Biosimilars to AMD Drugs: The Obstacles In Their Way

Off-label Avastin, Eylea and Lucentis are the primary treatments for neovascular age-related macular degeneration (AMD), a leading cause of blindness. A recent review article looked at the impediments to the biosimilars for these drugs Ophthalmologists are wary about using biosimilars to Avastin (which was approved as a cancer drug) for AMD. Biosimilars to Eylea and Lucentis are not on the market yet. Manufacturers’ rebates and Medicare Part B “buy and bill” policies could make it difficult for them to compete against their brand-name “originator” products.

Substantial reforms are needed to encourage the use of biosimilars in the treatment neovascular age-related macular degeneration (AMD) and realize the savings that they are supposed to yield, the authors of a recent review argue.

Victor Van de Wiele, LL.B., LL.M., a research coordinator at the Program on Regulation, Therapeutics, and the Law at Brigham and Women’s Hospital in Boston, and his colleagues recommend consolidating payment codes, setting standard physician reimbursement rates and allowing Medicare to negotiate prices for ophthalmology drugs. Their review was published in the Journal of Law and the Biosciences.

Currently, the primary treatments for neovascular AMD are Avastin (bevacizumab), Lucentis (ranibizumab) and Eylea (aflibercept). The three drugs are vascular endothelial growth factor inhibitors that work to restore visual acuity in people with AMD by reversing out-of-control blood vessel formation in the eye. Avastin, Lucentis and Eylea are administered by intravitreal injection — a shot into the vitreous fluid inside the eyeball.

Avastin, the least costly of three, is a cancer drug that is used off-label for AMD. Off label means using a drug for a purpose that hasn’t been approved by the FDA for this purpose.

Ophthalmologists, contending that clinical evidence is insufficient, tend not to use the two currently available biosimilar versions of Avastin for AMD, and biosimilars of Lucentis and Eylea aren’t available yet in the United States. But numerous biosimilars of the three agents are under development. If they were to get on the market, they could help drive down the price of AMD treatment.

As things stand now, there are major potential savings from using off-label Avastin. In 2019, the average sales price for off-label Avastin for AMD was $70 per dose, according to Van de Wiele and his co-authors, compared with a price of $1,877 per dose for Eylea and $1,717 per dose of Lucenits. Despite its much lower price, Avastin for AMD accounted for less than half (46%) of injections from 2013 to 2016, according to data from American Academy of Ophthalmology mentioned in the review article. Eylea accounted for about a third (32%) of the injections during that period, and Lucentis for about a fifth.

Off-label Avastin does, though, have some disadvantages. When it is used as an AMD treatment, Avastin must be sent to sterile compounding pharmacies to create the right dose. The possibility of impurities and subsequent infections resulting from this process contributes to ophthalmologists’ reluctance to use it. It also has to be injected more often than the other two drugs. Injections of Eylea are given once every three months compared with monthly injections of Lucentis. Off-label Avastin is injected as often as twice a month.

Still, studies in the European Union and United States have shown there are no clinically relevant differences between off-label Avastin and Lucentis in visual acuity gains for AMD, wrote Van de Wiele and his co-authors. And Genentech, the originator of Avastin, has chosen not to seek an ophthalmologic indication for the drug and instead developed and marketed Lucentis instead. Eylea got on the market in the United States after Lucentis. Even so, sales of Eylea soared past sales of Lucentis, reaching $4.6 billion in 2019 compared with $1.8 billion for Lucentis. The less frequent injection may be a factor.

Van de Wiele and his co-authors discuss Medicare Part B “buy and bill” policy as another factor that be limiting the use of off-label Avastin. Under buy-and-bill, when physicians use administer drug, they get reimbursed for that drug at its average sales price plus a percentage of that average sales price. (Nominally, that percentage is 6% although it has been reduced for budget reasons to lower percentage). Bumping up reimbursement based on the average sales prices incentivizes physicians to prescribe more expensive drugs. In the case of the AMD agents, that means Eylea and Lucentis rather than off-label Avastin. “Moderately increasing clinician reimbursement for bevacizumab (Avastin) administration could incentivize prescription rates,” wrote Van de Wiele and his co-authors.

Insufficient competition among drug brands and the fact that Medicare doesn’t negotiate drug prices also contribute to high costs and prices, the review article argues. Rebates paid by manufacturers to payers often incentivize those payers to continue giving preference on their formularies to agents with higher nominal prices. If manufacturers were to retaliate by canceling their rebates, this would force payers to move more patients to prescriptions for biosimilars, but that switch is not easily made. Moreover, write Van de Wiele and his co-authors, it would take a major shift to biosimilars to outweigh the financial incentives that rebates have for payers. “Even if a biosimilar provides a major price discount compared with the brand-name’s post-rebate price, the payer may have to successfully convert most of its patients to the biosimilar treatment to save on overall spending,” they wrote.

This pressure exerted by manufacturers appears to extend to other drugs. The authors cited a recent study of 535 health plan decisions by the 17 largest US commercial health plans. In this, just 14% gave the biosimilar preferred coverage over the reference product.

The authors recommended raising the off-label Avastin reimbursement rate to provide a stronger incentive for physicians to use it, and they advised that the add-on buy-and-bill payment for drugs be fixed rather than based on the cost of the underlying medicine. They also suggested consolidating Medicare payment codes, which are different for biosimilars than for originator products, even for a single drug type. “A single active ingredient-specific payment code would reduce manufacturers’ incentives to price drugs higher than the lowest-cost biologic,” they wrote.