Gary H. Lyman, MD, MPH, discusses the current parameters used to develop a biosimilar, the impact these products have had in the treatment and supportive care settings, and ongoing initiatives to address remaining challenges.
Gary H. Lyman, MD, MPH
The path toward regulatory approval for a biosimilar differs from that of a biologic, but educating the medical community on that path and making data accessible to the community are important measures to take to facilitate their adoption in practice, explained Gary H. Lyman, MD, MPH.
“Biosimilars are approved by a different process. We're used to seeing these large phase III trials demonstrating efficacy and safety, and we're not seeing that with biosimilars,” explained Lyman, senior lead of Health Care Quality and Policy at the Hutchinson Institute for Cancer Outcomes Research. “As such, there's a skepticism. Many don't want to be the first in their group to use a new agent when they've gotten very comfortable with the originator biologics. We need more education and transparency.”
In an interview with OncLive, Lyman, who is also a member of the Cancer Prevention Program in the Public Health Services Division, and a member in the Clinical Research Division at Fred Hutchinson Cancer Research Center, discussed the current parameters used to develop a biosimilar, the impact these products have had in the treatment and supportive care settings, and ongoing initiatives to address remaining challenges.
OncLive: Could you discuss the path toward regulatory approval for biosimilars?
Lyman: A biosimilar is approved by the FDA based on a different mechanism than the originator product. The originator biologics have to show preclinical and randomized controlled clinical trial data demonstrating efficacy and safety; that's an extremely costly process.
A few years ago, the FDA put a more expedited process in place for the development of biosimilars. It put much more emphasis on the molecular characteristics and structure of the [drug], as well as its immunogenicity and biologic behavior in the patient. Pharmacokinetics and pharmacodynamics are also evaluated to see whether antibodies form. All of these aspects have to be highly similar to the original product [in order to receive regulatory approval]. We can do that without having to conduct multimillion-dollar randomized phase III trials. Some of the biosimilars have [gone through] that [process] anyway, but the idea is to reduce the cost of drug development, increase competition in the marketplace, and reduce pricing.
Ultimately, we’re focusing on the preclinical work and safety profile of biosimilars. We’re [operating under the hypothesis] that it's virtually the same molecule with the same mechanism of action; it doesn't have any [additional] safety concerns and is able to function essentially the same as the original biologic product.
Could you discuss physician comfort regarding the use of biosimilars?
There is a huge need for more educational activities. We're continuing to pursue that in the medical literature and at medical meetings. Education is imperative. I've been doing these educational programs for the last 3 to 3.5 years. At each one, I see a more educated audience. When I get questions about the use of biosimilars, I can tell they're being asked by those who are more familiar with the concepts. They’re asking more nuanced questions. We’re seeing an impact [with these programs]. We have also gotten the National Comprehensive Cancer Network (NCCN), ASCO, and ASH to do educational programs on biosimilars. However, it's like anything that's new; it takes time. Hematologists and oncologists tend to be skeptical of new things.
Over the next 3 to 5 years, I'm anticipating that biosimilars will have a large-scale impact on healthcare costs. However, we need to continue to be vigilant [after they’re approved for use]. The FDA has put post-marketing surveillance in place to track any rare or delayed adverse events (AEs) that weren’t [observed] when the drug was approved. We need to stay vigilant—not only with the biosimilars, but with all drugs—and report any unexpected or new AEs to the FDA. With all of that in place, we have an additional way of reigning in growing healthcare costs in the United States, which will help improve access to these valuable drugs.
Could you discuss the use of the epoetin alfa (Epogen; Procrit) biosimilar epoetin alfa-epbx (Retacrit) in the treatment of patients with chemotherapy-induced anemia?
Epoetin alfa-epbx is the first and only biosimilar in the United States [for epoetin alfa]. The product was approved nearly 2 years ago, and its approval was largely based on the preclinical work as well as the pharmacokinetic and pharmacodynamic data in healthy volunteers. Investigators ran 2 large phase III trials in patients with chronic kidney disease—not in patients with cancer. The only data we have with epoetin alfa-epbx in patients with cancer is observational.
It turns out that epoetin zeta is approved in Europe. It's essentially the same molecule [as epoetin alfa-epbx], but it has been evaluated in large phase III trials in patients with cancer. Trial data show noninferiority to the originator epoetin alfa biologic and no safety or immunogenicity concerns. The FDA was going to accept the data from the same drug in Europe, plus a demonstration of safety and efficacy in patients with advanced kidney failure in the United States, and [extrapolate that] to patients with chemotherapy-induced anemia.
That indication is not used nearly as frequently used as it had been in the past. The use of these agents as opposed to transfusions has fallen off in the United States. However, having these biosimilars could lower the prices of these drugs. Hopefully, that will work to the advantage of patients in the overall healthcare system.
Could you discuss the potential cost reduction of biosimilars?
People want to know whether these biosimilars will reduce the cost of healthcare. Data from Europe, a country who is about 10 years ahead of us, suggest perhaps a 20% to 30% reduction in pricing when competitive biosimilars are available in the marketplace. It’s too early to know whether we'll see that type of impact in the United States. If we do, a 20% to 30% reduction in cost in a multibillion-dollar industry is a large amount of money. However, we do not know whether that will happen.
Two studies published in JAMA and JAMA Oncology this past year looked at the early utilization of the hematopoietic growth factor biosimilars and suggested about a 10% reduction in price thus far. As we get multiple competitors in a class of agents, we should see a greater impact on price.
How has the approval of PF-05280586 (rituximab-pvvr; Ruxience), a biosimilar for rituximab (Rituxan), affected the use of rituximab in the treatment of patients with non-Hodgkin lymphoma?
That has yet to be seen. It has been approved in Europe for a longer period of time, so we have some experience [with its use] there. At the 2018 ASCO Annual Meeting, a European research group presented data on the early utilization of the rituximab [biosimilar] in patients with lymphoma. The investigators reported that the utilization of [the biosimilar] was more favorable in patients with less curable forms of lymphoma. Oncologists were willing to use these new agents when the goal wasn't necessarily long-term survival or cure. They reserved the originator product for patients with diffuse large B-cell lymphoma, for example, where the goal of treatment is usually cure. There is some discrimination when it comes to [the use biosimilars], which is perhaps understandable.
In this scenario, we’re not talking about supportive care. This is the mainstay of treatment for these patients. If you're treating for curative intent, do you really want to take any chances if you haven't used the drug before? You’re more likely to use it either in solid tumors in patients with metastatic disease, or in low-grade lymphoma, where your goal is extending life but not necessarily cure. Those data are from Europe, but my guess is that we're going to see a similar kind of gradual uptake in the United States. Over time, that may lead to broad utilization across the various lymphoma subtypes.
Are biosimilars for granulocyte colony-stimulating factor (G-CSF) impacting the use of standard neutropenia prophylaxis?
Yes, although it’s still early. The first biosimilar for G-CSF was approved in recent years. We now have another biosimilar for the originator tbo-filgrastim (Granix) and 2 biosimilars for filgrastim (Neupogen). A couple months ago, the long-acting filgrastim, pegfilgrastim (Neulasta) was approved in the United States. In many institutions, it's not available yet. The only data we have is with the originator product and filgrastim-sndz (Zarxio), which was approved a couple of years ago. Those data suggest a rapid uptake of the biosimilar accounting for up to two-thirds of the utilization of G-CSF [products] in the United States.
The impact on cost is more challenging [to discern] as these are very preliminary data. However, the data suggest around a 10% to 12% decrease in price over the first year or two of the use of the [G-CSF] biosimilars. As in Europe, over time and with more competition, there will be further reductions in cost, perhaps to the extent of 20% to 30%.
What are the main challenges regarding the use of biosimilars?
I see two main challenges. The first is for the provider, and, to some extent, the patient: skepticism. ASCO [has done a lot of work to address that]. I had an opportunity to work with them, and we published educational guidance in the Journal of Clinical Oncology 2 years ago. We're putting on educational programs about [biosimilars] at the ASCO Annual Meetings, the ASH Annual Meetings, and the NCCN Annual Meetings. [These programs are designed to educate the community] on what a biosimilar is, what the [development] process looks like and how it's different, and why we should rely on [these products].
There's also skepticism about how much of an impact these agents will have on the rising cost of cancer care in the United States. [Biosimilars] are not the whole solution, but they’re a piece of the solution. We need changes to be made at the policy level to reign in healthcare costs. At the policy level, among professional organizations like NCCN, there's this hesitancy because they want to see the data; they want to see the evidence. Sometimes that evidence is made public. If there's an Oncology Drug Advisory Committee meeting, all of that [information is] transparent and made available. However, the more recent biosimilars have been approved without public disclosure. In these cases, it's really critical that the companies publish their preclinical and clinical data in the peer-reviewed literature.
We had an instance [where the company didn’t disclose their data]. That complicated the NCCN guideline update for the hematopoietic growth factor biosimilars because we didn’t have any public display of evidence. As such, as a guideline panel, we couldn't really recommend the use of that agent. Eventually the company forwarded the information to us directly. Regulatory approval is the first step. However, equally important is that the evidence the FDA reviewed for approval of these agents is made available to the medical community and professional organizations such as the NCCN, especially if they're going to be expected to endorse and recommend the use of these agents.