Editor’s note: Dr. Hudis hosts the ASCO in Action Podcast, which focuses on policy and practice issues affecting providers and patients. An excerpt of a recent episode is shared below; it has been edited for length and clarity. Listen to the full podcast online or through iTunes or Google Play.
I'm really delighted to have as my guest Gary H. Lyman, MD, MPH, FRCP, FASCO. He is co-director of the Hutchinson Institute for Cancer Outcomes Research at the Fred Hutchinson Cancer Research Center, and he's also a professor of medicine, public health, and pharmacy at the University of Washington School of Medicine. Dr. Lyman is the chair of ASCO's Biosimilars Work Group and the lead author of ASCO's statement on biosimilars in oncology.
CH: There's been expiration of several patents in biologic drugs recently, and there's an expectation now that we will be receiving a number of biosimilars into the marketplace. We think that cancer treatments are likely to comprise a significant number of the upcoming approvals by the U.S. Food and Drug Administration (FDA). While more biosimilars will likely be available in oncology in the next several years, their specific impact on patient care is going to depend on patient and provider acceptance of these agents. That, in turn, requires that our members and the entire community have an adequate understanding of the safety and efficacy of biosimilars. So, to kick off our discussion today, can you describe why ASCO decided that this was the moment to issue a formal statement on biosimilars in oncology?
GL: The ASCO statement and the work of the panel that was commissioned by ASCO to address this was largely focused on the education of our colleagues, patients, and their providers to inform them about the rapid changes taking place in this area. Of course, we're all thrilled about the progress of the new biologic therapies, but these have come, of course, with a downside: cost. As the patents on these biologic products used for cancer treatment expire, there's an opportunity for other manufacturers to produce highly similar biologic agents and provide some competition that might bring down the cost of these agents. However, these are very complicated molecules. They cannot be reproduced exactly. The panel felt it was essential that oncologists as well as our patients understand the regulatory requirements, the way that these agents are approved, how efficacy and safety is assured in that process, and through that education, hopefully lead to a better understanding and a better use of these agents in actual clinical practice.
As you pointed out, these are already in the marketplace, at least in terms of the supportive care of patients with cancer going through chemotherapy. We now have two approved biosimilars. Although they're not yet in the market, they will be soon for actual cancer treatment. That's raising the ante and, in some cases, concern among oncologists as they go to the biosimilar space for actual cancer treatment and want to be sure that they're doing the best thing for their patients.
CH: Your comments remind me that while we take some of these terms for granted, some of our listeners may be uncertain about what they mean, exactly. What is a generic drug versus a biosimilar drug?
GL: We're very familiar with generics—we've had generics now for decades. These tend to be small, low-molecular-weight chemical agents that can be reproducibly synthesized through chemical reactions in the laboratory. And you, in principle and in practice, end up with essentially identical copies of the original chemical. They can be completely characterized. They're stable. They don't tend to be immunogenic.
Biosimilars, as well as the reference (original) biologic product to some extent, are larger, more complicated molecules. They have a high molecular weight. They're very heterogeneous. They're produced in living systems, which is the essential challenge of trying to reproduce them. In the end, it's really impossible to ensure that you have produced an identical copy. The FDA uses the term, "They have to be highly similar." We can talk more about how they characterize that. But these are molecules that are very sensitive to external conditions. They may produce an immune response, at least, that needs to be monitored. The biosimilar is a highly similar agent to the original biologic, the reference biologic, but is not identical. Just like the original biologic over time, there may be batch-to-batch variation. And over time, it may not be exactly the same as it was when it was originally approved by the FDA. And all that is monitored very tightly by the FDA.
CH: Let's turn to the practical question. How can I be sure that I'm choosing the most appropriate biosimilar when I'm given that choice in the clinic? Are there particular clinical circumstances in which oncologists should be more or less likely to consider using biosimilars?
GL: Well, we're in early times here. The information that we have, based on the supportive care agents that are available, would suggest that no red flags have arisen. In fact, ASCO guidelines for use of the myeloid growth factors have explicitly stated that any the original biologics or the biosimilars that are now available may be utilized to reduce the complications of cancer treatment.
The concern arises, however, as we enter this era where we have biosimilar cancer treatments, things like trastuzumab and bevacizumab, which are now approved by the FDA and will soon be available in the marketplace. There, I think, the profession needs to understand—and I think the ASCO statement goes a long way to informing oncologists—all the extraordinary efforts that are undertaken, by manufacturers but also by the FDA in its regulatory approach, to ensure that these agents are very similar. Their mechanism of action is the same. Their pharmacology is the same. They have the same toxicity profile. They've not shown to have any immunogenicity.
I would add that we have one advantage here, which is that many of these agents have been available in Europe for well over a decade, and the experience there has been very reassuring. None of these agents have been removed from the market because of unexpected adverse events.
CH: If I turn the question around, is there a circumstance where an ASCO member or someone who is prescribing should notice or care that their patient is receiving a biosimilar instead of the name-brand product that they are used to using?
GL: We should always be concerned with the specific agent that the patient is receiving and that it's either exactly the same or virtually the same as what we have ordered for that patient. There is a process that the FDA has put into place that just finalized their rules for establishing a higher level of biosimilarity, and that's called "interchangeability." That has not actually been granted yet to any biosimilar in the U.S. But the rules have been laid down, which would say that you have to provide additional clinical evidence that you could switch from the original biologic to the biosimilar back and forth, as maybe a patient goes from New York to Florida for their care, and they might get a different version of the therapy that they're on, but there is a process in place where biosimilars could be approved to be interchangeable in that sense. In the absence of that, it's simply essential that oncologists know which agent the patient's receiving and that any unexpected adverse event or sense of a lack of efficacy is reported. Again, the European experience is none of that has played out. But I think we should always be vigilant that something could emerge because of the biologic nature of these products.
But that's true of the original, the reference biologic therapy. They're not exactly the same today as they were years ago when they were approved by the FDA, because of a process that we call "drift." Due to changes in manufacturing or some new manufacturing process, these agents can differ slightly. That's why every time there's a change in manufacturing, the FDA has to come back in and certify that the agent remains highly similar with no meaningful clinical differences in efficacy and safety. There's a process in place that is meant to reassure both the FDA and practitioners that these agents work as they're intended to. Oncologists should be comforted to know that that's the case.
CH: I want to turn to one of the big motivations for this entire field: the promise of some cost containment. Can you just talk for a moment about how these drugs are priced and how much optimism you actually have that they will control cost going forward?
GL: My optimism is guarded, I guess is the best way to put it. The introduction of generics has, to a large extent, brought down the cost of the small-chemical molecules that can be replicated in the manufacturing process. In the area of biologics and biosimilars, again, there's no getting around that these are complicated molecules, difficult to produce in living systems. There’s still a considerable cost in developing a biosimilar, even without needing to do all the large phase III trials that the original biologic did.
The European experience would suggest that there will be some curtailing of cost due to competition. It's probably going to be more modest than the 80% reduction in cost that we've seen with some generic products. With the biosimilars, it's estimated to be about a 20% reduction in the cost—but we're talking about 20% of a very large number. The use of biologic therapies in the U.S. alone is substantial and growing each year. If we can reduce the price and the overall cost of cancer care delivery using these agents by the introduction of competitive biosimilars, that, I think, is a promise. But it's in the context of rising health care costs in general, where the average cost or price associated with new cancer drugs at the time of FDA approval is in the range of $10,000 and often more per month of treatment. If we can contain, curtail, or just bend down that rising curve of health care cost, biosimilars have the opportunity to help. But they won't be the only solution and, obviously, there are many other areas where we need to consider ways to contain rising cancer care costs.
Listen to the full podcast online or through iTunes or Google Play. Read the ASCO statement on biosimilars and find a patient-focused podcast by Dr. Lyman on Cancer.Net. The FDA website includes information on the regulatory process for biosimilars, fact sheets, and online courses.