Please read CASE 8 then answer the 7 questions at the end.

Comparative Effectiveness: Avastin Versus Lucentis

Imagine that you are going to clean the windows of your home and you discover that your spray bottle of commercial glass cleaner is empty. You are about to go to the store to buy more when your neighbor points out that the main ingredient is vinegar and that it is far, far cheaper to buy vinegar and dilute it with water. You try your new homemade cleaner and find that it seems to work just as well as what you were using before. What would you do in the future?

This scenario resembles that faced by many people with age-related macular degeneration (AMD), as well as their providers and insurers, but with one wrinkle: What if you discovered that your homemade cleaner could be more toxic than the commercial product if mixed incorrectly?

Evidence-Based Medicine AMD is a debilitating eye disease that is the leading cause of blindness for older Americans, with 200,000 new cases diagnosed annually. In the more severe "wet" or "exudative" form (wAMD), blood and other fluids leak from abnormal blood vessels into the macula, a yellow oval at the center of the retina. A common, effective treatment for wAMD is injections with ranibizumab, a drug that Genentech, a division of Roche, sells under the trade name Lucentis. Chemically, Lucentis is almost identical to bevacizumab, a cancer drug that Genentech calls Avastin. The same active component found in both drugs inhibits the function of vascular endothelial growth factor (VEGF), which stimulates the growth of blood vessels. For cancer patients, it means less blood flow to support cancer growth; for wAMD patients, it means fewer vessels to leak fluids into the macula. To turn Avastin into Lucentis, Genentech made the molecule smaller; in theory, the molecular fragment would be better able to penetrate the macula than the full-sized molecule. Genentech also raised the price dramatically. The initial cost to Medicare of a Lucentis injection was about $2000. Injections can be given on an as-needed basis or on a monthly schedule. With a monthly schedule, the annual cost per patient per year came to $24,000. Genentech maintains that it specifically formulated and tested Lucentis for administration in the eye, and that the higher cost is necessary to recover the company's investment in research and development. While waiting for the FDA to approve Lucentis, doctors discovered they could take Avastin, have compounding pharmacists repackage it into smaller vials, and then treat their patients for around $50 an injection. Not surprisingly, Avastin is used in more than half the injections to treat wAMD in the United States, and ophthalmologists do not observe any difference in patient outcomes. This has huge financial implications for Medicare, which funds care for 95% of patients with wAMD. If all Medicare patients were treated with Lucentis, the annual cost would be $1-$3 billion, but if Avastin were used instead, the cost would be less than $1 million (Martin, Maguire,& Fine, 2010). Genentech has maintained that repackaging by compounding pharmacies raises safety concerns. It announced in October 2007 that it would no longer sell Avastin directly to compounding pharmacies. Angry doctors and professional associations argued the move would limit supply and create affordability problems for low-income patients. Genentech relented somewhat; it said it would sell directly to physicians who could then send it to compounding pharmacies if they wished. The International Academy of Compounding Pharmacists claimed Genentech was motivated by money, not reasonable safety concerns. The Lucentis versus Avastin controversy would appear to be low-hanging fruit for supporters of comparative effectiveness research (CER). If one treatment costs $600 a year and another costs $24,000, and they produce the same results, why would the CMS or any other fiscally responsible payer facilitate the use of the more expensive option? But as part of CER, someone would have to conduct a robust, head-to-head clinical trial to compare the effectiveness of the two drugs. The problem is that such trials are usually funded by manufacturers trying to prove their product's effectiveness to win FDA approval. Avastin's history provides a useful example of how clinical trials, which provide the foundation for CER and evidence-based medicine, typically occur in the United States. Avastin is approved for treating colorectal, lung, kidney, ovarian, and other metastatic cancers. It is approved for treatment of breast cancer in other countries, but not in the United States. The FDA had provisionally approved it for treating advanced breast cancer in 2008, pending further study. Genentech funded the additional studies. The findings showed the drug slowed progression of the disease, but because the studies failed to demonstrate that Avastin extended patients' lives or improved their quality of life, the FDA withdrew its approval.

Conclusion

But off-label use of Avastin to treat wAMD is a quite different and highly unusual case. Genentech has no interest in testing a cancer drug for treating wAMD when it already has an effective (and more profitable) wAMD-specific drug on the market. It does not want Avastin approved for wAMD, and the FDA had no standing to demand Genentech conduct a trial. Instead, funding for a head-to-head trial, called the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT), came from the National Eye Institute (NEI), which is part of the NIH. In 2006, NEI agreed to provide $1 million to purchase, repackage, and distribute the Avastin. Researchers initially assumed Medicare would pay for Lucentis as routine care for clinical trial participants, but it turned out that existing CMS policy did not allow for that. This changed with the adoption of new policies in 2007. This left the question of how to handle copayments for the 15% of Medicare recipients who did not have supplemental insurance and were on the hook for 20% copays. Ultimately, NEI was able to cover copays under the special circumstances provisions in the NIH guidelines. The complicated system of obtaining and billing for commercially purchased drugs, however, made it hard to devise a system for masking the identity of study participants. Resolving this issue required amendments to the Medicare Improvements for Patients and Providers Act of 2008. Martin, Maguire, and Fine (2010) noted that the ARRA provided $1.1 billion for CER, but after describing all roadblocks encountered by the CATT Research Group, they concluded that the infrastructure for implementing federally sponsored CER trials is inadequate. They called on the insurance industry to facilitate CER trials and on the government to develop a comprehensive policy to cover the drug-related costs of trials without relying on existing billing and payment mechanisms. The ACA requires most insurers to pay "comparative effectiveness research fees" to fund a new Patient-Centered Outcomes Research Institute to conduct research into comparative effectiveness of medical treatments, along with their risks and benefits. The CATT Research Group published its 2-year results in 2012 (Martin etal., 2012). The group found no statistical difference between the gains in visual acuity produced by the two drugs. There was no evidence that Genentech's "smaller molecule" approach made Lucentis a more effective treatment. The study did find that the rate of serious systemic adverse events was higher for participants treated with Avastin (40%) compared to those treated with Lucentis (32%). "The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF" (p.1388), the authors wrote. Monthly treatment had better outcomes than treatment as needed, although this must be weighed against costs and the risks associated with each injection. The authors concluded, "The choice of drug and dosing regimen for patients must balance the comparable effects on vision, the possibility of true differences in adverse events, and the 40-fold difference in cost per dose" (p.1397). The next year saw the publication of data from three randomized trials conducted independent of Genentech, all of which produced similar results despite different methodologies. IVAN, funded by the United Kingdom's National Institute for Health Research Health Technology Assessment Programme, published 2-year findings (Chakravarthy etal., 2013). The MANTA Research Group in Vienna, Austria, published 1-year results (Krebs etal., 2013). The study was funded by the Austrian Society of Ophthalmology. The GEFAL trial, which also published 1-year results, was funded by the French Health Ministry and the French Health Insurance System (Kodjikian etal., 2013). In 2016, the Netherlands weighed in with the BRAMD trial funded by the Organisation for Health Research and Development, with support from Dutch insurance companies. All found that neither drug was statistically worse than or better than the other in terms of efficacy or adverse events (Schauwvlieghe etal., 2016).

Analysis Process: Evidence-Based Medicine Concerns about possible contamination when compounding pharmacies repackage Avastin have proven to have some basis. In 2012, U.S. Representative Edward J. Markey (D-Massachusetts) introduced legislation to clarify and strengthen the FDA's role in regulating compounding pharmacies. The bill was a response to a fungal meningitis outbreak that sickened hundreds of people and killed 64. The outbreak was tied to contaminated injected steroids produced by New England Compounding Center in Markey's district. That same year, the FDA reported 12 cases of blindness in Miami following injections with bacterially contaminated Avastin from a single compounding pharmacy. Other cases were reported in Nashville, TN, and Los Angeles, CA. The American Society of Retina Specialists subsequently published a set of guidelines to help providers identify high-quality compounding pharmacies. In March 2013, the FDA announced it was recalling 40 lots of syringes containing Avastin. Five reports of eye infections had reached Clinical Specialties of Martinez, GA, a compounding pharmacy that had supplied the syringes to doctors in four states. A revised version of Markey's bill was enacted in November 2013. In late 2011, the FDA approved aflibercept, a third anti-VEGF drug using a different molecule. It is sold by Regeneron as Eylea. At $1850 per month, it costs about the same as Lucentis. In 2012, the sales of the three drugs for AMD were estimated at $1.66 billion based on Medicare claims data and distributed as follows (Whoriskey & Keating, 2013): Market (%) Total Spent on AMD Drugs (%) Avastin 55 4 Lucentis 34 73 Eylea 11 33 Data from Whoriskey, P.,& Keating, D. (2013, December 26). Medicare rules create a booming business in hospice care for people who aren't dying. The Washington Post. Retrieved from www.washingtonpost.com/business/economy /medicare-rules-create-a-booming-business-in-hospice-care-for-people-who-arent-dying/2013/12/26/4ff75bbe -68c9-11e3-ae56-22de072140a2_story.html Shaikh etal. (2015) used a retrospective chart review study to compare the costs of treatment of wAMD with the three drugs using various dosing frequencies. Eylea could be injected less frequently; still, the cost of treating one eye over 6months was estimated at $326 for Avastin, $11,400 for Lucentis, and $9,720 for Eylea. The use of more expensive drugs did not result in improved vision outcomes. The NEI conducted a 2-year study of the effectiveness of the three anti-VEGF drugs against diabetic macular edema. All three produced similar results in cases of mild vision loss. In the first year, Eylea outperformed Lucentis and Avastin in people whose vision was worse than 20/50, but the performance difference disappeared after 2years (Wells etal., 2016). Medicare allowable costs per injection in 2016 were approximately $1850 for Eylea, $1200 for Lucentis, and $60 for Avastin. The U.K. NICE has been working on guidance for the treatment of AMD, and final guidelines were expected to be issued in January 2018. The draft guidelines published in July 2017 (NICE, 2017a) state that "no clinically significant differences in effectiveness or safety between aflibercept, ranibizumab and bevacizumab have been seen in the trials considered by the guideline committees" (p.169). It also specified that bevacizumab (Avastin) is not licensed for intraocular treatment of AMD and cannot be prescribed as an alternative just because it is cheaper and more cost-effective. Clinical trials are under way for additional treatments, including one involving drops rather than injections.

Discussion Questions

1. If you were a retina specialist, how would the data in this case affect your drug procurement processes, your clinical practices, and your recommendations to patients? (You are currently allowed a 6% markup on outpatient injectable drugs.)

2. If you had AMD, what treatment choices would you make after reading this case? Would your choice depend on whether you had significant copays or other out-of-pocket expenses related to eye injections?

3. If you were a CMS official, what coverage-related policies would you promote?

4. If you were a legislator with oversight of a state Medicaid program, how would you respond to this case?

5. If you were a policy analyst, what would you recommend and to whom?

6. What policy changes might be needed to support government-sponsored initiatives related to CER and evidence-based medicine?

7. If you were an insurer, how would you respond to the recommendation that insurers facilitate CER research? What forms might such facilitation take

Reference

McLaughlin, Curtis P. & McLaughlin, Craig D. (2019). Health Policy Analysis: An

Interdisciplinary Approach. 3rd edition.