When the FDA approves a biosimilar, it certifies that it is as safe and effective as the originator drug not just for the indication the biosimilar was approved for, but also for all other approved indications of the originator drug. But what about for off-label uses that the originator drug is used for?
This is a grey area where a battle is currently playing out in the field of ophthalmology. On one side is the American Academy of Ophthalmology (AAO), a group of 32,000 eye physicians and surgeons, and on the other are payers.
Through Medicare Advantage plans, payers have been encouraged to use step therapy, and when it comes to macular degeneration and other, potentially blinding diseases, many are treating bevacizumab biosimilars as equal to the bevacizumab reference product (Avastin).
The AAO contends this is putting the cart before the horse.
Based on extensive clinical studies, Avastin has been used for these eye conditions since 2005, but little-to-no clinical evidence exists for the use of bevacizumab biosimilars (Zirabev, Mvasi) for ophthalmologic treatment, and one product is produced using a substance that may be toxic to the retina, the AAO contends.
For these reasons, the group is speaking out against payer policies that treat Zirabev and Mvasi as equivalent to Avastin in ocular medicine. The Center for Biosimilars® (CfB) spoke with George Williams, MD, clinical spokesman for and past president of the AAO, about these concerns.
What follows is a partial text of Williams’ remarks. The full video interview will be published on Deep Dive, an MJH Life Sciences™ Medical World News® program, later this month.
Editor’s note: Avastin helps control abnormal blood vessel growth and is FDA-approved in oncology. In ophthalmology, Avastin is not used in its original packaging form because the dosage requirements for intravitreal injection (eye injection) are very different. For this reason, Avastin is first sent to compounding pharmacies for conversion. It is currently the most-commonly-used compounded medication in ophthalmology.
CfB: Please could you give us an overview of the issue?
Williams: We have a long clinical experience that's been validated by multiple national international clinical trials that demonstrate both the safety and efficacy of compounded Avastin in the management of a variety of ocular conditions, most prominently age-related macular degeneration, diabetic retinopathy, and retinal vascular occlusions. We have confidence based on those clinical trials and our cumulative experience in using compounded Avastin for over 15 years, across literally tens of millions of injections. Based on that experience, we know that compounded Avastin has a significant efficacy in these diseases.
George Williams, MD
We believe that the decision for therapy should be made between the patient and the physician, so we have this very unusual situation where payers are denying FDA-approved treatments and requiring patients to go through a "trial" with a non-FDA–approved [use] of a compounded FDA approved drug, and I believe that is without precedent.
CfB: Should it be concerning that the originator company, Genentech, has not sought an FDA decision for use of Avastin in ocular disease and there has been no FDA ruling on the safety and efficacy of Avastin for such conditions?
Williams: The FDA hasn’t issued a ruling because they haven't been asked. Ideally, we would like to have a specific FDA approval process [for Avastin], but that’s unlikely to happen because Genentech has a similar product [ranibizumab, Lucentis] that they developed specifically for the eye that they believe has certain advantages over the compounded use of Avastin.
CfB: Could you elaborate on your concerns about the bevacizumab biosimilars?
Williams: Neither of these products has been studied in the eye at any level. Before people tried using Avastin in the eye, there were preliminary animal studies and toxicology work to determine whether or not the eyes would tolerate it, utilizing accepted clinical models.
None of that has been done with the 2 available biosimilars. First, "do no harm." We need to establish that these drugs would be safe. Second, we have no evidence that they would be effective. There are no clinical reports that I’m aware of, and certainly no clinical trials, comparing these drugs with what we have available. I think it’s important to remember that we’re using these therapies for potentially blinding diseases, and so it’s incumbent upon physicians to be able to tell their patients that there are compelling data, both to the safety and to the efficacy of any treatment. We simply don’t have that in the biosimilar space. Additionally, we are bothered by the fact that both the companies Pfizer [Zirabev] and Amgen [Mvasi] have specifically stated that these products are not to be used in the eye.
Increasingly, we are seeing payers and health insurance companies requiring the use of Avastin prior to the use of the 2 primary branded drugs (ranibizumab; aflibercept, Eylea). Many payers are now requiring step therapy starting first with Avastin, and we have definite problems with the way that’s being implemented. We believe that the decision for therapy should be made between the patient and the physician, so we have this very unusual situation where payers are denying FDA-approved treatments and requiring patients to go through a "trial" with a non–FDA-approved [use] of a compounded FDA-approved drug, and I believe that is without precedent.
We are actively campaigning to try and limit the use of step therapy specifically in this Avastin space. We have great experience with Avastin and I use it regularly, but there are patients in whom I don’t think it’s the best choice. Patients are often surprised to learn that even though there are 2 FDA-available therapies, their insurance requires them to start with the non–FDA-approved therapy. Many times, that will be an appropriate therapy for that individual, but not always.
CfB: How long have private payers been requiring the use of or preferring the use of bevacizumab originator and biosimilars for these conditions?
Williams: Prior to 2018, Medicare Advantage plans [the private companies administering Medicare services to beneficiaries] were specifically precluded from utilizing step therapy, because that’s not something that‘s allowed in Medicare fee-for-service. The previous administration dropped that regulation and allowed Medicare Advantage plans to institute step therapy [for Part B plans], so we now have a situation where 98% or more of Medicare Advantage contracts—and there are literally hundreds of Medicare Advantage contacts throughout the country—require step therapy for diseases such as age-related macular degeneration, diabetic macular edema, and retinal vascular occlusions.
That was really the big game changer in the commercial space. Since many of these plans are actually administered by commercial insurers—the Blues, the Aetnas, the Cignas, the Humanas—they have now taken that same policy and applied it to their commercial policies. They are incorrectly assuming that biosimilars of bevacizumab are going to behave the same as Avastin in the eye, and they’re making that assumption with absolutely no data.
CfB: So, given these payer policies, have eye doctors been treating patients for eye conditions with bevacizumab biosimilars?
Williams: I am not aware of any patients who have been treated with biosimilars.
CfB: Biosimilars are FDA approved as having "no clinically meaningful differences" from originator drugs, but should this apply only to indications for which biosimilars and originators have been FDA approved?
George Williams, MD
We want the public to realize what’s happening here. I would love to sit down with anyone from any health care payer and have a nice discussion about this. So far, our requests for discussions have [mostly] been denied.
Williams: I would argue my reading of the regulation is that extrapolation applies only to approved indications, and that’s certainly the position we’re taking.
CfB: What kind of reaction are you getting from payers when you raise these concerns?
Williams: It’s been disappointing, and that’s why we’ve gone public. We want the public to realize what’s happening here. I would love to sit down with anyone from any health care payer and have a nice discussion about this. So far, our requests for discussions have [mostly] been denied.
CfB: How about your appeals to CMS and HHS?
Williams: We are in the process of continuing to speak with those folks, and in fact we have meetings scheduled in the near future with senior CMS staff.
CfB: What’s the concern with edetate disodium dihydrate (EDTA), which is used as a stabilizer in the preparation of Pfizer’s Zirabev biosimilar?
Williams: We know that EDTA is toxic to ocular cells, specifically the corneal endothelium. Biologics are very big, complex molecules. They have to be stabilized. I‘m not an expert in that type of chemistry, but I do know that we have compelling data that EDTA is toxic to the eye. Now, perhaps it would be at enough of a diluted level that it wouldn’t have an effect, but don’t you think that should be studied before we are required to put that in somebody’s eye?
CfB: For bevacizumab biosimilars, do you know of studies in progress that might provide the clinical evidence you’re looking for?
Williams: I do not know of any active studies right now. We know that there are biosimilar candidates for ranibizumab and aflibercept, and we’re looking forward to seeing what those data show us, but I would argue that those biosimilar developers are doing it the right way. They’re doing the right studies. They’re going to have the toxicology; there’s going to be a comparison between the standard-of-care therapies. We welcome that type of data.
CfB: How would you assess the level of confidence in biosimilars among eye specialists at this stage—confidence and understanding of them?
Williams: I think we’re all learning about biosimilars, aren’t we? The position of the American Academy of Ophthalmology is, and always has been, that we support whatever technology is best for our patients, and if this technology can provide safety and efficacy at a significantly lower price—absolutely. We’re all in. We want to hear about it.