It is the best of times in oncology, it is the most expensive of times. Biologics have added a whole new layer of effective cancer treatment, but their high prices are contributing to the shocking “financial toxicity” of treatment, pushing budgets to the breaking point, and possibly putting the quasi-wonder drugs out of reach for patients who need them. , MD, has emerged as an important voice about biosimilars and their potential for corralling cancer costs. Lyman, the co-director of the at the Fred Hutchinson Cancer Research Center in Seattle, chairs the American Society of Clinical Oncology’s Biosimilars Work Group and was lead author of . He is a breast cancer specialist who has published extensively on both clinical and economic issues in oncology.
I read your piece about biosimilars in the
Well, as practicing medical oncologists for several decades, we’re all very excited, and continue to be, about the emergence of the biologic therapies across the multitude of cancers. It’s revolutionized cancer treatment, cancer care, on many fronts. So, of course, the goal is to make sure every patient who has a cancer that is amenable to biologic therapies has access and gets appropriate treatment. All of this has been extremely exciting, but we’ve also realized that these agents are coming with a huge price tag. The cost of cancer care, the price on these drugs and a whole range of medications—they have continued to rise, and this has presented a barrier to many patients and has put a burden not only on patients but on the entire health care system. So, as someone who is also concerned about, and does a fair amount of research around, the economics of health care, it seemed to me that we need to find ways to rein in—or at least ameliorate—the rise in the cost of cancer care management and the price of these exciting—but very costly—drugs.
There are many more biologic therapies in the pipeline. But unfortunately, over the past several years, the price of these drugs, even at the time they are approved by the FDA, has been extremely high. Average pricing over the last few years for these agents has been over $10,000 a month. This becomes very prohibitive for many patients, posing an enormous financial burden. We’ve shown it doubles or triples the rates of bankruptcy among cancer patients. Some patients may stop taking the medication altogether. And, of course, these drugs work only if you’re taking them.
Perhaps one way to sum up what got you interested is that biosimilars might be something of an antidote to the financial toxicity of today’s cancer treatment, which is, as you mentioned, increasingly reliant on expensive biologics. But it seems that we’re talking differences of maybe 12% to 20% in price between the originator and the biosimilars. I’m thinking of Neupogen and Zarxio. In the U.S., do you have any idea how much of an antidote biosimilars can be?
The truthful answer is we don’t know yet because we’re so early into this. Again, we have the European experience to look at, where they’ve seen in the range of 20%—in some cases 30%—price reductions, but not 80% like you see with generics. In the U.S., we’re so early into this process. The first biosimilar, which is Zarxio, a biosimilar to the originator Neupogen, which is a supportive-care product for helping patients get through chemo, reducing the risk of infection—that’s the one that’s been out there for two or three years. A recent study—it was in JAMA Oncology—suggested the pricing on the biosimilar may be a little more than 10% lower than the originator.
That has to be disappointing, right?
Well, yeah, but keep in mind that this is just the beginning. What we have seen in Europe is that one competitive biosimilar has a very limited effect, but when you get two, three, when you get multiple agents in a class that are competing with one another, then you start to see much bigger reductions in the pricing.
Of course, the U.S. is a very different health care environment, so we can’t draw too many parallels because most of those are national health systems. The U.S. is a more open, free market–type of health care environment.
But I’m going to reserve judgment because over the last year, of course, we’ve seen several other supportive-care competitors get approved by the FDA. They’re only starting to reach the clinic this year. We shall see. I think the next year or two will tell whether we’re going to see a similar type of reduction in pricing with two, three, or four competitors in the market, not just the one.
The other thing that is so unpredictable here is whether the experience we see with the supportive-care drugs will carry over to the biosimilars for cancer treatments like trastuzumab or rituximab.
Do you believe that the market share for the biosimilar treatment drugs is going to increase more slowly than the biosimilars for the supportive-care drugs because clinicians and patients and their families will feel that the stakes are so high with the treatment drugs? Maybe they’re not going to want to “experiment” with a drug that’s similar but not identical.
Well, I share that perspective that it very well may be slower. I do think the level of concern over using these new biosimilars is greater when it’s a cancer therapy rather than supportive care. It’s going to be slower uptake until everybody becomes comfortable that these truly are based on the FDA regulatory process, that they are as efficacious and safe as the originator products. A lot of people are not going to want to be the first on their block to try these [biosimilars] until there has been some real experience to say they are as good as the originators.
As a clinician, do you have this hesitancy? Would you be as comfortable prescribing Mvasi as Avastin for, say, a breast cancer patient?
I would, and I’ll tell you why. First, I believe there is a lot of rigor in the FDA process, although it’s much more focused on the molecular characterization and the pharmacokinetics than on large phase 3 trials. But the other reason is, you know, if you really study the area, what you realize is the original biologic that was approved by the FDA 10, 15 years ago, is not the same as that product in the clinic today. The originator biologic is just as susceptible to drift over time as biosimilars are. So, in a sense, the Herceptin today is a biosimilar of the product that the FDA approved 10 or 15 years ago.
I think the real issue is these are complex biologic molecules. They need to be monitored. The FDA is determined, at least as they publicly have stated in their action plan, to monitor all the biologics, including biosimilars over time, for safety and efficacy. We need to make sure that we’re not seeing any red flags, anything that might say that these aren’t as good as the others. But I will say, again, going back to the European experience, which is out now nearly 10 years, no biosimilar has been removed from the market because of safety or efficacy concerns in Europe. That’s reassuring to me that we’re on the right track here.
You are willing to prescribe Mvasi, but a patient might say, “I’ve read there might be a difference, and I want Avastin.” Would you agree? Would you try to talk the patient out of that? Would you say that’s your choice, there’s no clinical difference, and talk to your insurance company?
I would certainly have the conversation with the patient. A patient needs to be comfortable and participate. We talk a lot about shared decision making, and I think that extends to this area of biosimilars. I think we should explain why we’re comfortable using them, but that we want to know that they are comfortable, and if not, I’m certainly willing to prescribe the originator.
I think we have to be honest. There are a lot of drivers in utilization of these products that are outside the control of either the patient or the provider, and as you point out, the insurance company, or in some cases the health system, is involved.
Once the P&T committee decides that these drugs are all equally effective, and the guidelines are now saying these are equally valuable choices, then, of course, hospitals, health systems, and practices will try to find which of these equally effective and safe drugs they can get for the best deal. That may take the choice out of the hands of the clinician or the patient.
But in most situations, including my own here, if the patient feels very strongly, or if the doctor feels very strongly, that they want to stick with the originator, there is an appeal process, and it goes through either the hospital or the insurance company to request that they can use the originator, and presumably the more expensive agent. But the ultimate decision may not, in many cases, lie with the doctor or the patient.
Do you see issues with biosimilars that are special or particular to oncology that we wouldn’t see in other areas of medicine? I’ve wondered whether FDA approval, which is based on preclinical data and pharmacokinetics, might pose a problem for many oncologists who are used to seeing results from phase 2 or phase 3 trials, as proof that a drug is effective and safe.
I think what’s different is that cancer strikes fear in all of us. It strikes fear in the general population; certainly, patients who are diagnosed are often frantic. They feel desperate. They feel they don’t have any choice but to try to get the right treatment and get access to these. And they may feel, well, they have one chance, one crack at this. They may not want to go with something that’s only been around a couple of years, but go with something that’s been around 15 or 20 years. And I understand that.
But, as I pointed out, I think part of it is a little bit of a misconception that a drug that’s been around 15 or 20 years is the same as it was back when it was original.
“If I were at the FDA, I would probably put aside the interchangeability issue. But the states are probably going to preempt the substitution issues. Interchangeability then becomes a commercial marketing issue rather than something” designed to enhance access.
But you’re absolutely right that oncologists—and this is true of the other disciplines—we’re used to seeing all this hefty evidence from large phase 3 trials that was presented to the FDA, and what was part of the package that led to approval of those drugs. And we’re seeing less and less of that, with one exception that may be coming down the road, which is this concept of interchangeability. And this adds another complexity and level of anxiety around these.
Please discuss interchangeability.
The FDA is trying to finalize its regulations around taking a biosimilar and classifying it as an interchangeable biosimilar—one that can be given interchangeably with the originator, or with other biosimilars based on what we call switching studies. So, the FDA has laid out the types of randomized trials that would need to be done to demonstrate interchangeability of a biosimilar. No biosimilar has yet applied for or received interchangeable status in the U.S. because the regulations aren’t done.
One aspect of the current proposed rules for interchangeability is the proposal from the FDA that if a biosimilar was granted that designation of interchangeability, a pharmacist could switch an interchangeable biosimilar without notifying the doctor or the patient.
Because of that problem, which really all of us have anxiety about and don’t like, now nearly 40 states have put forward preemptive legislation that would require notification if such a switch occurred. It would not prevent a pharmacist from switching, but they would have to notify the clinician that ordered the drug that that switch took place.
Do you agree with the proposed rules for interchangeability? Or in your opinion are there important changes that should be made before those rules are made final?
Let me just say this would be a classification unique to the U.S. There’s not a classification of interchangeability in Europe or other parts of the world. It’s something that was proposed in the U.S. because the population is so mobile and the different health systems, unlike in Europe where there’s more control of how things are done across hospitals throughout the entire country.
I think what really irks me and many of my colleagues is just the idea that we wouldn’t be told. I understand for generics that happens all the time, but I also understand generics are synthesized in the laboratory and can be shown to be exactly the same as the original drug. But that is not the case for biologics. I think we want to continue to be vigilant even after the drug is available in the clinic and in the market. To be vigilant means you have to know what the patient is getting. If they’ve been switched from one product to another and some adverse event occurs, you want to know what they’ve been taking. Otherwise you’re working in the blind.
So, I’m not a terribly big supporter of [the FDA proposed rules on interchangeability]. I understand their goals here because of the huge variation in health care in the U.S. But I think this idea of not notifying or not requiring notification is misguided, and I would disagree with that. And I agree with the states that have decided to try to get ahead of this just in case that remains in the final rule.
Do you think this American-only, FDA designation of interchangeability is necessary?
If I were at the FDA, I would probably put aside the interchangeability issue. But the states are probably going to preempt the substitution issue. Interchangeability then becomes a commercial marketing issue more than something that’s really designed to protect or enhance access to these drugs.
I want to discuss post-marketing surveillance, which seems to be especially important given that these biosimilars—actually biologics in general—are being approved with less-robust clinical trial evidence behind them. But as you mentioned in some of your pieces, many clinicians find the reporting cumbersome. Are oncologists any more or less inclined to participate in post-market surveillance than other clinicians? Are there efforts to get them on board given that it seems that post-market surveillance is important with respect to biosimilars?
It’s another complicated area. We’ve had trouble getting clinicians—not just oncologists, clinicians in general—to report adverse events.
The FDA is partnering with ASCO and with other organizations to look at what we might call big data systems, like , which is the ASCO big data system. After a drug is approved and it’s in the marketplace, the data get captured prospectively in these big data systems. If there are signals that arise because adverse events are occurring more frequently, or patients relapsing more rapidly, this would be captured in these big data systems.
So the FDA is not only trying to enhance and strengthen the adverse-event reporting from clinicians, but they are also trying to partner with efforts to monitor large numbers of patients captured in these big data systems. They do take this post-marketing surveillance issue seriously.
Do you think the current post-market surveillance systems are up to the job as they presently exist? Because it seems that’s going to be key to the acceptance of biosimilars.
Well, I agree with you. I would emphasize that it’s not just the biosimilars. It’s also the originators. They all need to be monitored over time. I think we would all agree the system is not ideal. The reporting of serious adverse effects needs to be streamlined. It’s complicated, it’s time consuming. You don’t get reimbursed for it. There’s really little or no penalty if you don’t do it—there is in principle, but people generally don’t get penalized for being a bit sloppy with it.
I suppose these big data systems kind of backstop traditional adverse event reporting. I’m still actively involved with CancerLinQ operationally as a research tool. But it’s certainly not perfect because you may catch something, but you may catch it months or years after it’s actually being used in patients.
We need more real-time data. I know that’s CancerLinQ’s goal. I think it’s Flatiron’s goal. I think it’s the goal of many of these initiatives with the FDA.
This transcript has been edited for clarity and length.