Payers defend their policies on biosimilars in ophthalmic settings following allegations from the American Academy of Ophthalmology (AAO).
It all began in 2018 when, on prompting from former President Donald Trump, CMS reversed a prior policy and allowed Medicare Advantage plans to use step therapy for Part B drugs—those that are administered in a doctor’s office. Step therapy, also known as fail-first therapy, entails payers requiring use of less costly therapeutics before patients are prescribed costlier medicines.
The policy most recently has been blamed for spurring a domino effect of policy changes among payers requiring eye physicians to prescribe the off-label use of bevacizumab for ocular conditions before significantly more costly FDA-approved products (ranibizumab, Lucentis; aflibercept, Eylea) can be used. The American Academy of Ophthalmology (AAO) has called this a de facto “drug trial” in which patients are unwitting guinea pigs who face the risk of being prescribed ineffective or unsafe drugs.
Avastin, the bevacizumab reference product, has been used by eye doctors for 15 years based on what the AAO calls sound and ample clinical evidence, but bevacizumab biosimilars (Mvasi, Zirabev) have not been subjected to the same rigorous clinical testing in ocular disorders, and they ought to be, because there may be problems associated with their use in ophthalmology, the AAO contends.
Further, many payers now treat bevacizumab biosimilars as equivalent to Avastin in their step therapy policies, and this is wrong, the AAO says.
The factors in favor of off-label Avastin use in such eye conditions as age-related macular degeneration, diabetic retinopathy, and retinal vascular occlusions are indeed clinical experience with this product and the cost advantage, according to Sonia Oskouei, vice president of Biosimilars for Cardinal Health. “It is a fraction of the cost of other current anti–vascular endothelial growth factor [VEGF] options.”
However, Avastin must be sent to compounding pharmacies to create the different dosage units required for intravitreal (in eye) injections, which Oskouei said can contribute to some providers preferring not to use it. The repackaging of bevacizumab has given rise to concerns about impurities that could be introduced during the process, sterility, and dosage consistency.
In addition, the off-label use remains a concern for some. “You typically have 2 camps of providers in this space—ones who feel comfortable using Avastin off-label and others who prefer only on-label use of FDA-approved treatment options (eg, Lucentis, Eylea),” she said.
At least one company, however, is attempting to bring a bevacizumab version to market that would be specifically indicated for ophthalmologic treatment. Outlook Therapeutics' bevacizumab candidate ONS-5010/Lytenava is undergoing evaluation in NORSE TWO, a phase 3 study (N = 228) of safety and efficacy in patients with neovascular age-related macular degeneration (wet AMD). The trial involves a comparison of ONS-5010 with ranibizumab.
Earlier this month, investigators said NORSE TWO met the primary end point for the proportion of patients who demonstrated minimum improvement in best corrected visual acuity (BCVA) after 11 months of treatment. The percentage of patients in the intent-to-treat cohort who gained at least 15 letters in BVCA was 23% with ranibizumab and 41% with ONS-5010 (P = .0052).
One patient reported ocular inflammation in 3 trials: NORSE ONE, NORSE TWO, and NORSE THREE. In NORSE TWO, there was just 1 serious adverse event (AE) associated with the trial drug, and this was successfully resolved. “No unanticipated safety signals were detected,” the authors wrote.
The most common AE was intravitreal injection–related hemorrhage in tissues on the surface of the eye, and these were successfully resolved. “The ONS-5010 safety database continues to be consistent with previously published results for bevacizumab, such as in the 2011 CATT clinical trial,” authors of the study wrote.
Outlook plans to file a biologics license application (BLA) with the FDA under the Public Health Service Act 351(a) regulatory pathway for biologics and innovator biologics in the first quarter of 2022. “If the BLA is approved, it is expected to result in 12 years of marketing exclusivity for ONS-5010 as the first and only ophthalmic formulation of bevacizumab approved by the FDA to treat wet AMD,” according to an Outlook statement. However, it would not be considered a biosimilar.
Off-label bevacizumab repackaged at compounding pharmacies is estimated by the National Eye Institute to account for roughly 50% of all wet AMD prescriptions in the United States.
The AAO has alleged that multiple payers are now recommending bevacizumab biosimilars as alternatives to Avastin for the treatment of ophthalmologic conditions.
In a statement, Horizon Blue Cross Blue Shield of New Jersey disputed its inclusion on the list. The payer said it does not require biosimilar use in ophthalmic settings and has been collaborative with physicians, contrary to the AAO's position.
“Horizon works closely with New Jersey’s ophthalmologists and has formed collaborative relationships with many of the leading retina practices in New Jersey to jointly develop more effective protocols to treat wet AMD and diabetic retinopathy," Horizon told The Center for Biosimilars®. "These cooperative relationships are helping ophthalmologists deliver better quality care and improve the cost and experience for our members. Horizon’s policy concerning the use of an approved biosimilar for Avastin applies only to its use for patients who have certain cancers and who are new to treatment. As it relates to ophthalmic use for treatment of eye disease, the academy got it wrong—there is no policy requiring the use of a biosimilar for Avastin for any Horizon member.”
Aetna told The Center for Biosimilars® it considers bevacizumab biosimilars to be viable treatments for multiple ophthalmic conditions and views more costly treatments, such as Eylea and Lucentis, to be “not medically necessary unless patients have a contraindication, intolerance, or ineffective response to the available equivalent alternative VEGF inhibitors: Avastin (or its biosimilars, Mvasi or Zirabev).”
Regardless of what payers are recommending, there are risks associated with use of compounded bevacizumab for ophthalmic conditions. Pfizer has published study data revealing somewhat higher risks for use of intravitreal bevacizumab vs ranibizumab.
The Pfizer product monograph, updated June 17, 2021, indicates that Zirabev is not authorized for use in eye disorders and noted an observational database study of Avastin vs Lucentis that revealed an increased risk of intraocular inflammation for patients with wet AMD who received compounded bevacizumab vs authorized ranibizumab (HR, 1.82; 99% CI, 1.20-2.76) as well as a higher risk for cataract surgery (HR, 1.11; 99% CI, 1.01-1.23). The monograph also noted findings (from the same study) for increased risk of hemorrhagic stroke for patients who received intravitreal bevacizumab (HR, 1.57; 99% CI, 1.04-2.37).
To read more about this issue, click here for an interview with George Williams, MD, clinical spokesperson and past president of the AAO.