Molly Billstein Leber, PharmD, BCPS, FASHP:

 I think this is an interesting question, because I think as a pharmacist, we probably didn’t ever think about that until biosimilars came on the market. I thought of, when darbepoetin changed their formulation and no longer made it with albumin, that didn’t require FDA approval. And I don’t think that myself or many of my colleagues necessarily questioned whether or not that should have occurred.

I think that now that biosimilars are on the market and we’re starting to recognize how many different changes in manufacturing processes that the reference product took, that I think that’s shown that we didn’t have concern then, and that we shouldn’t have concern now, and that it’s something that we need to make sure that we are very vigilant on monitoring and reporting any adverse reactions moving forward.

When you look at the analytic data and the FDA approval process, most of the work has been done up front, and the drug is highly similar to the originator product. So as long as we know the originator product works, then we should feel safe that the biosimilar product does work. And we have seen, with some of the biosimilars that are out on the market, filgrastim, for example, a biosimilar, we’ve been able to track the increase in white cell blood cell count. So, we should feel that it’s safe and effective to use outside of the FDA approved list or clinical trials for the originator product.

I think what’s going to be very difficult going forward is we are now moving from the supportive care (so the filgrastim, the pegfilgrastim, and the epoetin that are currently available) into a more curative space. And we’ve seen that kind of with infliximab, where there’s no markers to measure. And, so, I think that we are starting to see a lot of the prescriber concerns on whether or not this drug truly works. And I think as we move into more oncologic indications, I think that concern is also going to be there. We don’t have anything that proves that the biosimilar is as efficacious as the originator product, which I think people are struggling with right now.

I think that oncology is going to be very difficult. I think that with the first ones out, like rituximab, I think it’s going to be a struggle or a hard sell to get providers on that comfort level to use them. I think what we’ve seen with infliximab, at least what I’ve seen is sometimes providers forget that it’s the biologics or that they’re chronic diseases and the originator product doesn’t work 100% of the time. And they tend, if the patient was on the originator product and switches to the biosimilar, sometimes they blame the biosimilar and not the disease progression. I think we’re going to have to remind providers, again, that [not] 100% of their patients that were receiving the originator product [responded and some] had disease progression, and it’s not the drug or the biosimilar that’s causing failure, it’s actually disease progression; that’s no longer the appropriate agent to be treating that patient’s disease state. We need to look and see whether we either need to add on or switch to a different class of drugs to treat the patient.

You have an increased risk of immunogenicity every time you change cell lines or manufacturing processes, so you look at some of these drugs that have been manufactured since the late 1980s. We know that the manufacturing process has changed. We know that the cell lines have changed. We’ve changed manufacturing processes to make them more efficient and to meet the FDA requirements for the plants, so that they’re in good manufacturing. So, I think that we just need to make sure that we’re constantly monitoring and being very vigilant in reporting any immunogenicity concerns for both the originator product and the biosimilar. And the biosimilars will be made in newer facilities, so they are going to be made differently. That could be a pro or a con compared to the originator product.

Videos

Molly Billstein Leber, PharmD, BCPS, FASHP: Pharmacists' Awareness of Biosimilars

 We trust the FDA to make the right decision. When the [approval of the] first biosimilar for adalimumab came out, I was at that FDA meeting and spoke. And there appeared to be some concern, particularly among the pediatric gastroenterologists because that particular biosimilar had never been used in that population. However, the FDA did approve it and did extrapolate to [gastrointestinal, GI] indications as well.

I think over the years, as we see the use in other disease states rather than just the one that it was studied in, and we don’t see any increase safety signals, the confidence will be there for extrapolation. Although one of the most recently approved biosimilars did not get extrapolation from oncology to rheumatology. So, it’s not a given that extrapolation will be to all disease states.

In terms of the specialties that might have the most concern, I think probably oncology, because if it doesn’t work, their patients die. GI; inflammatory bowel disease, if there’s a problem, increased hospitalizations, infections, more surgeries. So, I think depending on what the adverse event would be if there is a problem will determine which specialty will have more concern.

As a rheumatologist, our field basically surrounds immunology. And autoimmune patients have, for lack of a better word, a "finicky" immune system that can be triggered by the slightest thing. We understand now about epigenetics and how something as simple as sunlight can affect the epigenes, change the DNA methylation, and cause increased T-cell activation. So, we are always concerned about immunogenicity, and that may be one of the reasons why you’ll find more rheumatologists concerned about immunogenicity with biosimilars. Because any small changes within the immune system in our patients can cause a flare.

So, I think the patient population is going to determine whether there’s going to be more of a problem with immunogenicity. It’s kind of a code word now. Everybody’s like, “Oh, we don’t want increased immunogenicity. If we switch too many times, is there going to be immunogenicity?” And I think there, sometimes, may be a little bit an over concern. Again, an infection changes the immune system in our patients. So, I think there’s concern and I think there should be, but I think, again, real-world evidence will hopefully show us that our concerns are unfounded. One of the things that I think in terms of switching, because I think that’s where the term immunogenicity comes out a little bit more is when we switch from the reference to the biosimilar, I think what’s going to happen, again because of our drug delivery system here, I mean we could have switching between biosimilars, among 5 different biosimilars. And the phrase that I coined at that first meeting was the great American switching experiment. And that may be, but what really is and hopefully it will all work out just fine.

Rheumatologists have had to become comfortable with pharmacy benefit managers switching our patients from one medication to a completely different medication. We’re not comfortable with it but it happens. That is one thing that I think we may have a big problem with. It remains to be seen. Obviously changing from a reference product to a biosimilar is nowhere near as problematic as having the drug itself be changed to a completely different drug, maybe even a different mechanism of action. So, I think the concern won’t be as great. There are some large health systems that have been switching from the reference to the biosimilar, and I think that there is going to be some pharmacovigilance and some studies being done. And I think as that proceeds and we see no new safety signals come up, I think again that will create a little bit more confidence. The Europeans do things completely differently than how we do it here, so I’m not sure their interchangeability discussion is sort of apropos or works in the United States. We have powers that be that change our drugs as well.

Madelaine Feldman, MD: Physicians' Concerns Regarding Biosimilars

 I think the biggest misunderstanding is actually the FDA approval process and how they use the totality of evidence to actually make the approval. I think that people don’t truly understand the amount of time and energy and efforts that are actually put into the analytic data to make sure that the molecules are highly similar before they’re approved by the FDA, which is why we won’t see a lot of large phase 3 clinical trials.

I also think that among providers there is some concern about and misconceptions about the safety of being able to switch back and forth between biosimilars and between a biosimilar and the originator product. I don’t think that they truly understand that they’re highly similar and you should be able to switch back without harm to the patients. I think, also, there’s been a lot of miscommunication to patients that they should only receive 1 particular product, typically the originator. So, a lot of times there’s some misconceptions or concerns from the patient regarding which drugs should be provided.

As a pharmacist, or a health-system pharmacist, I think the majority of the content at the pharmacists’ meetings have been very good and accurate. I think that most health-system pharmacists, in an effort to manage healthcare costs and manage the pharmacy budget, have been very proactive in trying to enhance the acceptance of biosimilars and make sure that we’re educating all of the pharmacy staff members, students, interns, residents, etc., about biosimilars and how they work, and what they are, and the advantages of biosimilars.

I think right now, as far as pharmacy conferences go, I think we’re moving more away from what is a biosimilar and trying to share our experiences on how we’ve gained acceptance and how we have overcome issues such as reimbursement, so that other institutions can learn and make those adoptions.

I personally have not attended a lot of the subspecialty physician conferences. I have heard through the grapevine that there have been some presentations about how biosimilars don’t work in patients. I think the big thing to think about there is look at what the dosing was. Have they actually gone back and had those conversations? They may have gone back to the initial dosing and not at the dose that the patient was titrated up to, and that’s why they’ve been seeing failures. I think the other big thing to remind people of is that these are chronic diseases, and that they do change. We don’t see 100% response rate to biologics, the originator product, so we’re not going to see that with biosimilars. So, if they’re not responding to the biosimilar, it may be disease progression and we may need to go to another class of agents.

I talk to a lot of the different physicians who are in some of these subspecialties and I think the conversation is changing. And I think as we start seeing a lot of those guidelines come out from the big societies that are now recognizing that biosimilars are safe and effective and can be considered as first-line of care, I think that’s also helping to move the needle with biosimilar acceptance.

So, I think misinformation around biosimilars will affect the acceptance of biosimilars. I think if people don’t understand how they’re approved, how similar they are, and how effective they are, then they will not be willing to use them or try them, and then we are not going to see more biosimilars enter the market. If we don’t see more biosimilars enter the market, we’ll continue to see sole-source originator products with no competition. And, as we’ve seen in the past, we have seen steady price increases with those which may limit access to patient care.

I think it’s really important for nurses to understand what a biosimilar is because oftentimes they’re the ones administering the drug to the patient. And I think it’s important that they have that deep understanding, so that they’re able to answer any of the questions that the patient has and assure them that this is the appropriate drug for the patient. And, if they need to explain why that was chosen to the patient, I think that providers really need to understand it because they also need to have that conversation with the patient and make sure that the patient understands the benefits of a biosimilar product.

Molly Billstein Leber, PharmD, BCPS, FASHP: Dispelling Misconceptions About Biosimilar Approval and Use

 I think there’s polarization, in terms of physician and prescribers’ attitudes toward biosimilars, everywhere from “biosimilars are completely different than the reference product and they should be treated as a completely different drug” to “they’re exactly the same.” And you know, it probably falls somewhere in between, maybe a little bit closer to being exactly the same. So, prescribers can be confused as to, are they the same or are they completely different?

So, there are a couple of issues out there that I think probably create the most confusion, and that’s the idea of interchangeability, and maybe interchangeability versus substitutability, because interchangeability is not a qualitative characteristic at all. It actually refers to a policy where pharmacists can substitute a biosimilar for a reference product without a new prescription, without notifying the physician or the prescriber at the time of switching.

And that becomes a little bit problematic when physicians think, well, we need to wait for a biosimilar to get an interchangeable designation before we should even prescribe it because that must mean it’s better, that must mean it’s safer. And I think that’s one of the main areas of, I don’t even know if it’s a miscommunication but it’s sort of a confusion among prescribers.

And then I think the other thing that’s kind of, in a way, ironic—the biosimilars were fast-tracked through the FDA because they’re going to cost less and supposedly will help bring down, and will, if eventually they can ever make it to a formulary, the cost of medications and general health costs in the United States. One of the problems is reference products. Biologics are expensive and so are biosimilars. So, patients will not be able to afford even the biosimilar unless it’s on their formulary. And to get on the preferred tier of a formulary, you really almost have to have a higher list price and market share. You really look at what the rebate is, the list price times the discount times the market share.

So those 2 things right there, a lower price and new to the market puts the biosimilar behind the 8-ball right away. And I think there is a misunderstanding that a biosimilar is going to be able to just hop right in as soon as it’s approved. Unfortunately, that’s a problem that we’re going to have to deal with in order to get uptake of biosimilars.

I think a lot of the issue revolves around, do providers and prescribers even know about post-manufacturing changes? Years ago, I was completely unaware of that. I think that’s where education comes in. Over the years there’s been a drift in terms of the change in what the reference product is. Perhaps the reference product now is no more like its original than the biosimilar is. So, I think to ask the question, are they concerned about that, I think the first thing that needs to happen is that prescribers need to be educated. And a lot of us, we’re seeing patients every day. We’re dealing with electronic health records. We’re trying to qualify for [Merit-Based Incentive Payment System, MIPS] and [Medicare Access and CHIP Reauthorization Act of 2015, MACRA]. It may seem like this is something everyone should know. But that gets fairly intricate, so I think education about what that really means, and does it have an impact on whether that will determine if you’re going to prescribe a biosimilar or not?

Madelaine Feldman, MD: Prescribers' Understanding of Biosimilars

 So it’s interesting that you say that, and I’m going to invite comments from everybody about who’s ultimately got the responsibility for doing this. But the corollary is true, therefore, if we go back to what was asked for our misinformation, education, appropriate promotion of these products, that if we don’t succeed, if those messages that are misleading can prevail for the next year and a half, we may not actually ever see a successful competitive biosimilars market in the United States.

I’m going to ask each of the panel: recognizing we’re at this critical juncture, that drug pricing is a very, very big issue in this country right now, that we do have the opportunity with the FDA having approved a good dozen biosimilars—even if they’re not all launched, we do have the [intellectual property, IP] patent thicket that we haven’t addressed in any detail, but we do need this commercial pull-through&mdash;who is most responsible?

How can we break this loose in this critical window, recognizing some urgency to both solve what is a priority for this country on healthcare access and affordability and see competition? What is the single thing you guys would suggest that can break this loose most immediately?

I’m not asking for new legislation. I’m not asking for anything complicated. What can we do to allow biosimilars to contribute in the United States in the manner that they do in Europe?

 We are at a juncture. I think that there’s a perception that biosimilars have not been successful in the United States so far, notwithstanding the fact that we’re early in the process, if you may. There are examples, as Kashyap and I have mentioned. There are already some insights into cost savings, which is one of the goals, and reshifting the resources for good use, as you have described.

There’s also the current landscape, from a CMS and an [Health and Human Services, HHS] perspective, that is favorable. We’re seeing action at the FDA level and at the CMS level in trying to encourage biosimilar useage. But I don’t have one single answer, unfortunately. I think it’s going to take more than one.

For biosimilars to be effective, they have to be prescribed. So certainly prescriber education, as you mentioned, is very, very key. They have to be accepted by patients. And what you said, Kashyap, is very encouraging, that you believe that patients are not as concerned. We’ve seen otherwise, but I think there’s still a component of education to patients in order to have acceptance. And maybe as importantly—and you could argue more importantly&mdash;is that payers need to come onboard. They need to change their reimbursement policies. They need to change their approach to biosimilars. They need to really get onboard. If payers don’t get onboard, it really doesn’t matter.

So I think all stakeholders are important because you have to prescribe, and you have to accept to use, but you also have to be able to fairly reimburse biosimilars. If that doesn’t happen, then we’re not going to be successful.

 So, Julie, I’m going to give you the opportunity to sum up both what we started on, in terms of the whole idea of education, appropriate information being out there, but also invite you to pull in this consequence of, if this doesn’t happen, what does it mean? And if you’ve got the magic bullet, please feel free to share it.

Multiple things have to happen. We need the FDA to do more on education and to combat misinformation. As stakeholders, though, we need to use the FDA as the trusted source of information, and we have to help disseminate that information. That’s a key piece.

But the silver bullet—the most significant thing that has to happen here in the United States to create this robust, sustainable marketplace that will drive cost down&mdash;is [addressing] the anticompetitive access and coverage barriers that are out there. The payers have to engage. The payers have to support and drive uptake of biosimilars. That’s not just the commercial payers. That’s also the government. So we need to do that. That’s the silver bullet, and it needs to happen. We have 5% over a year with 2 infliximab biosimilars on the marketplace. The market share after over a year is only at 5%. So it needs to change, and it needs to change now.

 And, of course, we’ve seen the recent launches of the adalimumabs in Europe, but those same products, even when they’re already approved here, won’t be launched until 2023.

 And I think that’s really key, because one aspect that you mentioned that we didn’t talk about is the patent landscape in the United States. It’s totally different from what we see in Europe in great measure. There are products that have been approved by the European Medicines Agency and by the FDA, and these same products are being used in patients. They’re making an impact in Europe, but they’re not in the United States. Just to give you an example, we obtained approval of our etanercept biosimilar in August 2016, over 2 years ago. We’re in patent litigation right now with the reference product manufacturer, so we can’t launch the product yet. We’ve estimated that for every month that we are not able to bring this biosimilar to market, that could be costing the healthcare system up to $95 million.

We did a similar study but on access for the infliximab biosimilars, and our study showed over $500 million—a half a billion dollars&mdash;of lost cost savings per year while that market share and the coverage remains the same. So we’re leaving cost savings on the table.

 So, overall, what I’m hearing is the good news, the experience with biosimilars worldwide has said they are every bit as safe and effective as their reference products. They’ve been extensively used in Europe and, we should say, various other markets around the world as well. They’re all made to the same appropriate high-quality standards, approved by the same reviewers at the FDA as any others. So there is no evidence of any reason for anybody to lack confidence in these products as alternatives to their reference.

However, we do have fundamental elements—it’s a little bit ironic being the United States and the ultimate competitive, putatively free market in the world&mdash;we do have fundamental elements in the United States that, unless they are changed, are precluding, in all likelihood, the long-term success of biosimilars in the United States. And that would be unfortunate for patients who will then lack access to these critical medicines, and I think none of us would say we want to undermine how important these medicines are. They really are life saving, life changing for patients.

So thank you very much. This has been an extremely informative discussion. And I appreciate the time you’ve spent considering the questions.

On behalf of our panel, we thank you for joining us, and we hope you found this Stakeholders Summit

 discussion to be useful and informative. Thank you.

Allowing the US Biosimilars Market to Flourish

 So, Julie, can I ask you to address how important biosimilars are to our healthcare system, but also to weave in—based on your citizen petition&mdash;what responsibility the FDA does have to deliver and make this work? How much is it about protecting and promoting the public health, the FDA mission, as Commissioner Scott Gottlieb, MD, has expressed it? Therefore, back to your petition, what does it mean if they are able to do this to the healthcare system in the United States?

 Sure. Thanks, Gillian. The success of biosimilars in the United States is critical, and we are at a critical juncture. Biosimilars are a private-sector solution to lowering drug cost in this country through competition. Competition is how we want to lower drug costs. Other policies are probably not what the industry would like to see. So it’s a robust biosimilar marketplace in the United States, and driving costs down through competition is key.

It’s not just about the FDA, though. Again, we’re grateful that the commissioner and Dr Christl and the FDA are doing what they’re doing to approve biosimilars. That’s key. The safety and efficacy is there. There are no clinically meaningful differences. We need to do more education.

But we need to take it now to the other stakeholders in this industry. Industry needs to support biosimilar uptake and support the competition. Physicians need to support and prescribe biosimilars. Insurers and payers and purchasers and pharmacy benefit managers need to cover biosimilars and provide access. It’s not just about the citizen petition and the misinformation; that’s 1 component. Education is another component. Access and coverage is the third component that needs to happen. Employers need to set things up. Ten, 12 years ago, I don’t know how long ago it was, we were working on getting this very pathway set up and getting the law passed here in the United States. It was the employers who came to support biosimilars, as well as the payers, that we needed lower-cost alternatives, and we needed competition in this space.

 Kashyap, I’m going to ask you to elaborate, particularly on the role of some of the other stakeholders. But Julie, what I’m hearing you say is the FDA can give the other stakeholders basic tools, basic sound bites, basic documents, whether it’s downloadable brochures or whatever it is that helps get those very, very fundamental, indisputable, simple messages out there. But then, of course, we do have to have alignment of the stakeholders to be pro-competitive. This is not anti-originator. This is not a size debate, and it is about access and affordability and expanding the market to those who can’t currently afford these often very complicated but very expensive medicines.

Kashyap, can you say something about the other stakeholders and how this system that we currently have will or will not help foster the uptake and use of biosimilars?

 Sure. There are 2 perspectives. One is we’ve walk this path. So we, being in the Oncology Care Model, adopted biosimilars early on. And as a case study, I presented our findings both at the [American Society of Clinical Oncology, ASCO] quality care symposium in Phoenix, Arizona, as well as at multiple meetings. We have been able to reduce the cost of care. In the first year we saved $34,000. That doesn’t sound like a whole lot of money, but actually, for my practice size, that’s the amount of money that came back from [The Center for Medicare & Medicaid Innovation, CMMI] as a shared savings.

We put that money back into hiring additional nurses, so we’re able to improve access because for us to expand access to same-day walk-in patients, we need to have extra money to hire employees. So the savings that we achieved, that came back to us from CMMI, we put it back into the practice for hiring more employees, so we are able to improve access indirectly, through putting money back into the system as we just said. Patients’ out-of-pocket costs have gone down.

And I remember 2 studies. One actually was specific to the product you mentioned, Carlos, Zarxio, where they showed that over the next 5 years, patients’ out-of-pocket costs, the total across the country, could be down by close to $34 million. The same study also mentioned that CMS would save close to $100 million and commercial payers would save close to $80 million dollars, give or take a little bit here or there.

But from a much more holistic perspective, every day we see a different announcement from the CMS regarding drug prices. We have the International Pricing Index as one of the models. Flat fees could be another possible alternative. You could have mandatory alternative payment models that are selected for the geographic areas. I think we have once-in-a-lifetime opportunity to address the drug pricing, and that is to use the biosimilars.

When you look at the RAND Corporation’s projections, they project that appropriate assimilation of biosimilars in the US healthcare space could save close to $50 billion in the next 10 years. We look at Dr Miller from Express Scripts: he wrote about 4 years back that appropriate assimilation of biosimilars in the mainstream space for patients’ treatment—either at infusion centers or in a hospital&mdash;could save anywhere between $100 billion to $250 billion over 10 years…beginning in 2020. So the number speaks for itself. My own case study says that there’s a significant savings that could be achieved.

But the tough job is when the FDA is doing its job and you are doing your job. Where I see there’s a silo is we need to educate the true stakeholders and the boots on the ground about extrapolation, safety, and what the class of drug is, and you have to do it for only 1 drug. Once you’re able to successfully implement strategies between the physicians, pharmacists, the PBMs [pharmacy benefit managers], commercial payers, advantage plans, and CMS, take 2019 or 2020 to put every possible effort into putting source and strategy into place. Second-drug start-up would not be a problem, I think. But next year will determine whether we are going to have biosimilars, as a class, succeed or fail, and I think the stakes are way too high. We cannot afford to make a mistake at this juncture.

The Role of Biosimilars in the US Healthcare System

Gillian Woollett, MA, DPhil: If we look to the future for biosimilars in the United States, I would like some conjecture from you all as to what does it mean to have biosimilars available as part of this multisource competitive environment for our health system, for patients, for all of the stakeholders we’re talking about? Why does it matter, Carlos?

Carlos Sattler, MD: I think we’ve already seen the impact of biosimilars in other parts of the world. And again, we always go back to Europe, but Europe has the most experience in both approving and launching these products. In many European markets, we’ve seen the impact of biosimilars, both from an increase in uptake and usage, appropriate usage of biologics in patients who need them, as well as in savings to the healthcare system. We talked earlier about the fact that biosimilars are clinically equivalent, if you may, to the reference products. From a clinical perspective, there’s no difference. The real impact that biosimilars can bring to the marketplace is increased competition, which will lead to decreased prices and overall decreased healthcare costs, that will then liberate some monies to fund innovation—innovative products are coming down the pipeline. I think we have seen that in Europe.

In the United States, it’s a younger market, if you may. A more nascent market. But with the product that was launched 3 years ago, the Sandoz filgrastim product, Zarxio, we’ve already seen an impact on healthcare costs. Just to give you an example, an early adopter of Zarxio was the Yale New Haven system, and they’ve already seen, at a 20% discount, about $400,000 in savings each year in their drug costs. 

So we’re already starting to see some impact in the United States. But I think we can look to Europe to see how much of an impact biosimilars have had, both from an increased access perspective as well as a decrease in healthcare costs.

The Future of US Biosimilars

 Do you see a point ever where we need no clinical studies whatsoever? And this can be a very short answer—no clinical studies whatsoever for a biosimilar to be approved, safely available, and used in the United States. And I’ll just go in order.

 Based on history, I told you that we don’t use an FDA-approved process for every use in clinical practice. I think having the biosimilar in the market for extrapolation designation would allow me to use that drug in spite of not having enough studies.

 I think the science will continue to evolve. I think it’s very important that it’s not a one-size-fits-all concept. The regulatory agencies will evolve, but they won’t lower standards, which is extremely important for this space. But I think the education and the physician expectation that there’s clinical data, we need to evolve that as well.

 I think we will get there. Again, let’s remember why clinical studies are required. They’re required to remove any residual uncertainty about the biosimilarity of a proposed biosimilar to the reference product. If that residual uncertainty has been taken care of, if you may, through other earlier steps in the biosimilar development process, whether it be through analytical comparability or pharmacokinetic studies, then there wouldn’t be a need.

And in fact, this month* a pegfilgrastim product was approved based on a large pharmacokinetic study. It was not based on a clinical study. So analytics, pharmacokinetics led to an FDA approval of a biosimilar, pegfilgrastim in this case. So it has happened. And as we evolve our techniques, as we understand better the relationship between structure and activity or function, then there may be less of a need for clinical studies.

 And to loop back right to the very beginning, Janet Woodcock, MD, testified in 2007 that when using comparability in support of manufacturing changes, less than 1 in 50, 1 in 100 times when comparability is used are any clinical studies required at all. So it would appear based on the regulatory science already in use at the FDA, that we may, maybe even in our lifetimes, reach that point.

Clinical Studies for Biosimilars

 The next big issue is interchangeability. Now, as you know, in Europe interchangeability is used more as a practice-of-medicine concept, switching between the biosimilar and its reference under the authority of the given prescriber. And in Europe, as a central regulatory decision, there is no designation by the [European Medicines Agency, EMA] as to whether a product is interchangeable or not.

Now the regulators have published, in their independent capacity, that they consider every biosimilar they’ve approved as already interchangeable with its reference. Meanwhile, the FDA has said, as a prescribing decision, FDA agrees with that same concept. Every product they’ve approved as a biosimilar can be switched by a physician for its reference. But in the United States, as a matter of law, the so-called interchangeability designation is to allow the pharmacist to be able to switch, subject to state law, but in a manner of a generic that’s therapeutically equivalent, a biosimilar for its reference, based on their own judgment, and which may be financial as to what’s beneficial to the patient.

So we have a difference between Europe and the United States. But it’s also led to this confounded situation, going back again to the citizen petition, that many physicians are apparently waiting on the FDA designation in order to themselves feel comfortable with switching between a biosimilar and its reference.

So if I can ask the question, do you think this is a pervasive problem even for those biosimilars, biologics that are both prescribed and administered by the physician? Is there going to be a reluctance to switch patients that are currently being prescribed the reference to the biosimilar? And then, Juliana, I’ll turn to you on the impact we think that has economically for the future of biosimilars.

 As a prescribing physician, I’m not terribly concerned about interchangeability once the FDA has approved the drug. The challenge, in all honesty, is that we need to let patients know that we are going to switch them over to a different drug with established efficacy, safety, and the profile that exists.

The problem may become more confounded because, in the United States, again, the healthcare system is different than in Europe. So in the hospital system, a lot of times it’s a pharmacy director who makes the decision about going for a contracting piece. So, if a hospital has contracted with a manufacturer to use only 1 class of drug, then clearly everybody automatically switches over. So interchangeability does not even remain as a question.

For our practice, for example, being in the oncology care model, we have an obligation and partnership with [the Center for Medicare and Medicaid Innovation, CMMI] to look into less expensive, equally effective, safe alternatives to what we can do. So we didn’t have an issue switching our patients into the biosimilar [granulocyte colony-stimulating factor, G-CSF].

There may be some differences when it comes to the pharmacy benefit managers, how they administer the drug, if they take a step therapy approach within a different class. So this is an issue that probably, again, would have to be resolved by joint efforts from the manufacturers, from the FDA, as well as from, again, the physician, which includes the GPOs [group purchasing organizations] and everyone else, to adapt to the fact that we have a less expensive, equally effective, safe alternative approved by the FDA that are available and that we can we run with.

So what I’m hearing from you is that as a physician you don’t have a problem.

Operationally, there are still some significant challenges. Julie, can you address how this impacts the prospects? The prospects for biosimilars commercially in the United States.

 I will address the misinformation. I think that’s really important because yes, thank you for stating that the physicians don’t require interchangeability.

And what we’re seeing impacting the marketplace is that we have seen payers, and purchasers, and some stakeholders say that they don’t want the biosimilar. They cannot cover the biosimilar or provide access to the biosimilar until it is interchangeable. And that misinformation is another piece the FDA needs to clarify.

As of today, there are 7 biosimilars in the marketplace in the United States. None of them are interchangeable. We don’t have the interchangeable guidance yet to develop an interchangeable biosimilar. Yet, prescribers can prescribe biosimilars, and they should be. Payers and insurers can provide access to biosimilars and cover them without the biosimilar being interchangeable. If folks are waiting for interchangeability before they cover or prescribe a biosimilar, we’re going to continue to see low market uptake. So that’s a key piece to correct that misinformation. We need these stakeholders, these insurers, the physician to prescribe these products.

 And I think part of the misinformation or misunderstanding is that somehow there is a belief that an interchangeable biosimilar is a better or higher quality biosimilar than a non-interchangeable biosimilar. Somehow, it’s a better product. When, in fact, a designation of interchangeability relies not on a better product but on additional data and additional analyses. It’s the same product. We’ve heard that some stakeholders are waiting, whether physicians or others, for an interchangeable product because they believe it’s just a better biologic, and that is not true. And I think that’s part of the misconception, misperception, misinformation.

 We need to limit interchangeability to what it is. It’s a pharmacy substitution enabler.

 So that a pharmacist can interchange and substitute without calling a physician.

Even though in the United States it’s a unique additional opportunity, it’s now being used to prejudice the mere biosimilar that in Europe they don’t have the designation at all.

Misconceptions About Interchangeability

 You introduced the term immunogenicity. Now, I always like to remember that with vaccines, immunogenicity is good. However, in the context of biosimilars, we’ve had this flag that somehow immunogenicity is bad. And I think what’s evolved is immunogenicity can indeed compromise the efficacy of some of these products over time, particularly perhaps in the immunology space of some of these chronic diseases such as rheumatoid arthritis.

However, that can be intrinsic to the molecule itself that you’re matching and a biosimilar is going to be essentially equally as bad, as well as just as good as the reference product. We’re doing comparative immunogenicity in these limited studies. We’ve got the data from Europe in which we’ve seen that in real-world use, the patterns match and they’re the same. So really, is there any particular concern with immunogenicity and biosimilars that physicians, patients, providers, anybody should be concerned by, or is it just something we monitor?

 I’ll start and then I’ll ask my colleagues to opine. I think it’s important to evaluate immunogenicity. But as you mentioned, Gillian, the goal here is to demonstrate that the immunogenicity characteristics or the immunogenicity or immune response of the biosimilar is equivalent or matches what you would expect in the reference product. Some biologics are more immunogenic than others. There are more complex biologics. Some of the monoclonals are more immunogenic than the simpler biologics. And amongst the monoclonals, some are more immunogenic than others. But again, what we’re trying to demonstrate here is that there is no difference in the immunogenicity profile of the biosimilar and the reference product.

We look at this in all of the clinical studies, whether they be human volunteer pharmacokinetic studies or efficacy and safety studies, phase 3 confirmatory studies in patients. And then this is evaluated also through pharmacovigilance and other means.

And again, I just want to emphasize that in Europe, where biosimilars have been available for over 10 years and millions of patients have received them and there is experience so far, there’s been no difference. And there are also a series of studies now that have shown that there is really no difference in the immunogenicity profile comparing a biosimilar to a reference product.