 To the point that, Hope, you’re asking about, and Marcus, you’re addressing, what do you think is the level of familiarity with rank-and-file physicians about the nuance of biologic manufacturing?

I think it’s not large. I think that this is something that the basic scientists, the PhDs who deal with this, have known this for years. But I think that rheumatologists who write for infliximab think infliximab is infliximab. And it’s very, very, very, very similar. But at the same time, the infliximab of today is different than infliximab of 2005.

 Yes. It’s just so interesting to me because I only learned about this…

 Even before we started the trials, I’ve been using trastuzumab since it was approved. And we did bevacizumab studies, all the new antibodies, etc, and never thought about that. Then, we had this conversation with the FDA as we were designing a biosimilar trastuzumab trial, and the FDA said, “You’re going to have to do an initial trial in healthy people showing that Europe’s and the United States’ trastuzumab have the same pharmacokinetic equivalence and immunogenicity.” I’m like, “Really? Is that true?” And it’s been fascinating. That was a long time ago, now, to understand that they really were considered different by the FDA, how they’re made, and their processes.

Yes, it’s something that opened my eyes as I was reviewing this. Much like you mentioned, I think it is something that is important to know. But moving forward, I think we still are going to need to have continued pharmacovigilance of each product as they hit the market.

This is just the beginning—once these medications hit the market.

 So, you address the issue of pharmacovigilance with these products that are going to have to be ongoing. Do you anticipate your institution will be trying to get some idea of comparative effectiveness, even if it’s just through a real world evidence—based analysis as these drugs come into the market?

 Yes, I would hope so. I don’t know if, ultimately, we will be one of the sites. As we review this, as rheumatologists, I would hope for real world experience in reporting, not just in studies. With what we can do with electronic medical records nowadays, the American College of Rheumatology has its own network that can extract data from electronic medical records once the appropriate permissions have been procured. And hopefully we’ll be able to monitor things like this, monitor drugs, and make sure that there are no unusual safety signals that develop after 5 years of use or 10 years of use or switching from one version to another version and back to another version.

Videos

Physician Understanding of Biologic Manufacturing

 Marcus, one interesting area that’s likely to be much more significant in rheumatologic disease is going to be patients on chronic therapy and on an established agent that may now have a biosimilar, and let’s say there is a delta greater than 20%. So, it’s a different scenario of starting a patient on an agent of a class they haven’t had before versus actually switching that patient to a different drug manufactured by a different company. And, again, it’s a scenario of making that distinction between biosimilars and generics that are not identical molecules. They’ve gone through clinical testing, but different clinical testing because of the role of extrapolation, which we’ll get into later. So, I’m curious about the switching phenomenon. What’s coming out? Is there actually any guidance being provided, right now, from the [American College of Rheumatology, ACR] that’s going to help in maybe creating a national statement of how we are willing to proceed? Because, right now, it’s like you’re moving in the dark.

 Yes. These medications potentially can be lifelong, and so you start out on a biologic medication—infliximab, for example. You start out on infliximab and you’re on infliximab for 10, 12 years. And then, your carrier decides, “Now I’m going to switch you to the biosimilar, infliximab.” It’s a different molecule, as you mentioned. And for your immune system, it has been proven to be efficacious. It’s been proven to have similar effects. It was proven to be near identical, but it’s not identical. Does your body react to that long term? Do you lose efficacy? Does it increase your immunogenicity, which basically means that you have more drug-to-drug antibodies because you switched from product A to product B and maybe then to product C then back to product B, depending on how the winds blow with the formulary? That’s something that, as rheumatologists, we are very concerned about. And it’s something that we are trying to help regulate with the FDA. We’re trying to work with the FDA to offer some guidance, and this is hopefully for an interchangeable medication, which not all biosimilars, at this point, have.

 Have any been granted interchangeability? I don’t think any have.

 I have not seen that any have been granted interchangeability.

 If somebody has been on this drug for 10 years, haven’t they already seen different formulations of the same product over time? I mean that you change where you’ve made it or where you get it from or that, in fact, you change the process. And that does occur, over time, for most of these drugs.

 Absolutely, and I think that is a great point. I don’t know how many variations of infliximab there have been, but there have been well over 20 versions of infliximabs, and they have to file with the FDA and let them know that they’re changing a process in their manufacturing.

 But, we don’t necessarily know that as prescribers.

 No, absolutely not. And so there is probably some lot-to-lot variability, and my patient has likely seen multiple versions of the originator product. The question is, ultimately, how does that happen in the long run? We think it will be okay. I think that, innately, we have no evidence that it will be a horrible thing, but I think that we have to take a lot of caution with this because we just don’t know. There are no studies with this. You’re going from products that are made in a different cell or made in a different lab, and these products are different.

Chronic Therapy and Switching

 Let me get back to that question, though, about how much variance you see in prescribing behaviors and doctors favoring, if we use that example, one taxane over another taxane in the treatment of a breast cancer patient.

 I think Marcus was alluding to it. It depends on what the insurance coverage is. For our physicians, they would usually use the reference product. But sometimes if there’s insurance approval…

 And how is that communicated to the physician? Is that your job? You’re supposed to be able to tell them, “You can’t give that to this patient.”

 The state board of pharmacies are also implementing changes and legislation to help support that. And the communication to the physicians varies depending on what that is. But it would be if there was a substitute. We haven’t encountered that situation yet, except in outpatient coverage where the physician was notified of the substitution the biosimilar. If the physician wanted the necessary brand, they could also indicate that on an outpatient prescription order. At an institutional level, I don’t think they have the same control. It goes to the therapeutics committee, which would be chaired by a physician that would approve that. I’m not aware of any automatic substitutions, and I don’t see that right now in the landscape because of the interchangeability and variant data. And the physicians would want to interpret that and be able to use that before automatic substitutions were made. That may change in the future with the 

 Are you talking specifically about therapeutics, there? And chemotherapy and more biosimilars? I just wanted to be clear about where you wouldn’t see the automatic substitution, because we do have relatively automatic substitution for the filgrastim product. But we don’t have anything. Of course, there aren’t any therapeutic biosimilars, so we don’t really have to address the question right now.

 Now, it would just be supportive care with the growth factor. And I think that would be made at an institutional level. Currently, we give, at my institution, the branded Neupogen product. But a biosimilar, at other institutions, may get approved through a therapeutic committee.

 For chemotherapy—actually, we should say “biotherapy”&mdash;it would be a whole different game. We’ll see how pharmacy and therapeutics committees dictate that at their institutions.

Prescribing Behaviors and Biosimilar Substitution

 Marcus, do you see that as well? And, probably, rheumatology has been much more affected.

 In regard to oncology, there is political correctness of putting in step edits and formulary management, maybe, for growth factors, but not typically for therapeutics. But, in rheumatology, this has been the way for a decade.

 Yes. For example, if I’m starting a patient on a tumor necrosis factor inhibitor, I will write for etanercept or adalimumab. That medication will be altered by the formulary of the insurance company of this patient, and usually it will be altered with a preferred product. There are 5 tumor necrosis factor inhibitors on the market. Usually, they prefer 2 or 3, or they’ll shunt me one way or the other. In general, we have no head-to-head studies of these medications. But, we generally think of them as equivalent. That’s the reality.

 But, there are scenarios where—maybe in early, rapidly progressive rheumatoid arthritis&mdash;it may be that these agents don’t work as well, and you want to use a different mechanism of action drug to begin with, or you may want to be able to challenge that. Can you successfully challenge those decisions?

You can try. Generally, the lack of head-to-head data has, in essence, kept some of these discussions from happening. I do think that, in rheumatology, we tend to think of aggressive control. It doesn’t really matter, necessarily, which agent you use, but we need to get control quickly. And whether that involves simply methotrexate or whether it involves a biologic medication, we have tons of options, thankfully, right now. You can push along. The biggest determining factor for me, when I’m prescribing medications, is my patient side effect profile. If they have a history of cancer, I may shy away from one medication or another. If they have a history of multiple sclerosis, I’m going to head away from the tumor necrosis factor family. Obviously, you have to choose based on your patient profile, so that’s where my objection to a step edit that exists will end up in a peer-to-peer review. Depending on the situation, that has been successful at times. But, it takes time, and it takes effort. It takes me taking time out of clinic. It takes a delay from my patient. We know that rheumatoid arthritis is a progressive disease, and the longer you wait to get control of their disease, the more damage you can have.

 Can I just be clear? If you’re talking about a step edit, it’s like using the same drug but a different brand?

 It’s a different drug that they want you to use.

 So, for the most part, if you graduate from our traditional disease modifying agents—methotrexate, hydroxychloroquine, sulfasalazine&mdash;and with few exceptions, you have to start off with those, if I wanted to move to a medication that is not a tumor necrosis factor inhibitor, it would be rejected by the pharmacy until I fail 2 tumor necrosis factor inhibitors. Once that happens, then the armamentarium is opened up from there.

 And that’s what a step edit is. They say, “No, you can’t.”

 Yes. You have to take “this” step before you can go…

Biosimilar Prescribing and Cost in Rheumatology

 You introduced cost. Do you really believe it will be a fraction of the cost? It raises the other issue, and you can all weigh in on this. What does that differential need to be? Is a delta of 10% going to be enough to really change behavior? Would it be enough for even a payer to really champion that cause? Does it need to be 30% in order to do that?

Do we have any examples that already exist? The one I can think of is in hepatitis C, but it really took one of the competitors to drop prices by 50% to change the market pattern. I’m curious as to what you think that may be and, in terms of how close that delta might be, how that won’t allow change or how wide it has to be to drive that change?

 From my perspective, the delta has to be at least 20% or more. That’s what people in the general field think. Being an academic oncologist, we really don’t think too much about cost, but we need to be thinking more and more about it. And I think that there is something unique about the supportive care products. You were talking about long-acting agents for rheumatologic diseases, but we don’t really have that in the therapeutic area of oncology. It’s just in supportive care.

You have a combination of what the cost is for the originator product versus the biosimilar in the short-acting area versus giving a long-acting drug, which already costs a lot more than the originator product, versus the 5 doses of filgrastim. So, it’s a complex basis, and sometimes I’ve had insurers come to me and say, “We’re not going to give you growth factor for this patient’s chemotherapy.” And I say, “Well, I can’t give them chemotherapy without growth factor,” and, “Look, here’s the papers that show the rate of febrile neutropenia.” We are really getting into an area where there is a lot of consideration about what people are going to approve up front. We have a lot of peer to peer discussions, now, with insurance companies about what’s going to get approved or not. It’s going to be very interesting to see.

 I’m curious. I’m hearing you talk about some of the kind of practical pragmatic issues of everyday patient care, and you’re at a renowned institution. And I’m thinking, when you talk to people in the community, are they suspect? You’re having those kinds of problems. You don’t know what problems are until you’re in a community practice with 3 doctors and you’re trying to deal with an insurance company. And so, I’m surprised by the fact that I’m hearing that recognition coming from your level—that higher position in the hierarchy of medicine in a major institution.

Cost and Biosimilar Uptake for Oncology

 Hope, this brings up a couple different points that we hear from Marcus and hear from Brandon. One is the distinction that might be made by both patients and providers between a supportive care drug—a drug for a chronic disease that doesn’t have a short-term or immediately life-threatening component&mdash;and a life-threatening disease. Will those differences be the kinds of differences that will create higher bars in order to gain that acceptance? Institutionally, and within your practice and within your peers, what has been the adoption of the biosimilar for Neupogen?

 This is a fascinating world, because therapeutic drugs obviously are a different consideration and require different considerations. But, for the growth factor used—and we use a lot of growth factors in breast cancer oncology, as well as in other areas of oncology&mdash;the decisions about what agent we use are very much determined by negotiations, as you pointed out, with practices, but the insurers also. So, they’re going to tell us what we’re going to do. And what happens at the university level, and I think in many of the managed practices, is that there are contracts that are developed. If you’re going to use a certain amount of product, you’re going to get it for “this” price. The actual biosimilar has been adopted, and there was an email that went out about discussing it if we had any comments or concerns. We’ve all looked at the data, and we didn’t have comments or concerns. And so, now we have actually adopted the use of the biosimilar for what we’re giving in patients in the outpatient pharmacy and in the inpatient setting.

For patients who received their growth factor at home, then it very much depends on this injectable pharmacy plan that many people have—where you actually make a contract and get approval through this identified group that delivers the medication to the home, as opposed to going to the pharmacy itself. And so, that just depends on the individual pharmacy and what they want to cover. I think that for us, what’s been interesting is to see how that’s changed over time.

We give a short-acting growth factor. That’s where the biosimilar is. But, we give a lot of the long-acting growth factor, pegfilgrastim. Pegfilgrastim, now, has come out with a new delivery system where you put this little white package on your skin and it flashes this little green light for 24 hours until it delivers itself, automatically, into the skin. So, for anything where we’re dosing, for example, dose-dense chemotherapy, we give doxorubicin and cyclophosphamide, dose-dense, every 2 weeks. We’ve been using this product—the sort of delayed delivery of pegfilgrastim, which is known as Nuelasta Onpro&mdash;in almost everybody. We’ve taken away that whole question. Where we’re using the biosimilar is mainly in metastatic disease where, obviously, there are different considerations.

 It’s interesting, because it brings up this issue that it’s more complicated than just drug-to-drug comparison. It’s a dynamic, moving marketplace. I don’t know if you know the statistics from your institution. I know there are national statistics. But, in terms of the use of the long-acting pegfilgrastim versus the short-acting daily option, do you know what the difference is in your institution?

 In our practice, it depends on the chemotherapy regimen. But, we are almost always using the long-acting option. In specific situations—for stem cell transplant as well as when a chemotherapy regimen is given more frequently than every 14 days&mdash;we would use Neupogen instead. So, our use is kind of variable, but the long-acting option is typically the largest use for us. The number of doses would be the Neupogen, since we give it daily.

 I’ve seen that, outside of mobilization for stem cell transplant, the use is almost all with the long-acting option. The long-acting product has somewhere in the range nationally of 85%, 90% market share. Now, on top of that, Hope, you introduced this idea that you’ve already got this distinction and there will be a biosimilar to the long-acting option. But, now the long-acting option has upped its game because they have a different delivery system. That difference in delivery system is going to be looked at, now, as we look at other biosimilars coming into the market.

One would be a drug like rituximab, which is also on this short list of drugs to come off patent for which there are biosimilars in development. But, in that case, you’ve now got subcutaneous administration as opposed to a long intravenous infusion. I kind of see this as a pattern.

Marcus, within the world of rheumatologic drugs, now you’re going to have 5 biosimilars. They’re likely to be in use. Are we seeing any differences in terms of this manufactured obsolescence, where there’s going to be a better anti-CD20 antibody that’s likely to take the place of the old and, so, the biosimilar will become a dated product, or are we seeing changes in terms of the administration delivery system that’s going to facilitate a difficulty in adopting these products because it will have a quality of life concern or less consumerism around it?

 Yes. Those are being developed and they’re starting to hit the market. Tofacitinib hit the market and then a longer acting product came out soon thereafter. So, we see that, and that’s a small molecule, not a biosimilar. But, you know we see this in every different type of medication in oncology and rheumatology. I do not think that’s going to be a big issue at this point, mainly because the medications we use are life-long and the delivery devices are things that certainly play a role. But, when you’re dealing with a medication for rheumatoid arthritis, it’s more the medication than it is the delivery device.

 It is interesting. Just to point out the growth factors and delivery systems—for example, a lot of people use the pegfilgrastim with docetaxel/cyclophosphamide for breast cancer, but you probably only need filgrastim for 5 doses for most situations. And in some places, the HMOs (health maintenance organizations) might choose not to give any growth factor for the first cycle because the rate of febrile neutropenia may not reach their criteria for giving growth factors up front. And then, if you have a biosimilar product that’s a fraction of the cost, and if that’s what it turns out to be for the institution, you’re giving 5 doses of that versus the Onpro. That decision may be taken out of our hands in some situations.

Delivery Systems and the Acceptance of Biosimilars

 titled “Clinical Advances and Challenges with Biosimilars.” The biologics drug industry has seen a significant growth in recent years, both in terms of the drug pipeline and FDA approvals. Prescription drug spending is high with biologics. However, branded biologics worth more than $70 billion will come off patent by 2018, and the RAND Corporation predicts that infusing market competition with biosimilars can reduce direct spending on biologics by $44.2 billion from 2014 to 2024. At the time of this filming, 5 biosimilar products for inflammatory diseases and oncology have been FDA approved. Today’s discussion will focus on some of the practice challenges faced by care providers as they navigate the use of these follow-on products in the clinic.

I am Dr Bruce Feinberg, and I’m vice president and chief medical officer at Cardinal Health Specialty Solutions in Dublin, Ohio. Participating today on our distinguished panel are: Dr Hope Rugo, professor of medicine, director of Breast Oncology Clinical Trials and Education, and a breast cancer specialist at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, California; Dr Brandon Shank, a clinical pharmacy specialist in Houston, Texas; and Dr Marcus Snow, rheumatologist and director of the Scleroderma Clinic at the University of Nebraska Medical Center in Omaha, Nebraska.

Thank you so much for joining us. Let’s begin. Marcus, I think I want to start with you because the biosimilar experience is somewhat limited in this country.

 But, there is experience overseas. Across the pond, throughout Europe, there is experience now with a half-dozen different biosimilar drugs, most in rheumatology, and the rates of adoption have been very different. What is that, as far as you know—the patient experience, the provider experience&mdash;and why are those rates of adoption so different?

 Most likely, the rates of adoption are very different because we have a different healthcare system. In Norway, it is basically a single-payer system. When infliximab went off patent and there was a biosimilar available, the government was able to negotiate, essentially carte blanche, that the new infliximab was a biosimilar. And so, you see extreme differences in rates of adoption due to that.

 And we’ve seen as high as about 70% market share in Europe? And more 10% to 30% in other markets—France, Germany, and others?

 Are there any lessons for us? Are there any learnings that we can take? Is it going to be, really, insurance—whether government or commercial payer determined adoption&mdash;because of formularies, step edits, and other mechanisms that will likely be in place in rheumatology? Will that drive it, rather than it being patient or physician directed?

 Yes. I think this is going to be driven by formularies in the United States. In Europe, it has been driven by a single-payer system, or the government has been changing those contracts. That’s what we’ve seen. We can learn amazing amounts from the Norway experience and the NOR-SWITCH trial, which showed that multiple indications when switching infliximab to a biosimilar had noninferiority. And so, the lessons we can learn will help us in the United States as we try to figure out how these medications fit into our armamentarium and how they fit into formularies.

 Brandon, as a pharmacist in a large institution in Houston, you had the opportunity to experience the first, I would say, oncology-related biosimilar. That is the biosimilar to the reference brand for G-CSF (granulocyte-colony stimulating factor)—Neupogen. I’m curious to hear if, as an institution, they’ve adopted that product?

 Currently, we keep that reference product as our formulary. However, some patients’ insurances for outpatient administration do require the use of a biosimilar. In those situations, we have switched patients. But, our current formulary status and all of our order sets and designs just currently include the reference product, Neupogen.

Adoption of Biosimilars in the United States and Europe

What are your thoughts on the recent launch of Renflexis in the United States?

I think that it will be very interesting to see what happens now that we have 3 versions of infliximab on the market. Will this drive the cost down? I think that it remains to be seen. I think, as you look at what has happened since the first biosimilar for infliximab has hit the market, you have seen insurance companies—United, for example, actually signed a contract with Remicade to stay with the bio-originator. I think you are going to see some of this, but I think it will be interesting to see the uptake and how this happens, and I think we will start to see the outcomes of this moving forward.

Marcus H. Snow, MD, Assistant Professor Rheumatology, University of Nebraska, discusses the recent launch of a new biosimilar infliximab, Renflexis, in the United States. 

Dr Marcus H. Snow: The US Launch of Renflexis

If the [Affordable Care Act, ACA] is repealed, what becomes of the [Biologics Price Competition and Innovation Act, BPCIA]?

So, the BPCIA is part of the ACA, and if Congress repeals it lock, stock, and barrel, without having some replacement ready to go, technically the BPCIA goes with it, right? I don’t think any of us expect that that’s going to happen, but I’ll tell you that with the current administration and with the current Congress, uncertainty seems to be the rule. The BPCIA so far, in all the debate that we have been hearing and monitoring in Congress and in the administration, seems to be flying completely under the radar. It does not appear to be one of the controversial aspects of Obamacare that the president and Congress are really focused on. From that standpoint, that’s good for biosimilar applicants, but again, because there is this uncertainty, we have at least been watching it. I think I can say that nobody really expects the BPCIA to go away, and we don’t think it is seriously at risk, but certainly we watch what Congress is doing in this respect.

Robert Cerwinski, JD, Partner at Goodwin, discusses what becomes of the BPCIA if the Affordable Care Act is repealed by Congress. 

Robert Cerwinski: Healthcare Reform and the BPCIA

Ha Kung Wong, JD, Partner at Fitzpatrick, Cella, Harper and Scinto

Justice Breyer seems to be indicating that the FDA’s interpretation of the [Biologics Price Competition and Innovation Act, BPCIA] would be eligible for Chevron deference. And that might make sense with respect to the timing of the notice of commercial marketing. So, for example, the FDA might have some incentive in the future to say that they interpret the BPCIA to require 180 days between formal FDA approval at the expiration of the biologic exclusivity and commercial marketing.

But with respect to the civil procedure requirements—the “patent dance” aspect of the Sandoz holding, it’s not really clear what the FDA’s incentive would be or how the FDA’s authority would extend to parties’ standing before the Article III courts. It’s uncertain if the FDA has any incentive to weigh in on the patent dance, and whether they would feel confident that their interpretation of the procedural aspects of patent litigation would be entitled to deference, you know, Justice Breyer’s concurrence notwithstanding.

Ha Kung Wong, JD, Partner at Fitzpatrick, Cella, Harper and Scinto, discusses whether the FDA might clarify its stance on the BPCIA. 