 Hello, and thank you for joining The Center for Biosimilars

 Stakeholders Summit entitled “Provider Education on Biosimilars.” I’m Gillian Woollett, senior vice president at Avalere. Participating today on our distinguished panel are Juliana Reed, vice president, Corporate Affairs, Global Biosimilars lead at Pfizer; Carlos Sattler, MD, head of Clinical Development and Medical Affairs at Sandoz; and Kashyap Patel, MD, medical oncologist and CEO of Carolina Blood and Cancer Care. Thank you so much for joining us. Let’s begin.

So, Pfizer recently submitted to the FDA a citizen petition asking for guidance on how product sponsors can communicate about biosimilars. Why did you see the need for this citizen petition?

 Thanks, Gillian. So, Pfizer saw in the marketplace educational materials and other materials created by reference product sponsors that created doubt and confusion about the safety of biosimilars. These materials, as we create the doubt and lower the confidence, will lower the uptake of biosimilars, so we felt it was necessary to file the citizen petition and ask the FDA to proactively do something about the misinformation about biosimilars in the marketplace.

 So, Carlos, does Sandoz have an opinion on both the issues raised in the citizen petition and also the ask that Pfizer has for FDA to provide additional guidance?

 Thanks, Gillian. We do, we actually do. We’ve also seen a lot of misinformation out there on biosimilars. I think it’s really important to take into account the following: Healthcare providers, prescribers, must be free from any influence that inhibits them from making the best decisions for their patients. Misinformation and unbalanced information on biosimilars inhibit them from making these decisions. So we believe that something must be done, and we agree with the citizen petition. But beyond the citizen petition and the fact that it requests that guidance be authored or created by the FDA in order to take care of this misinformation, there are other steps that the FDA, we believe, can take.

For example, they could partner with a Federal Trade Commissioner and identify the sources of misinformation. They could send letters to the sources of misinformation, to the companies and others that are doing this, to tell them to stop. They could make the names of these companies and other groups that are spreading this information public so that stakeholders, patients, physicians and others know who are spreading this misinformation. And finally, they can continue with the educational efforts that they’ve embarked on but specifically addressing some of the topics of misinformation that are out there.

Pfizer's Citizen Petition on Biosimilar Communications

 So, one would be most polite in using the term “misinformation.” What are we actually saying? We’re saying that some companies are promoting a concept that is overtly misleading, that biosimilars are somehow—let’s say, less effective&mdash;in nature of their development, which means they’re less reliable than the reference product, is that right?

 So…those misleading pieces of information are outlined in [Pfizer’s] citizen’s petition. But I want to go back to what Carlos said—and we saw this when we launched the first biosimilars in Europe 10 years ago, and the same misinformation was introduced in Europe, and we’re seeing that again today in the US, and it’s to lower the confidence and the prescribers and the patients in using biosimilars.

Ten years ago, we asked the [EMA, European Medicines Agency] to help us with that, and the same programs and actions…that Carlos outlined were taken by the EMA 10 years ago, where they were the source. And this is key. The FDA, like the EMA, needs to be a primary source of education on biosimilars regarding their safety and efficacy, and we need to help distribute and disseminate that information.

The FDA, like the EMA, needs to combat the misinformation that’s out there about biosimilars and send letters to these companies, the reference product companies that are doing this, or other organizations. It’s time. We need that here in the US.

 So, Kashyap, as a physician, as a provider, what have you seen from the clinical side, working with patients about this sort of misinformation that’s out there? Are you seeing it in day-to-day practice? Do you understand what’s being alluded to here by the sponsors?

 Thanks, Gillian. I think I have a little different perspective on this. I was not so much aware of this misinformation campaign, for the lack of better words. I wouldn’t use that, but I’ve done some intensive physician education at 5 national meetings in the last 2 months, and I was very unpleasantly surprised to find out so many misconceptions among physicians who are the prescribers.

I spoke at 3 large meetings and 1 of the national conferences, and the first question a lot of physicians asked me was “So, what’s the difference between a generic and biosimilar?” And I said, “Oh, where do I start here?” Because there’s a huge difference between a generic drug and a biosimilar. The generic drugs do not have the new trials; they are simply chemical components called [API, active pharmaceutical ingredient]. You buy it in a bulk, like kilograms or a ton, and convert them into the tablets.

But because there was a perception that there’s not a lot of difference between the generic drug and biosimilars, they say, “Well, why are they priced so high?”

And I said, “Listen, these drugs have to undergo multiple steps that establish the totality of evidence compared to the referenced product. It’s not an easy task. It’s not an easy solution, and that’s 1 of the reasons why you don’t see a huge price, or you definitely would see some of incremental decline in the price, but you don’t expect them to behave like generic drugs that happened back in 2004, 2005, 2006, when the paclitaxel went generic, when carboplatin went generic, when cisplatin went generic.”

So there’s a lot of misconception. It may not be intentional that they’re not learned, but we have to do a lot of—at least now&mdash;education at the physician level to have them become aware of what biosimilars are as a different class.

And the second observation I made was that patients were not as much reluctant with biosimilars, and then I’ll share, when our discussion points in the direction, that for patients who are least likely to resist adoption of biosimilars, I think the providers, the nurses, the mid-levels, and maybe the peers of the team that we need to work with in educating about biosimilars and what the class of drug is.

Combating Misinformation and Misconceptions About Biosimilars

 Well, then certainly I think what we’ve seen is that half of the problem is not exclusively wrong in the statements, but they’re ill impressions, and it starts with the name. For basically 15 years, we’ve seen that “biosimilar” means similar and not the same. But that forgets about no meaningful clinical differences having been determined by FDA. Now, obviously at this point in the debate, we’re not going to rename biosimilars as anything else. So what do we now do about it, given that complete information is a challenge? People use shorthand. Does this mean that we have to target specific populations in those settings where this misleading information is already out there? Is it certain stakeholders? For instance, you’ve alluded to the patients perhaps being less concerned if their healthcare providers have confidence.

So, is it physicians, patients, nurses, payers? For any of the panel, are there particular people who’ve got to have this full understanding, using FDA with primary sources? FDA does have on their website already that every biosimilar approved by them is as safe and effective as any other biologic. What is the form of the information that we need? What do these stakeholders need to receive?

 So, I think the stakeholders need to receive, and this is key in order to combat the misinformation, they need to receive the FDA educational materials. And as either industry or physician groups or patient groups, other stakeholders—insurers and payers&mdash;we need to help disseminate that. We need to proactively help the FDA to get that&mdash;those materials&mdash;down to the physician office level. It’s the source. The FDA needs to be the source of all truths about biosimilars.

 Just as in Europe we see all that with the [EMA, European Medicines Agency] and with the commission. Carlos, as a physician and as a sponsor, what have you seen similarly? You have launched products, too.

 Sure. A couple of thoughts based on the question that you asked: You’re right that because biosimilars are highly similar to the referenced product but not identical by the nature of the fact that they’re biologics. That is a handicap, if you may, although biologics are inherently variable. That’s just the way they are, because unlike a generic that is manufactured through chemical synthesis, biologics need to be produced in living organisms, and that by its nature introduces some variability that occurs from lot to lot, for example.

And I think a lot of the misinformation or misunderstanding comes from that. A generic is identical to the reference product because it’s a small molecule, and, therefore, you expect the same clinical effect. Biologics are so complex, and the biosimilar is not identical to the reference product; maybe you’re going to see some difference in clinical effect. But like you mentioned, even though there is this variability in biologics that makes a biosimilar not be identical to the reference product, it must meet the criteria of no difference in efficacy, safety, and immunogenicity, and I think that’s what’s lost. And I think education—basic education&mdash;on what a biologic is would go a long way, obviously adapted to the audience.

But to add to what Juliana said, where should the source of education come from? Certainly the FDA, I completely agree. It’s a trusted source; it’s independent from manufacturers. But I’d like to talk about how EMA went about this, right? EMA started education, but they brought in a series of stakeholders in order to create guidance documents. This included manufacturers; it included professional societies; it included patient and patient advocacy groups; it included payers and others. And so now they created this consensus among all stakeholders that put out educational material, and I think went a long way. I think the FDA should look at that and maybe try to do something that is similar.

In the end, I think it is a responsibility of many stakeholders to educate about biosimilars—not just the FDA&mdash;and it could be done through a single multistakeholder setting, but certainly patient advocacy groups, professional societies, manufacturers, and managed care to their membership should also assume that responsibility. I think for biosimilars to succeed…the educational effort has to be multiprong.

Targeted Education for Biosimilar Stakeholders

 So, what I’m hearing a lot of is basically that the business model is not relevant to the safety, efficacy, and quality of these products. The FDA has made that determination; they then need to help get the message out. So, do you believe that the primary source being FDA is essential to the physicians, the stakeholders you work with? How does the dissemination by others make a difference, or doesn’t it? If the FDA is the primary source, is that the only source? Can we accept European analyses? Are they pertinent, or does it all have to come through the FDA?

 So, probably there’s a difference in the European healthcare market and the US healthcare space. In Europe, you have the government-controlled contracting system. If the government decides they need for a common entire country, it’s going to be utilization, and then they’ll go with that.

In the US, you have to realize that the FDA’s role kind of pretty much is done when the information is sent out, but then you have to jump through the hoops of physicians, you have…[GPOs, group purchasing organizations], you have a contracting structure. Here, like, 50 states—and each state has its own managed Medicaid plans. You have Medicare Advantage plans, and you have pharmacy benefit managers. So the system is a lot more complex in the US compared to Europe.

So my suggestion is, yes, we definitely need the reassurance about the safety, efficacy, immunogenicity, and other relevant parameters of the biosimilar class as a drug class. But for the utility pattern, for the end users, unless physicians who are the gatekeepers of prescribing medicines—unless the message is out to them, either through national meetings, associations, not-for-profit educational utilization forums like this one&mdash;it’s not going to have an uptake. So no matter how many things we do to FDA following the [EMA European Medicines Agency] model, in the US, at the end of the day, the part of panel, the prescription of physicians, is the one that will determine the utilization?

 Yes, that’s where it’s worth emphasizing…and then, Juliana over to you…that most of these medicines are both prescribed but also administered by the physician. And in that sense, they’re a little bit different from a lot of the drugs where they’re dispensed in pharmacies separately from the person who prescribes them. So I just want to make that point clear that the physician is intimately involved in both prescribing and administering the medicines. Juliana, you had a point there?

 No, I agree. But I do think…the physician plays a very, very key role in all of this. So does the insurer.

 The insurers need to provide access to these products. The insurers and the [PBMs, pharmacy benefit managers] need to cover these products. But the FDA needs to combat the misinformation.

 What we’re thinking, then, is a catch-22.

 Because the biosimilar cannot say it’s better, then. Therefore, most physicians, most providers, could say, “Well, if we stick with the reference, that’s fine; we’re getting that option available to our patients.” So, we’ve got to level the playing field so that the value in terms of competitive pricing, alternative supply of the biosimilar, can contribute, get market share, and be part of this multisource marketplace that we now see in Europe.

 Yeah, a competitive marketplace. And you’re proactively engaged across stakeholders to support biosimilar uptake. It’s not going to just happen if not all the stakeholders are engaged. I’ll talk a little bit about what Carlos mentioned about what we did with EMA when we first launched, and the EMA had their congresses and continue to have them. Because we don’t have that model in the US, the Biosimilars Forum, of which we’re members, started that model independently, and the FDA—every few months we have over 60 stakeholder groups to a workshop and the FDA is there, the EMA is there. We have multiple physician groups, pharmacy groups, patient groups. Payers are there. It’s about supporting the biosimilars market. What do we need to do? And we started just with education and how we can get that. And as you mentioned, everyone has different information, and that’s why it’s very key that we go back to the one trusted source of information and education about biosimilars, the FDA. We also have to simplify this. We’ve made it very complicated. And really the source, the FDA&mdash;there are no clinically meaningful differences in a biosimilar, and the safety and efficacy is there. It’s that simple. We need to simplify it.

 And that’s what we’ve seen in Europe. So maybe the most pertinent information from Europe is in their multiple, multiple million days of patient treatment with these products, that is in 10 years what they’ve seen.

 Seven hundred million patient days of experience over 10 years and no difference from a clinical perspective. No unexpected adverse events that you otherwise would not see with a reference product. That’s a lot of experience.

 And the EMA published that. The EMA—so the authorities, the regulatory authority published that information and those statistics in their educational materials for healthcare providers.

US Versus EU Education on Biosimilars

 Let me address the comment that Kashyap made, which is that the FDA approves a product, and then your opinion is that the responsibility for education should be more at the provider level, or from providers or personal societies.

Again, as I mentioned, I think every stakeholder should be involved in education, and it can take many forms. But what we’ve observed from the FDA in the last year or 2 is a different approach.

For example, when they published their biosimilars action plan in July of this year, that is something that I thought was somewhat unexpected from the way the FDA normally operates. I think it has a lot to do with their perspective—a lot to do with the Commissioner, Scott Gottlieb, who really believes that biosimilars are part of the solution to increasing health care costs, so they’re taking action. We’ll see how far it goes, but I have expectations that they will actually adopt a different approach to biosimilar education and their interest in adoption in a healthy biosimilar market rather than the FDA did before.

 And then others can get that information out there.

The FDA's Approach to Biosimilar Education

 So, comparability is an issue that’s raised in the context of biosimilars. Comparability is a regulatory tool developed in 1996 whereby manufacturing changes can be made to an existing biologic. Then it was adopted internationally in 2005 and under so-called [ International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH]. Now, comparability—you can make a manufacturing change to an existing biologic as long as you show that the critical product quality attributes, including immunogenicity, haven’t changed. That’s been used extensively for many products including, I believe, infliximab&mdash;it’s published; it’s been used over 50 times since the product was approved.

Now, I say in general and shorthand, that makes every originator biologic essentially a biosimilar to itself. It’s been subject to changes, but the important point is, the clinical outcomes are no different. In the US, it’s an entirely confidential trade secret when comparabilities occurred, and most physicians, most providers, and patients—they don’t know that’s happened to their existing medicine because the label on the product doesn’t change.

 And because there’s no difference in the clinical performance.

 You could say that comparability is already the standard for extrapolation between indications and even interchangeability. So from a manufacturing perspective, does it matter? Is it important for physicians to know about these changes in the US in order for them to be more comfortable about biosimilarity? How much do you think education goes back to these fundamentals, understanding the variations of biologics both batch to batch, pre— and post–manufacturing change? But fundamentally, to this citizen petition that the clinical outcomes are unchanged—that’s the important other part of both comparability and both biosimilarity.

So, Carlos, do you find, as a manufacturer, there’s any understanding? Is there interest? Where are we on this fundamental understanding of biosimilarity and comparability being the same as a scientific asset?

 So, manufacturing changes, as you mentioned, occur frequently, and they’re there for very good reasons—for example, if there’s a scale-up in the manufacturing process that represents a change or there’s a change from one manufacturing line or facility to another or if there’s an improvement in the process. All of these are good justifications for manufacturing changes. But they do introduce potential variability in the product from an analytical perspective, from a characterization perspective. And again, as you mentioned, the pre—manufacturing change product and the post–manufacturing change product have to be shown to have the same clinical efficacy, safety, and no difference, no change in immunogenicity.

This is not well known. This is not well known among providers. In fact, when you describe this manufacturing change and the fact that it does result potentially in a change to the product, they’re not aware. But I think what’s critical is also what you mentioned. These changes occur frequently. They occur for good reasons, but there must be a demonstration that there’s no clinical impact. And they can happen multiple times, as they do, and you mentioned the example of infliximab. It’s been available now for a long time and has undergone many manufacturing changes, some of which are relatively minor; others may be somewhat less minor.

But as long the pre— and post–change product is shown to not have any change in the clinical effect, then the product remains on the market. There’s no change in the label. And I believe in that case, it’s interesting to make that known, because it provides some insight into biosimilarity because you’re absolutely right—the scientific concept between the comparability exercise of manufacturing changes and the biosimilarity exercise in demonstrating that a biosimilar is highly similar to the reference product is essentially the same. And you get a lot of “ah-has” from prescribers, even more so when you mention, then, that it is conceivable that a reference product is a, quote, unquote, “biosimilar of itself” over time&mdash;that also raises an ah-hah moment. And I believe that for products that have been on the market for many, many years, a product that was first launched compared to a product that’s currently available in the market is probably a different product from an analytical perspective, but, again, the efficacy&mdash;the clinical performance&mdash;has to be the same.

 So basically, what we know, then—and FDA did lead the world in 1996 with comparability protocols as the basis of manufacturing changes&mdash;is that the FDA knows how to do this. That’s 22 years of experience, by definition, with the very biologics that are the referenced products for biosimilars.

So, Julie, we talked about the experience in Europe. The European regulators have been absolutely explicit that biosimilarity and comparability are the same. Do you think we need that from the FDA too? Is that an opportunity—again, in terms of a primary source of educational materials&mdash;for FDA to add to this clarity? That doesn’t mean they have expose for individual products when comparability is being used, because in the US, that’s a trade secret; in Europe, it’s public. But would it help for the FDA to articulate some of these primary principles and, quite frankly, laud their experience on successful use of comparability?

 Thanks, Gillian. And yes, I think it would be supportive and helpful if the FDA was to clarify this. But I think—and I go back to what Carlos said&mdash;it’s important to understand that both Pfizer and Novartis Sandoz are innovator companies and biosimilar companies, as well. And I think if the FDA could clarify this but also clarify that the standards for biosimilar and its innovator biologic or its reference product are not different…So, I think those are very important as far as manufacturing changes, comparability, the data, and everything else goes. So we need to simplify that message. The FDA should take the lead on that and then continue to provide…

 This is not anything new we’re asking really at the FDA.

 In fact, they’ve got everything on their website, which I personally find phenomenal, because there’s so much stuff there.

 But you need to know for it look for it, so we’re essentially asking simple summaries.

What Juliana is asking is the basics, right? Just understanding some of the basics would clarify some of these misconceptions. For example, the quality standards and requirements of biosimilar manufacturers and reference part of manufacturers are exactly the same. As Juliana mentioned, at Novartis, for example, we manufacture our original, originator biologics and biosimilars in the same manufacturing facility. So the standards are the same, and this is the same in the [European Medicines Agency, EMA] as it is in the FDA. There’s this perception that somehow the standard and the requirements for biosimilars are lower than the referenced products, and that’s just not true.

Biosimilarity, Manufacturing Changes, and Comparability

 For clinicians, do you think this whole idea that the originators vary but biosimilars vary too, and they’re all within the same range as overseen by the same people at the FDA—is that a useful message?

 It probably would be a very useful message because there are a lot of physicians who are on the fence right now, not understanding the class as a whole. So something coming out from the FDA highlighting that the originator has undergone multiple modifications without compromising the quality, efficacy, or safety—it would reassure the physicians who are prescribing that yes, I’m not going to compromise the quality of care because I’m choosing something that’s likely less expensive but I’m going to sustain and maintain the quality of care.

It would be extremely helpful information coming out from the FDA. Because for me, I don’t have personal expertise in judging all these aspects. But I trust the FDA as a very reliable source of information that would help me make very important treatment decisions.

 And this is a good message, I think, that the FDA is doing its job. They are overseeing all biologics to the same standard, consistently. Therefore, physicians, patients, providers can have equal confidence.

 Just to give an idea of the scope of biologics that have been available since recombinant technology actually became available—we’re talking about the 1980s&mdash;there’s a recent publication&mdash;actually, this year&mdash;that identified approximately 260 biologics that have been approved since. And you can expect that virtually all of them, or most of them except maybe the most recent ones, have undergone some manufacturing change. And in just 3 cases were there any issues between the pre— and post–manufacturing change product&mdash;1 of them having some significant safety issues… and some of these happened, like, decades ago, right?

 And the scrutiny and the process and the released specification for products now are even tighter, but that should speak to how controlled manufacturing changes are and how the comparability exercise is so very well refined. And understanding, again—like you mentioned, Gillian&mdash;that the scientific concept behind comparability and biosimilarity is the same would, I think, go a long way in accepting biosimilars as high-quality products.

 And certainly one thing that I’ve always noted is, given the extent of the data by about the time a biosimilar is approved, on both the originator and the biosimilar, we do have to bear in mind that the product that we always know the least about at the point of initial approval is the truly innovative product, and we all want those approved. This is a risk—benefit exercise. We’re trusting the FDA to it, and they’re doing it based on some very, very well-founded science and principles. So I think that context is important because we want the new, cool products too.

Clinicians' Understanding of Manufacturing Changes

 So, I’m going to move to the next issue, which is extrapolation, which is another much misunderstood issue. So by way of introduction, extrapolation is the use of a product for more than 1 indication, but for a biosimilar, when the studies are limited to other than complete clinical studies in every indication. Now, it’s the same as comparability, where if you make the same molecule, ultimately, it has to do the same thing clinically in all of the indications.

So I think what’s confused this debate a lot is that people are assuming it’s extrapolation between indications that may be fundamentally different diseases. So I just want to clarify that it’s not. It’s the same molecule, and it has to do the same thing as the reference did, as the premanufacturing change did. But it does mean we have more limited clinical data sets specific to the biosimilar on the day the biosimilar is launched.

Physicians are used to seeing clinical studies on each indication at the day of approval and launch of an originator product. So maybe to our physician, how much is this misunderstanding, based on the molecular match being the basis of extrapolation—how much is that confounding biosimilar uptake if there are no specific clinical studies on the biosimilar available to put in front of the physician?

 So, I want to answer that question in a couple of different ways. First of all, extrapolation is something that’s very important—that the FDA kind of grants its designation to a drug when it’s approved, and maybe the FDA can play an important role in helping physicians understand what extrapolation is. And the second thing is, in oncology, if you trace back the history of how we use drugs, a lot of times we may not have phase 3 randomized controlled studies in all of the indications that we use. We initially, before [the National Comprehensive Cancer Network, NCCN] came into existence, used to use compendia listing for indications that were not part of the FDA-approved indication.

Subsequently, with NCCN establishing a robust pipeline evaluating, analyzing, and granting these data—like, you know 1A, 1B, or 2A&mdash;we are very comfortable that even if the drug has not undergone all clinical trials in all indications, if it comes into the guidelines, whether they’re the [American Society of Clinical Oncology, ASCO], [American Society of Hematology, ASH], or NCCN up to 2A, we would be very comfortable using that drug in those categories. Now, what the FDA could do is to help physicians understand about how extrapolation is kind of derived, and how it probably would be helpful.

Also, getting into the NCCN, or ASCO, or other guidelines would help a product get appropriate payer coverage, because we just don’t need to kind of look at the approval process; we also want to look at are payers and whether we cover that or not.

So, I think extrapolation is a very important part of the educational piece that does to be highlighted, and the FDA would be the most competent authority to do that in conjunction with not-for-profit educational forums.

The Extrapolation of Indications

So it’s fundamental. I think the greatest value for sponsors is this ability to extrapolate between indications once they’ve established high similarity. We often hear this discussion, and Carlos, I’m going to ask you this question about the most sensitive population, that you are only studying the biosimilar limited confirmatory clinical studies in the most sensitive population. Can you help us understand what the most sensitive population means and how you choose which studies you do clinically for a biosimilar?

Sure. I just wanted to highlight a couple of things about extrapolation and I'll get to the question. It will lead to that. I want to emphasize a couple of things. Extrapolation has to be scientifically justified by the sponsor. It’s not automatic. And as Gillian mentioned, it is based on the totality of the data that show that a biosimilar is highly similar to a reference product and that you don’t expect any clinically meaningful differences between one and the other. Other aspects also taken into account when determining extrapolation, for example, include the mechanism of action. But the essential component here is that if the molecules are highly similar to the biosimilar reference product, then they should behave the same across all indications. That is number 1.

Number 2: I think it is absolutely understandable why clinicians would feel uncomfortable prescribing a biosimilar if there are no clinical data because, as Gillian mentioned, they are used to clinical data. That’s how they make determinations. So here it is incredibly important that providers, clinicians, prescribers understand the biosimilar concept because without understanding it and understanding how that leads to extrapolation, there will be this discomfort and resistance. 

I also agree that the FDA is in a really special position, because they granted the extrapolation of indications, to be able to educate about that. 

I think the last thing I’ll say and I’ll get to your question, I promise, is that for the biosimilar paradigm to be successful and for sponsors of biosimilars to be able to bring these products to market at a lower cost, the development costs have to be lower. And with new biologics, the majority of development costs are spent in clinical trials, and we’re talking about sometimes hundreds of millions of dollars, depending on the product and the size of the trial. By scientifically justifying extrapolation, then a manufacturer can do a study in 1 population, and this is where we’re getting towards the most sensitive population. The Sandoz approach to this is we try to identify a population where a few things happen. 

Number 1: We see the greatest effect of the particular biologic on that particular disease stage, so the biggest delta. And that allows us to see that if there are any clinical differences between the biosimilar and the reference product, they will be identified. So that’s one concept.

Secondly, we’re looking at populations that are not highly variable. So you can actually, when you measure the impact, attribute it to the biosimilar or the reference product. And we’re also looking at populations that are not necessarily using concomitant medications that could obscure some of the measurements that you’re looking at. So, for example, patients who are receiving other immunosuppressants may be difficult to evaluate immunogenicity on, or compare the immunogenicity between products, between the biosimilar and the reference product. So that is how we choose the most sensitive clinical population in order to determine biosimilarity. But it’s also important to note that is the last step in biosimilar demonstration. 

It hinges on having demonstrated that, analytically, the reference product and the biosimilar are highly similar, that it’s a structural and functional perspective, that you’ve demonstrated, if applicable, in preclinical models that there’s no difference from a clinical performance perspective, and that you’ve evaluated bioequivalence to pharmacokinetic, pharmacodynamic evaluation in patients or in human volunteers, depending on the situation. So this is the last step in the biosimilar development paradigm, if you may, and hence, why the ability to extrapolate from that indication hinges on all of the other information and data. 

I think you’re making a good point there. These are confirmatory studies.

And if you haven’t established high similarity analytically in the first place, you can do all of the clinical studies in the world and you’re never going to be a biosimilar. So I think it’s very important that the clinical studies address what is variously called “residual uncertainty.”

Selecting the Most Sensitive Population for Confirmatory Trials

 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.

Immunogenicity and 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

 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

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

 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

 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

 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

Molly Billstein Leber, PharmD, BCPS, FASHP:

 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

 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 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.

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

 To get final approval there is phase 3 data at this time, and I think that’s something that should remain at this time. I trust the FDA, and as long as they have that as sort of a mandatory component of the biosimilar approval, I think it should remain. Again, these are autoimmune patients that are taking this, and if you really want prescribers to prescribe biosimilars, you want to do as much as possible to give them confidence that it works in their patients, that there’s not going to be any problems with their patients. And if you take out the phase 3 data, yes, it may save time and it may save money, but if no one is going to prescribe the drug because they have less confidence in it, that point becomes moot. So, the time to get to the approval, once they’re approved, we got that patent thicket. That already is going to set them back, and then they may not ever get on to the formulary. So, you want to do as much as you can to instill confidence in the prescribers out there. And if they think that it hadn’t been tested in that final group of humans, their kinds of patients, they may be less apt to prescribe it.

When we have preferred tiers, as we know, these are all very expensive medications. So, you have to have tried a lower-cost alternative before even getting to a biologic or a biosimilar. Even if biosimilars come in at 30% or 40% off reference prices, which we know probably won’t happen, patients still won’t be able to afford them unless they’re covered by their insurance. And in order to get on to the preferred tier, there are certain requirements that at this point, biosimilars just are not going to be able to make it. They’re new to the market, so they have no market share. Their list price is less, so the [pharmacy benefit managers, PBM] don’t make as much money. Even if they give a 50% discount with a market share of zero, that doesn’t equal a 30% discount on a higher list price with a market share of 50%.

So, I think that’s probably after the patent dance that I’m not going to get into, I think that’s probably going to be the biggest problem. However, if the biosimilar manufacturer does happen to have the market share either in that disease space or in another disease space, it would make it more likely that the biosimilar might be able to get to the market. And I think it’s a shame that safety, efficacy, and lowest list price are not the determining factors for what makes it to the preferred formulary. And if we can make a change with that, then I think the lower cost of biosimilars will actually propel them forward and have a much higher uptake in the United States.

It’s felt that [state-level interchangeability legislation] needs to be passed in order to have biosimilars prescribed and prescriptions filled. Some of the most common criteria for that legislation is that the physician needs to be notified by the pharmacist. How long of a time between the fill of the biosimilar and the notification has been some sticking around the country and various states have different lengths of time, whether it’s 5 days or they actually use the term “within a reasonable amount of time.” The other thing is, how are physicians notified? And I think the electronic interoperability will help not just faxing. That too was a problem with pharmacists. Who’s going to pay for us to do all of this extra work?

And then finally, I think one of the other things is that things are similar in terms of record-keeping. You need to keep a record for several years. And I think we have all but maybe 4 or 5, there’s some sunsetting biosimilar legislation in a few states, but most of the country has passed some type of legislation where the physician, the prescriber gets notified. It’s designated how they get notified, what’s the length of time, and record-keeping.

I probably will sound like a broken record in saying this. I honestly feel that biosimilars will be a great help in reducing the cost of medication because as we continue on, we’re going to have more and more patients taking biosimilars, and more and more biosimilars coming to market. And, if they can’t get on the formulary, no one will be able to take them. So, I think if we can somehow reform that system, the natural flow of biosimilars will occur much more smoothly.

In terms of the future of biosimilars globally, we really think that perhaps there should be some global harmonization to the naming. We didn’t talk about naming in the United States. That seems to have been sort of set by the FDA. But globally, because there are so many varying places with manufacturing and changing of the proprietary names from one country to another, at this time it’s really important that we have some type of standardization in terms of not just the biosimilar but the reference product as well. Then there can be some pharmacovigilance, which some seem to think is overused these days. But I think when we look at the world and some parts of the world may not have the capabilities of pharmacovigilance of others, if we had global harmonization, safety, and the ability to track if there are any adverse events, I think that’s very important.

Madelaine Feldman, MD: Practical Considerations for Biosimilars

Molly Billstein Leber, PharmD, BCPS, FASHP: 

I think the biggest challenge is provider acceptance. I think that’s probably, for the supportive care agents, less of an issue now because we are able to track lab values and show that the drug is working. I think provider acceptance into some of these new curative agents is going to be difficult. I think from a payer standpoint, where a lot of organizations are struggling right now, is they would like to switch to the biosimilar product. However, some of the commercial payers do not cover the biosimilar product. And so, depending on the organization’s payer mix, you may or may not be able to switch the majority of your patients to the biosimilar. And so, you may need to continue to either maintain the originator product as your sole formulary or you may need to stock multiple products, depending on the payer coverage issues.

Stakeholders Summit: Provider Education on Biosimilars

Pfizer's Citizen Petition on Biosimilar Communications

Combating Misinformation and Misconceptions About Biosimilars

Targeted Education for Biosimilar Stakeholders

US Versus EU Education on Biosimilars

The FDA's Approach to Biosimilar Education

Biosimilarity, Manufacturing Changes, and Comparability

Clinicians' Understanding of Manufacturing Changes

The Extrapolation of Indications

Selecting the Most Sensitive Population for Confirmatory Trials

Immunogenicity and Biosimilars

Misconceptions About Interchangeability

Clinical Studies for Biosimilars

The Future of US Biosimilars

The Role of Biosimilars in the US Healthcare System

Allowing the US Biosimilars Market to Flourish

Madelaine Feldman, MD: Prescribers' Understanding of Biosimilars

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

Madelaine Feldman, MD: Physicians' Concerns Regarding Biosimilars

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

Madelaine Feldman, MD: Practical Considerations for Biosimilars

Molly Billstein Leber, PharmD, BCPS, FASHP: Adoption of and Education on Biosimilars

Molly Billstein Leber, PharmD, BCPS, FASHP: Interchangeability Laws, Substitution, and the Future Role of Biosimilars