• Clinical Update

    Step Therapy: Clinicians’ Concerns and Challenges

    By Mike Mott, Contributing Writer, interviewing Lisa S. Schocket, MD, Paul Sternberg Jr., MD, and John T. Thompson, MD

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    In 2019, when CMS allowed Medi­care Advantage plans to implement step therapy for Part B drugs, some plans started to require that patients be treated with bevacizumab before retina specialists could try the more expensive anti-VEGF drugs, ranibizumab and aflibercept. Since that time, much has happened, including bevacizumab supply chain problems, use (and then retraction of use) of less expensive bio­similars, and more. Through it all, the Academy has been lobbying aggressively to roll back the step therapy require­ment, which it considers to be subopti­mal clinical care. (See “D.C. Fighting to Reverse Step Therapy.”)

    Yet the fact remains that until CMS disallows step therapy, ophthalmologists must continue to provide the best pos­sible care for their patients under the constraints of the policy. Although the policy may save costs, it poses signifi­cant concerns and challenges for retina specialists.

    What Is Step Therapy?

    With step therapy, or “fail first” therapy, health plans require that patients try and fail the insurers’ preferred med­ications before another therapy will be covered. For retina specialists, it’s important to note that step therapy is most relevant for the use of anti-VEGF agents in treating proliferative diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration (AMD), said Lisa S. Schock­et, MD, at the University of Maryland in Baltimore.1

    What’s the policy’s ra­tionale? “The presumption with step therapy is that there’s largely a compara­bility of a less expensive anti-VEGF with the more expensive one and that [by adhering to step therapy] you’re not compromising the patient’s care … all while achieving significant cost savings,” said Paul Sternberg Jr., MD, at the Vanderbilt Eye Institute in Nashville, Tennessee.

    Policy on the ground. But step therapy does raise a host of issues for physicians in terms of how to navigate the system, educate patients, and determine the best course of disease management, said John T. Thompson, MD, at Retina Specialists in Baltimore.

    Wet AMD
    WET AMD. There are several caveats when using step therapy guidelines for treatment of retina patients, such as those with wet age-related macular degeneration, said Dr. Thompson.

    What Step Therapy Does Well

    The primary reason for step therapy is the potential for significant cost savings, said Dr. Sternberg. Working primarily with wet AMD patients, Dr. Sternberg’s team at Vanderbilt unknow­ingly introduced step therapy before it became required by any of the plans he works with. In fact, his department was able to demonstrate considerable savings to some local payers, including Medicare Advantage. These payers responded, not with a mandated step therapy, but with a capitated rate that incentivized step therapy.

    “Ultimately, we weren’t motivated to save us money,” said Dr. Sternberg. “We were motivated to save our patients money—especially a co-pay of several hundred dollars if they didn’t have secondary insurance to cover the more expensive alternative.”

    He also felt an obligation to the health care system because many, if not most, of his AMD patients do just as well with the less expensive bevacizumab as their primary starting therapeutic. “Hundreds of millions of dollars are being spent each year on more expensive anti-VEGF drugs for treating AMD when there are well-conducted randomized clinical trials—CATT and IVAN—showing comparability in efficacy and safety in both bevacizumab and ranibizumab,” he said.2,3

    Clinicians’ Concerns

    The cost savings are laudable, said Dr. Thompson, and it’s true that many pa­tients do just as well with bevacizumab for all of the three major indications—choroidal neovascularization (CNV) from macular degeneration, diabetic macular edema (DME), and venous occlusive disease. However, he outlined several caveats to be aware of when following the step therapy guidelines.

    Patient intolerance. Some patients can have an immune reaction against certain anti-VEGF medication, said Dr. Thompson. This was brought to light recently with the use of brolucizumab. “Its efficacy and duration looked particularly good alongside the other three anti-VEGF medications, but there was a rare immune reaction that caused vasculitis in a very small percentage of patients.” Reports of this complication triggered an extensive safety review by the drug company, he said. “That’s one of the reasons why retina specialists are a bit skittish about switching drugs around.”

    Appropriateness of treatment. It’s also known that patients with certain diseases tend to do better with the more expensive medications, said Dr. Schocket. For example, the randomized DRCR.net study Protocol T demon­strated that aflibercept is superior in patients with DME whose visual acuity is 20/50 or worse.1 As such, she added, it is inappropriate to mandate step therapy in patients with poorer vision from DME because they may not im­prove as much with bevacizumab.

    There are also subtypes of CNV, such as polypoidal choroidal vasculop­athy, in which patients seem to be more resistant to anti-VEGF drugs, said Dr. Thompson. In these cases, retina spe­cialists tend to use the FDA-approved drugs rather than bevacizumab.

    In addition, said Dr. Schocket, some patients with persistent fluid from AMD simply do not respond to bevacizumab. “In these cases, we would need to switch them from bevacizumab to aflibercept,” she said. “And the question is, if you have a mandate for step ther­apy, where’s the turning point? What if you can tell the patient’s not getting better—should you still be required to first follow through with all three [bevacizumab] injections because of protocol?”

    Comorbidity: stroke. Patients with a history of stroke are also theoretically at an increased risk with bevacizumab, said Dr. Schocket. And getting around step therapy in these cases can be chal­lenging. “One of my diabetic patients in her 40s has a clotting disorder, anti-phospholipid antibody syndrome, the result of which has been dozens of strokes throughout her life,” she said. “The patient does require intravitreal injections for diabetic macular edema, but I certainly wouldn’t want to increase her stroke risk because of a require­ment to fail first with bevacizumab.”

    Dr. Thompson noted that stroke is one of the complications of higher-dose anti-VEGF drugs in patients with cancer. There’s evidence, he said, that ranibizumab is absorbed less into the systemic circulation than are other anti-VEGF medications. “So retina spe­cialists will tend to favor ranibizumab for people with histories of cerebrovas­cular accidents.”

    Delays in obtaining compounded bevacizumab. Dr. Sternberg’s big­gest concern with step therapy is the challenge that some ophthalmologists have in accessing compounded beva­cizumab. Although obtaining the drug might not be an issue at a large health care system such as Vanderbilt, where compounding is done internally, he said, “it’s a very different situation for private practices or community-based practices that have less access.”

    And when access is a problem, it’s a big problem, said Dr. Thompson. “Whether it be state regulations, com­pounding contaminations, or licensing issues, the use of outsourcing facilities to produce bevacizumab has resulted in intermittent shortages,” he said. For example, if one particularly large out­sourcing facility is cited by the FDA for contamination, the result is that many private practices have to scramble to find other sources—sources that aren’t able to handle that giant uptick in demand all at once. “At that point,” said Dr. Thompson, “how can you abide by step therapy?”

    A Wrench in the Works

    In the near future, Outlook Therapeutics is hoping to launch the first FDA-approved formulation of bevacizumab (bevacizumab-vikg) for use in retinal indications. It has completed phase 3 trials and could create a conundrum for step therapy, said Dr. Thompson.

    No one is exactly sure how this new bevacizumab for ophthalmic use will be priced, he said, but the Drug Quality and Security Act specifically prohibits the repackaging of a drug when there is an FDA-approved equivalent. “So if bevacizumab-vikg is indeed approved, we could have a situation where it’s no longer possible to use repackaged bevacizumab,” said Dr. Thompson. “That’s an interesting wrinkle, and it will be important to see how the FDA handles this because their rules are very clear.”

    Another biosimilar. In addition, the Lucentis biosimilar Byooviz (ranibizumab-nuna, Samsung Bioepis) is expected to come to market soon and may appear in some step therapy programs. 

    Considerations for Your Practice

    Your day to day. How step therapy affects your day-to-day practice can largely depend on what type of practice you are operating in, said Dr. Sternberg. He said that in the academic setting at Vanderbilt, step therapy has simplified daily life. “When patients come in with wet AMD, we already have a treatment plan in place. This helps our staff know exactly what to have on hand and exactly what our treatment protocols will be.”

    At Dr. Thompson’s three-physician private practice, however, step therapy has created a number of headaches. Many of his patients have different in­surance plans, and many of these plans have different subclasses of coverage, each with different sets of rules that may or may not pertain to step therapy. “We spend too many resources figur­ing out when we can or cannot start a patient on a particular anti-VEGF drug,” he said. “Yes, we can petition the insurance company for our preference, but that results in additional delays in treatment because the insurance company doesn’t give you immediate approval in most situations.”

    The physician/patient relation­ship. Step therapy’s layers of rules can interfere with the physician’s treatment of the patient, as well as the patient’s choice, said Dr. Thompson. “When I see a patient with new-onset CNV, for example, I tell them about all three drugs and present a balanced view of each,” he said. “At least half of these patients feel strongly that they want an FDA-approved medication for their oc­ular problem. They don’t want to have to fail another therapy first, especially if they’re losing vision.”

    Dr. Sternberg has had similar experi­ences with new patients requesting certain treatments that they see offered on television or online. And if they feel strongly about it after discussion, he accedes to their wishes. “The patient is the boss—I’m not,” he said. “We always try do what is in their best interests—clinically and financially.”

    Regardless of step therapy protocols, there is no circumstance in which Dr. Sternberg forces an existing patient to switch to another medication. “That’s not good medicine,” he said. “I’m more than happy to fight the insurance company and have a peer-to-peer discussion with their medical director if they’re trying to push me to move a patient off a medication that’s giving them a good result.”

    And that is what’s at the heart of the step therapy dilemma, said Dr. Schocket. “Practicing medicine is an art and not a cookbook or an algorithm prescribed by a third party. I shouldn’t be making a decision based on a medication being less expensive, and I shouldn’t be making a decision based on a medication being more expensive. I should be making a decision based on what’s best for the patient.”

    D.C. Fighting to Reverse Step Therapy

    The Academy has urged CMS to “move swiftly to reinstate the step therapy prohibition in Medicare Advantage plans for Part B drugs.” Although the agency seemed open to stricter guardrails in recent interactions, the Acad­emy, as part of a broad effort, is leading another push for a full ban on the cost-cutting practice.

    Nearly 60 patient and provider groups, including the American Medical Association and Medical Group Management Association, joined the call for action in a November 2021 Academy-led letter to CMS. The letter reiterated that step therapy in Medicare Advantage plans has caused “clear instances of patient harm [including] patients becoming legally blind or experiencing long-term hospitalizations, infections, increased disease activity, and disabil­ity.” The letter reinforces the message from an Academy-led meeting with CMS in September, in which the Academy convened several patient and pro­vider groups to share how step therapy harms patients. CMS requested recent examples after dozens of societies signed an Academy-led letter last April opposing the practice. 

    Health equity. George A. Williams, MD, Academy senior secretary for advocacy, said it’s also an issue of health equity. Medicare Advantage plans disproportionately serve patients from minority groups, compared to Medi­care fee-for-service. As long as Medicare Advantage plans continue to allow step therapy, patients treated under these private for-profit plans don’t get the same health care as those in fee-for-service. That practice violates the law.

    “If you or your mother came to me and you had already lost vision in one eye, and you had advanced disease in your other eye requiring immediate treatment, I think you would want all your treatment options available. I know I would,” Dr. Williams said. Medicare Advantage patients don’t have all those options, and profit-motivated insurers that require step therapy continue to interfere in the physician-patient relationship, including clinical decision-making.

    Biosimilars. In early November, just weeks after the Academy and the American Society of Retina Specialists told CMS that Medicare Advantage plans are putting profits over patients, the agency put some restrictions in place to keep ophthalmic patients safe from “potentially dangerous” biosimi­lar drugs.

    Agreeing with Academy concerns, CMS stopped its insurers from requiring off-label biosimilars Zirabev and Mvasi as substitutes for Avastin in treating eye conditions in their step therapy programs. In a letter to Medicare Advan­tage plans, CMS said that “Part B step therapy programs may include a drug supported only by an off-label indication if the off-label indication is support­ed by widely used treatment guidelines or clinical literature that CMS consid­ers represent best practices.”

    Although CMS took this positive action, it reiterated that biosimilars that are FDA approved for ophthalmic use can be used in step therapy programs in Medicare Advantage. (See “A Wrench in the Works.”) The Academy strongly believes that step therapy should not be allowed at all. CMS prohibited step therapy (for Part B drugs) from 2012 to 2018 but removed the ban in 2019. To reimpose a step-therapy ban, CMS would likely have to include the change in a formal rule.

    If you observe adverse reactions or patient harm because of a step therapy requirement, email healthpolicy@aao.org to help guide the Academy’s on-going work with CMS.

    This D.C. article originally appeared on aao.org/advocacy/eye-on-advocacy on Dec. 2, 2021.

    ___________________________

    1 Wells JA et al., for the Diabetic Retinopathy Clinical Research Network. N Engl J Med. 2015;372(13):1193-1203.

    2 Martin DM et al., for the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group. Ophthalmology. 2012;119(7):1388-1398.

    3 Chakravarthy U. Lancet. 2013;382(9900):1258-1267.

    ___________________________

    Dr. Schocket is associate professor, vice chair for clinical affairs, and chief of the retina division at the University of Maryland, Department of Ophthalmology, in Baltimore. Relevant financial disclosures: DRCR.net: C.

    Dr. Sternberg is G.W. Hale Professor and chair­man at the Vanderbilt Eye Institute, chief medical officer at the Vanderbilt Medical Group, and associate dean for clinical affairs at the Vanderbilt School of Medicine in Nashville. Relevant finan­cial disclosures: Novartis: C; DRCR.net: C.

    Dr. Thompson is in practice with Retina Special­ists in Baltimore. He is also an assistant professor of ophthalmology at the Wilmer Institute of Johns Hopkins University and associate clinical professor of ophthalmology at the University of Maryland in Baltimore. Relevant financial disclosures: EHR Command Center: O; Genentech (Roche): S; Ocutrx Vision Technologies: O.

    For full disclosures and the disclosure key, see below.

    Full Financial Disclosures

    Dr. Schocket AstraZeneca: E; DRCR.net: C.

    Dr. Sternberg DRCR.net: C; International Retinal Research Foundation: C; Novartis: C.

    Dr. Thompson EHR Command Center: O; Genentech: S; Ocu­trx Vision Technologies: O.

    Disclosure Category

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    Description

    Consultant/Advisor C Consultant fee, paid advisory boards, or fees for attending a meeting.
    Employee E Employed by a commercial company.
    Speakers bureau L Lecture fees or honoraria, travel fees or reimbursements when speaking at the invitation of a commercial company.
    Equity owner O Equity ownership/stock options in publicly or privately traded firms, excluding mutual funds.
    Patents/Royalty P Patents and/or royalties for intellectual property.
    Grant support S Grant support or other financial support to the investigator from all sources, including research support from government agencies (e.g., NIH), foundations, device manufacturers, and/or pharmaceutical companies.