STATEMENT OF NEED
Retina specialists now have several approved therapies at their disposal for the treatment of age-related macular degeneration, in addition to some off-label treatments as well. It is impotant that we have a mechanism that allows us to compare the relative benefits and outcomes among different treatments, based on clinical trial results, and factor in adverse events. When we have a method whereby this can be accomplished, we can then also factor in the costs of treatments and come up with a way of determining value.

TARGET AUDIENCE
This activity is designed for retinal specialists and other ophthalmologists.

LEARNING OBJECTIVES
Upon successful completion of this learning program, the participant should be able to:
• Identify the treatment options that retina physicians currently have in their armamentarium and the clinical trials that accompany these treatments.
• Cite the components of a value-based analysis.
• Cite the evidence that value-based decisions are based on
• Discuss how visual outcomes are correlated with utilities.

METHOD OF INSTRUCTION
Participants should read the learning objectives and continuing medical education (CME) program in their entirety. After reviewing the material, they must complete the self-assessment test, which consists of a series of multiple-choice questions. This test is available exclusively online, at www.CMEToday.net. Once you register and log in, you can take the test, get real-time results, and print out your certificate. Please e-mail ckoury@bmctoday.com or call 484-581-1821 if you have any questions or technical problems with the Web site.

Upon completing the activity and achieving a passing score of ≥70% on the self-assessment test, participants can print out a a CME credit letter awarding AMA/PRA Category 1 Credit.™ The estimated time to complete this activity is 1 hour.

ACCREDITATION
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The Dulaney Foundation and Retina Today.

The Dulaney Foundation designates this educational activity for a maximum of 1 AMA/PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activity.

DISCLOSURE
In accordance with the disclosure policies of The Dulaney Foundation and to conform with ACCME and FDA guidelines, all program faculty are required to disclose to the activity participants: (1) the existence of any financial interest or other relationships with the manufacturers of any commercial products/devices, or providers of commercial services that relate to the content of their presentation/material or the commercial contributors of this activity; and (2) identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved.

FACULTY CREDENTIALS
Melissa M. Brown, MD, MN, MBA, is Director, Center for Value-Based Medicine, Adjunct Senior Fellow, Leonard Davis Institute for Health Economics, University of Pennsylvania, Adjunct Assistant Professor, University of Pennsylvania School of Medicine, Scheie Eye Institute, and Principal and Director of the Center for Value-Based Medicine, LLC. She may be reached at mbrown@valuebasedmedicine.com.

FACULTY DISCLOSURE DECLARATIONS
Dr. Brown disclosed that she is a consultant for Allergan, Cochrane Collaboration, EMMES, ERI, Eyetech, Genaera, Genentech, Merck, Novartis, Pfizer, and the National Institute on Aging.

INTRODUCTION
One of the most important questions facing retina specialists today is what treatment to use for patients with age-related macular degeneration (AMD)?1 Now, when we see a patient with neovascular AMD, a visual acuity of 20/100, a decrease in vision after 1 week, and a fundus photo like this (Figure 1) our stomachs do not necessarily have to fall right to the floor.

After performing the appropriate tests, we consider the current treatment options available to us, including laser photocoagulation, photodynamic therapy (PDT), pegaptanib sodium (Macugen; OSI/Eyetech and Pfizer, New York, NY), and ranibizumab (Lucentis; Gentenech, San Francisco), as well as the off-label choices of PDT plus intravitreal triamcinolone acetonide (Kenalog; Bristol-Myers Squibb, New York, NY), and bevacizumab (Avastin; Genentech, San Francisco).

COMPARING BENEFITS ACROSS CLINICAL TRIALS
How do we compare benefits of the various interventions based on the outcomes of varied clinical trials? Different trials have different baseline visual acuities, different treatment endpoints, and different control groups (Table 1). We also have to factor in the adverse effects associated with various treatments. Some of the adverse effects associated with AMD treatments include endophthalmitis, stroke, back pain, phototoxicity, and glaucoma. To compare treatments while taking these factors into consideration, I suggest that we use a value-based approach. We first look at value from the perspective of a change in the quality of life (QOL), and then a gain in the length of life (LOL). We measure these two factors in terms of quality-adjusted life years (QALYs), and we also take into account costs to determine cost-utility.

Let me be very clear that when we compare treatments, we first look at value. When we talk about value, we are not talking about dollars, we are talking about increased QOL and LOL. In particular, with regard to AMD, we are talking about QOL.

START WITH THE EVIDENCE
This formula is not smoke and mirrors—it is good economic analyses. We start out with the best evidence-based clinical data that we have, so we strive to use randomized clinical trials. Our value analyses is only as good as the clinical data that we use, so we take our very best evidence-based data and we convert that data to value form. We factor in the effects of the benefits as well as the adverse events, and then we can compare the values among treatments. This allows us to compare the treatments that offer the same types of outcomes and the same kind of value—and then we can look at the actual costs.2

We start with the evidence (Table 2), and then we can determine value with a utility analysis. Utility analysis is a method to quantify the QOL associated with all health states. Interestingly, these data are unaffected by gender, ethnicity, age, education, income or nationality—which was big a surprise to us.3

We can then correlate visual outcomes with these utilities. At our center, we use a large QOL Valuation Database that consists of time trade-off methodology and more than 40,000 utility value data points. The database enables us to cross-reference with many other QOL health classifications across most health fields (Karnofsky Performance Status Scale, ECOG/WHO scale, Likert Scale, ACR, AHA Classifications, Rankin Scale, etc.), in addition to visual acuity.

We have learned that the ocular utilities correlate with the better seeing eye. Using this information, we can now look at, for instance, the typical patients with AMD (Table 3).4 We can take a particular drug, (Figure 2) and look at the clinical trial data, and the prevalence of adverse effects are seen and how often there are no adverse effects, apply the basic utility or the effect from a patient standpoint on their QOL and determine what the improvement is with this drug.

EVALUATE QOL FOR MACULAR DISEASE
In patients with macular disease, we are evaluating the QOL, less so the LOL. We take that total improvement in utility value and multiply it by the duration of how long that person will have the benefit from treatment, in years (in these models we use 12 years as the reference case for AMD) and we get a total QALY gain.

We can also talk about conferred improvement in terms of percent value gained. For example, the use of statins is associated with a 3.8% value gain, according to our data from the Center for Value-Based Medicine. We have calculated the value gain data in terms of treatments for classic subfoveal choroidal neovascularization (CNV) (Table 4), all according to Level 1 evidence from large clinical trials. The value gain associated with laser treatment, based on evidence from the Macular Photocoagulation Study (MPS),5 is 4.4%. The value gain for pegaptanib is 5.9%, based on data from VEGF Inhibition Study,6 the value gain associated with PDT, based on TAP (Treatment of Age-related Macular Degeneration with Photodynamic Therapy),7 is 8.1%, and for ranibizumab it is 17.0%, based on the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) 1-year data.8

What about for occult subfoveal CNV (Table 5)? For pegaptanib the value gain is 5.9%, for PDT it is 6.3%, for ranibizumab it is 15.7%, and for PDT plus intravitreal triamcinolone, it is 11.2%. Please note this last value gain is based on Level 4 evidence. The discounted 12-year costs of treatment based on their use in clinical trials are $15,277 for PDT; $24,313 for pegaptanib; and $52,652 for ranibizumab.9 In the United States, we talk about cost utility in terms of cost divided by QALY. An intervention is considered very cost-effective if it is <$50,000 per QALY and not cost-effective if it is >$100,000 per QALY.

COST-UTILITY FOR TREATMENTS
If we look at the discounted cost-utility, in terms of US dollars per QALY, we see that pegaptanib, in all types of AMD, is $66,978; for PDT, occult <4 disc areas (DA), $33,078; and for ranibizumab, nonclassic disease, it is $50,691 per QALY. For the sake of comparison, the cost-utility of statins is $69,300 per QALY and hypertension is $11,500, based on Center for Value-Based Medicine data.

Value-based assessments compare the value of all AMD interventions and allow us to incorporate the benefits, adverse effects and the costs into our analysis. We can maximize patient quality of care by knowing what treatment is the best to use; this is an excellent scientific basis for treatment decisions.

For AMD treatment, the clinical trial evidence today indicate ranibizumab to be a clear leader in value, improvement in quality of life assessed by visual outcome utility, and those of adverse effects. Treatment with ranibizumab is, at this point, within the that commonly accepted parameters for cost-effectiveness. We are currently using 12 injections per year in our analyses based on current evidence, however, it is more than likely that over time that number will go down.

Of course another important question is what about bevacizumab? Clinically gathered data to date show promising QOL improvements not only with bevacizumab, but with PDT plus intravitreal triamcinolone. This data is, however, very early.

1, Brown M. Cost-effectiveness of AMD Treatment. Presented at Retina 2006: Emerging New Concepts. Nov. 10-11, 2007. Las Vegas.
2. Brown M, Brown G, Sharma S. Evidence-based to value-based medicine. AMA Press. 2005.
3. Brown GC, Sharma S, Brown MM, Kistler J. Utility values and age-related macular degeneration. Arch Ophthalmol. 2000;118:47-51
4. Brown MM, Brown GC, Sharma S, et al. Health care economic analyses and value-based medicine. Surv Ophthalmol. 2003; 48:204-222.
5. Macular Photocoagulation Study Group. Visual outcome after laser photocoagulation for subfoveal neovascularization secondary to age-related macular degeneration. The influence of initial lesion size and initial visual acuity. Arch Ophthalmol. 1994;112:480-488.
6. Gragoudas ES, Adamis AP, Cunningham ET, et al for the for the VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for Neovascular Age-Related Macular Degeneration. N Engl J Med. 2004;351:2805-2816.
7. Brown GC, Brown MM, Campanella J, Beauchamp GR. The Cost-Utility of Photodynamic Therapy in Eyes With Neovascular Macular Degeneration—A Value-Based Reappraisal With 5-Year Data. Am J Ophthalmol. 2005;140: 679.e1-679.e10.
8. Brown DM, Kaiser PK, Michels M, et al for the ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1244.