These data are converted to a “utility” value by a standard formula.
From there, the length of time that the effects of the intervention are expected to last (often the rest of the patient’s life) is factored in, as well as the effects due to adverse events of treatment. The resulting “total utility gained” is measured in quality-adjusted life years (QALYs).
Finally, the cost of the treatment is considered in order to arrive at a cost-utility ($/QALY) assessment.
How value is interpreted. The parameters for what is cost-effective depend largely on what society is willing to pay for health care, said Dr. Melissa Brown, principal and director of the Center for Value-Based Medicine, Flourtown, Pa. By convention, an intervention is deemed very cost-effective if it costs less than $50,000/QALY. Anything over $100,000 is thought of as not cost-effective. A gray area exists between $50,000 and $100,000. Thus, cataract surgery, the most common major operation in ophthalmology, is very cost-effective at $2,020/ QALY.
PDT, on the other hand, was not cost-effective, when calculations were done with early trial data. A more recent calculation, using new data based on longer treatment time, found PDT with verteporfin for classic subfoveal CNV to be very cost-effective.1 “Over time, the clinical trials showed that PDT became more cost-effective because the results were better,” Dr. Brown said.
Now the Browns are awaiting the publication of a number of clinical trials to analyze other AMD treatments. The analyses should be published within a year. Value-based medicine, in essence, provides a Consumer Reports to all stakeholders in health care, Dr. Brown said.
|Lucentis or Avastin? |
Are we about to witness the end of a love affair, the casting aside of off-label Avastin (bevacizumab), in favor of its FDA-approved cousin, Lucentis (ranibizumab)?
“Most retina specialists in the U.S. will probably switch, for legal reasons,” said Dr. Fekrat. She can imagine a scenario in which a patient has a heart attack, blames it on Avastin, and asks why the doctor didn’t use Lucentis? “That’s what we’re stuck with in this country.”
Outside the United States, she predicts doctors will probably stick with Avastin, because it’s so inexpensive, yet very effective. Avastin costs about $65 per injection; the wholesale cost of one 0.5 mg vial of Lucentis is $1,950.
Caracas, yes. Copenhagen, yes. Cleveland, I’ll see you in court. Dr. Brown agrees that the fear of litigation could trump cost in this country. “I don’t think there’s any question that in other countries Avastin will be used,” she said. “But in this country, with the legal system we have, I don’t know what will be chosen.”
“If Avastin works as well as Lucentis, and Avastin is inexpensive, is that better value for patients?” said Dr. Holekamp. “It could be, unless you’re talking about safety. Although we think Avastin is safe, we have no phase 3 clinical trial data to back that up. Physicians have to realize that safety has value for patients.”
Lucentis was approved June 30 after its safety and efficacy were demonstrated in a number of clinical trials bearing jaunty nautical names—ANCHOR, MARINA, PIER. Approximately 95 percent of patients treated with Lucentis (0.5 mg) maintained vision (loss of less than 15 letters), and up to 40 percent improved (gain of 15 letters or more) at one year.
Avastin, developed as an oncology drug, hasn’t undergone the rigors of a highly controlled ophthalmic clinical trial. But one recent case series study of 81 eyes by Robert L. Avery, MD, and others1 concluded that 1.25 mg of Avastin is well tolerated and is associated with improvement in visual acuity, decreased retinal thickness and reduction in angiographic leakage in most patients, the majority of whom had previous treatment with PDT and/or pegaptanib.
Dr. Blodi hopes that there will be a number of anti-VEGF options to choose from, allowing retina specialists to tailor their treatment, but noted, “For cost-effectiveness, we will need to look for a long-acting agent.”
Memo to public sector: pick up the ball! Genentech is the developer of both Avastin and Lucentis, and so has no obvious incentive to conduct the kind of studies that would compare the two. That shouldn’t leave the question hanging, said Philip J. Rosenfeld, MD, PhD, the doctor who first injected Avastin into the eye. “This is the perfect role for NEI and NIH. The whole world is looking for us to study this molecule in a comprehensive, prospective fashion.”
Until then, doctors are likely to selectively pick and choose. Dr. Fekrat imagines that Medicare-only patients, who have a 20 percent copay, may decide to choose the cheaper drug. In fact, Genentech anticipates that the average patient will pay $50 out-of-pocket per Lucentis injection even if the patient is covered by Medicare and supplemental insurance.
1 Avery, R. L. et al. Ophthalmology 2006;113:363–372.
Or the Quality of Quality?
On a different front, some ophthalmologists assess the value of a treatment by measuring the effect of a particular treatment on quality of life. The most common assessment tool, the NEI’s Visual Function Questionnaire-25, a 25-question survey tool used in most clinical trials, captures those perceptions.
This measure, said Tom S. Chang, MD, associate professor of clinical ophthalmology, University of Southern California, determines whether a treatment improves a patient’s visual function by asking about activities of daily living—such as the ability to see things up close and in the distance—and how they rate their sense of dependence.
Dr. Chang called the VFQ-25 results from the MARINA study, which tested Lucentis vs. sham, “very robust.”2 He said that for the first time in ophthalmology, there is a pharmacologic agent that demonstrated a clinically meaningful difference, as well as a statistically significant improvement in quality of life. “This is directly related to the large treatment effect of the drug,” he said, adding that the results were consistent across two randomized trials.
While quality of life assessments are used extensively in oncology and orthopedics, ophthalmology embraces visual acuity as the standard metric, Dr. Chang said. But that may not be as important for patients. Patients want to know how their function will change. Will they be able to drive, knit or recognize a friend from across the street? By that measure, he said, Lucentis is a breakthrough.
Variables. How often does a treatment have to be given? That’s another cost-effectiveness consideration, said Barbara A. Blodi, MD, associate professor of ophthalmology and visual sciences, University of Wisconsin, Madison. For example, PDT with intravitreal steroids is very cost-effective because even though one PDT treatment costs around $2,000, the use of the adjuvant steroid treatment (Kenalog is $5 to $10 for a single treatment) appears to prolong the therapy’s effectiveness, Dr. Blodi explained. “We find we may only have to give the treatment once or twice, if we do this combination,” instead of more than six treatments of PDT alone over two years.
Frequency of treatment could become an issue with Lucentis, despite its good trial performance. In the phase 3b PIER study findings, patients treated with Lucentis showed, on average, an improvement after three monthly injections. But those benefits dwindled after additional doses, and visual acuity drifted back toward baseline.
Dr. Blodi sees her highest risk patients—those who have lost central vision in one eye—every four to six months. She also noted that retina specialists are relying more on optical coherence tomography, which is more cost-efficient than fluorescein angiography. In fact, a small study (n = 40) out of Bascom Palmer Eye Institute found that by monitoring Lucentis patients with OCT, fewer injections were needed.
Seeing is believing. At the end of the day, if a treatment works well, it will be considered cost-effective by many people even if it is expensive. But if it performs poorly, it will not be cost-effective at virtually any price. “People fear going blind even more than death,” said Dr. Holekamp. “We’re fortunate to be in a specialty where our interventions tend to be cost-effective, because people so greatly value their vision.”
|Where PDT Stands Now |
Photodynamic therapy with verteporfin created a stir when the first clinical trial results were unveiled. Finally, there was a treatment for choroidal neovascular AMD.
But some experts predict that PDT will be sidelined now that Lucentis and Avastin have captured the spotlight. Others say it will remain part of the AMD armamentarium. “PDT is effective in stabilizing vision,” said Dr. Blodi. But she called Avastin and Lucentis more exciting. We can see in some patients improvement that’s never been seen before.”
In fact, the ANCHOR study, which compared verteporfin PDT to Lucentis, showed that patients treated with Lucentis gained an average of 8.5 letters in the 0.3 mg dose group and 11 letters in the 0.5 mg group. Patients treated with PDT lost an average of 9.5 letters.
Preliminary data from phase 3 found approximately 94 percent of patients treated with 0.3 mg Lucentis and 96 percent treated with 0.5 mg maintained or improved vision compared with approximately 64 percent of those in the PDT group.
With results like that, PDT may fall by the wayside, Dr. Fekrat said. Dr. Holekamp agrees. “There will be a very limited use of PDT in the future. The anti-VEGF treatments in clinical trials are having better results.” She added that PDT loyalists are still using PDT in combination with Kenalog and Avastin, and reporting good results. “Then you have to ask: Why wouldn’t you use Avastin alone?”
Frequency of treatment may answer that question, Dr. Chang noted. Lucentis, at least, is required on a monthly basis. “It’s conceivable,” he said, “patients won’t tolerate monthly injections.” But a combination of PDT with verteporfin plus Lucentis might reduce the number of treatments.
As monotherapy or in combination, at least for now Dr. Fekrat predicts that Lucentis will be the drug of choice.
|AMD Treatment Options |
|DRUG ||DESCRIPTION ||COST PER DOSE |
|PDT with verteporfin (Visudyne) ||Shown to be effective in preventing moderate visual loss compared with placebo for eyes with predominantly classic CNV. However, the treatment provides little visual acuity improvement on average. ||$1,288/intravenous injection |
|PDT with verteporfin plus intravitreal triamcinolone acetonide (Kenalog) ||It is estimated that most of the PDT usage in North America is performed in combination with intravitreal steroid. Advocates suggest that this regimen could reduce the number of PDT sessions. ||Add $5 to 10 per treatment to PDT monotherapy |
|Pegaptanib (Macugen) ||The first successful use of an aptamer to inhibit vascular endothelial growth factor (VEGF) in the eye. Visual improvements are limited. ||$1,000/intravitreal dose |
|Ranibizumab (Lucentis) ||Anti-VEGF agent shown to be effective in preventing visual loss and improving visual acuity in up to 35 percent of AMD patients with subfoveal AMD. ||$1,950 wholesale/0.5 mg vial |
|Bevacizumab (Avastin) ||Anti-VEGF agent approved for treating colorectal cancer but widely used off-label to treat neovascular AMD. No clinical trials have been conducted, but small studies have found that treated eyes had a significant decrease in macular thickness and improvement in visual acuity. ||$65/intravitreal injection |
1 Am J Ophthalmol 2005;140:679.
2 Miller, J. et al. Randomized, controlled phase 3 study of ranibizumab (Lucentis) for minimally classic or occult neovascular age-related macular degeneration. MARINA Study Group data presented to the American Society of Retina Specialists 23rd Annual Meeting, July 16–20, 2005, Montreal, Canada.
|Meet the Experts |
Barbara A. Blodi, MD
Associate professor of ophthalmology and visual sciences, University of Wisconsin, Madison. Financial disclosure: None.
Melissa M. Brown, MD, MN, MBA
Principal and director of the Center for Value-Based Medicine, Flourtown, Pa., and adjunct assistant professor and adjunct senior fellow at the Leonard Davis Institute of Health Economics, University of Pennsylvania. Financial disclosure: None.
Tom S. Chang, MD
Associate professor of clinical ophthalmology, University of Southern California. Financial disclosure: Consultant for Alcon, Allergan, Bausch & Lomb, Genentech and Novartis.
Sharon Fekrat, MD
Associate professor of ophthalmology, Duke University. Financial disclosure: None.
Nancy M. Holekamp, MD
Associate professor of clinical ophthalmology at Washington University, St. Louis, Mo. Financial disclosure: Consultant for Alcon and Genentech, and on Novartis speakers’ bureau.
Philip J. Rosenfeld, MD, PhD
Associate professor of ophthalmology, Bascom Palmer Eye Institute. Financial disclosure: No equity interest in any company; receives clinical research funds from Genentech, Eyetech and Alcon; member of scientific advisory boards for Genentech, Novartis and Allergan; received past funding from Novartis and QLT.