Print BCTV: Biosimilar Report Card -- EMA biologics head, Amgen evaluate 7 years of biosimilars in Europe

Biosimilar Report Card

Transcript of BioCentury This Week TV Episode 138




Thomas Moore, Director of Value, Access and Policy, Amgen Inc. (NASDAQ:AMGN), Thousand Oaks, Calif.

Peter Richardson, Head of Biologicals, European Medicines Agency (EMA), London, U.K.




EuropaBio, Brussels, Belgium

European Commission (EC), Brussels, Belgium

European Medicines Agency (EMA), London, U.K.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.



Steve Usdin, Senior Editor




STEVE USDIN: The United States is still waiting for low cost versions of biologic drugs. Europe has had biosimilars for seven years. Is the biosimilars market working as planned? And are there lessons for the U.S.? I'm Steve Usdin. Welcome to BioCentury this Week.


NARRATOR: Your trusted source for biotechnology information and analysis, BioCentury this Week.


STEVE USDIN: Unlike pills, it isn't possible to make exact copies of complex biological drugs that are infused in doctors' offices and hospitals. But it is possible to make biologics that are similar to each other. In the U.S. and Europe, so-called biosimilars are deemed to have the same safety and efficacy as the innovator medicine.


Policymakers hope they'll be cheaper. In the U.S., a law allowing biosimilar copies went into effect three years ago. But no companies have applied for FDA approval. To understand what might happen, Americans can look to Europe, where biosimilars have been on the market for seven years.


Three classes of biosimilars are approved in Europe. Human growth factors, primarily used to treat children with growth hormone deficiency. Erythropoietin, or EPO, is used to treat anemia. And Filgrastim is used to stimulate white blood cells depleted by chemotherapy.


So far, biosimilars have produced only modest savings in Europe. This led the European Commission to ask for a study to see if new laws or regulations are needed to increase the market share for biosimilars. The study was recently released. It doesn't answer the question, but it does say biosimilars are starting to provide economic benefits.


Now the European Medicines Agency is reviewing the next generation of biosimilars: monoclonal antibodies for autoimmune diseases like rheumatoid arthritis and cancer. These promise more economic savings, but it'll be harder to show that these more complex molecules are actually biosimilars.


I'm pleased to be joined today by Dr. Peter Richardson, who is head of biologicals at the European Medicines Agency in London, and Thomas Moore, director of value, access, and policy at Amgen. He represents the pharma trade group EuropaBio on a European Commission working group on access to biosimilar medicines.


Dr. Richardson, I wanted to start with you. Seven years of experience with biosimilars in Europe, three different kind of product categories of biosimilars, have there been any safety issues with biosimilars? And if there were, are you confident you'd know about it?


PETER RICHARDSON: Well, the opportunity to have a biosimilar in Europe is going back nearly 10 years now since the first legislation was introduced. So we've progressively seen, over the early time, three product classes, as you mentioned, somatropin, erythropoietin, and GCSF being authorized since 2006 to 2011.


So there's a good degree of experience in terms of the use of these products. To date, we've had no safety issues particular to these products being addressed to us. So we're confident that the process at work is producing and delivering safe and effective medicines the European market.


STEVE USDIN: And Tom, Amgen probably has as much as any company to lose from competition from biosimilars. You've got as much at risk. You have announced plans to develop biosimilars. So you're kind of on both sides of the fence. Is this a kind of, if you can't beat them, join them situation?


THOMAS MOORE: Good question. I don't think it comes down to that. It's not that simple. It's not a question of having anything to lose from competition. It's really looking at what we can do, as an innovative biotechnology pioneer with 30 years of experience in this space, and taking a look at some of these molecules whose patents will be expiring in the next decade and making the determination that we think we can develop medicines that are similar to those that could be of a high quality, just as Dr. Richardson alluded to, and produce plentiful and reliable supply, which, theoretically, could help expand access to this class of medicines.


STEVE USDIN: So the reason to produce biosimilars, the only reason to have them is because they would be cheaper than the reference products, the original products, or in other ways would lower the overall cost of healthcare. How has that worked in Europe?


PETER RICHARDSON: Well, I think since the introduction, it's been a little bit of a slow uptake. It's probably taken a little bit longer to get going then, maybe, we would have hoped. But the price competition is certainly there. And certain member states, certain countries in Europe have taken a more progressive approach to biosimilars and are actually proactively pushing to have those products introduced in their markets. And typically, the price reductions have been something like 30% from the originator's original price after introduction.


STEVE USDIN: So that that's a price different that's nothing like the 70 and 80% price decrease you see for generic drugs, but it's off of a much bigger price, so it could be significant.


THOMAS MOORE: Yeah, I think it's just important to recognize. And I've lived in Europe for the last two years and worked for our European headquarters in Switzerland. And I'm in the process of relocating back here to the U.S.


And it's fundamental that this audience understands that Europe isn't one market. It's not one country. The EU is basically 27 countries, plus 1 about to join, and then Norway and Switzerland. So you're dealing with 29 individual healthcare systems that are place -- each of which regulates prescribing and reimbursement along its own guidelines. So if you look at this biosimilars experience in Europe, there isn't a clear analog. And that level of discount that you see can be greater in some markets, or almost nonexistent in others.


STEVE USDIN: So this report that came out recently from the European Commission, the so-called Tejani report, which was looking at these market issues, it was prompted by concerns that there wasn't sufficient market access for biosimilars -- that they weren't doing what they're supposed to do. Broadly speaking, what did it conclude?


PETER RICHARDSON: Well, I think the report is really being introduced to try and provide a better platform of communication on biosimilars, so to make it clear to everybody what a biosimilar is in terms of how it's been authorized and that it is a safe and effective copy version of the originator's product. So it's trying to eliminate some of the noise that has built up with various stakeholders providing their own story at times.


STEVE USDIN: So that's a polite way of saying that some people have been disparaging the safety of biosimilars, or the efficacy of them in their reports, trying to take some of that ground back.


PETER RICHARDSON: So there are different views. And I think even from some of the professional bodies have actually advised their members not to use biosimilars in certain situations. So we think that that should be put onto a clearer platform of communication as to what a biosimilar is.


And it looks, really, at the usage of the biosimilars across the various European countries, looking a little bit at how they're used. And it goes on to talk about things like whether substitution could be an option or not. So that's not something that we're going to do in Europe, but it's certainly a key feature, I think, of what's on everybody's lips, I think.


STEVE USDIN: Well, you know, that's a good point. Unlike traditional drugs, biosimilars aren't substitutable in Europe. And that changes the market dynamics. We're going to take a look at those snapshot market dynamics now. And we'll be back in just a moment.


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STEVE USDIN: We're talking with Peter Richardson of the European Medicines Agency and Thomas Moore of Amgen discussing the European experience with biosimilars. Dr. Richardson, from a scientific standpoint, do you think that we'll ever get to the point where biological copies or biological versions of drugs are actually substitutable for their reference drug in the same way that a generic drug is substitutable for the original small molecule drug?


PETER RICHARDSON: Well, I think we've got legislation in Europe which specifically defines a generic and it's quite strict. It says the substance should have the same quantitative and qualitative form, so a biosimilar will always have some degree of variability in the maybe the isoform structures, whatever, in the substance.


So what is critical is that the quality is analyzed at a very high level of detail and characterized and compared directly against the originator's reference product. So once that is established, it will set out the pattern of differences that we see at the quality level. And some of the differences, I think, will come through to be mainly non-critical types of differences, so they're differences that don't affect the safety and efficacy of --


STEVE USDIN: The whole premise of it is that clinically, it's going to be the same, even if there are some differences that you can detect.


PETER RICHARDSON: Right. So that's the foundation stone of the biosimilar analysis, the quality is very high quality, and it's shown to be highly similar to the reference product. So based on that, depending on how good that is and the history and understanding of the product itself, there is an opportunity to reduce non-clinical and clinical data packages. So that's really the philosophy that we've had in Europe to try and drive down the amount of non-clinical and clinical data.


So whether that gets down to the level of a generic, which is a bioequivalence study, is something that is still debated. But I think, we'll live with the European legislation, which specifically defines a biosimilar but it also defines a generic. So the biosimilars are not generics in terms of legislation, so that affects maybe some prescribing activities within the member states of Europe, but it also gives quite a broad flexibility in terms of the data requirements that are needed for a biosimilar.


So in complex situations, maybe we need a bit more than for products, which are easily characterized, and then the data requirements may tend to approach those of a generic in some way. So that's a spectrum of data.


STEVE USDIN: So there's two kind of issues, one is interchangeability, whether two products are the -- can be considered the same, and then the other one is substitutability, whether a pharmacist, for example, can substitute one drug for another. And in Europe, that decision about substitution is made at the member state level, correct?


PETER RICHARDSON: That's correct.


STEVE USDIN: I remember you saying that. There's one member state, Norway, that Amgen actually sued to prevent them from substituting a generic -- I mean a biosimilar, I'm sorry -- a biosimilar version of one of your products of a Neupogen, right?


THOMAS MOORE: Before we get to Norway, just to quickly come back to what Peter was discussing with this recent European Commission report that was issued, it specifically notes very strong double-digit growth of all the established biosimilar candidates that are in the market, annual double-digit growth and that that's taking place without substitution.


So the commercial marketplace is evolving even without it and it's important to know because oftentimes, people look at Europe and say OK, something's wrong there in the commercial sense. These molecules aren't taking off. But if you look at the data, they're actually doing quite well.


STEVE USDIN: I'm sorry, and that report also said that over a one year time period, it had 240 million euros as the market size for biosimilars in Europe. Isn't that kind of disappointing? Isn't that a pretty small number?


THOMAS MOORE: No, because you have to look at the overall value of the market in which they compete, which is basically about -- excuse me, it's about 100 billion euro worth of sales for those short acting candidates whose patents have expired and are subject to competition.


So as Peter was alluding to, these are basically new molecules. They're not generics, that have gotten up and running, that now have about 25% of the sales value of the market. That's not a bad place to be. The report also notes that biosimilars may not necessarily always be less expensive than their reference product.


So it's an interesting dynamic because of the pricing reimbursement mechanisms in each country, the way these companies would seek to market them could be on parity with an established entity and could ultimately result in having a more expensive price just depending on what the originator might do to compete. To the last point about substitution, the report notes that no European country has either authorized it yet -- quite a few have taken legislative or regulatory steps to prevent it.


The Norway case was more -- it had to do with Norway's law and that the Medicines Agency wanted to require automatic substitution of filgrastim at the retail pharmacy, and the law did not allow for it.


STEVE USDIN: We're going to get back to that in a minute, I'm sorry. We've been discussing Europe's experience with biosimilars. Here's a look at the range of biosimilars that are on the market in Europe.




NARRATOR: BioCentury This Week.


STEVE USDIN: We're talking about Europe's efforts to create a market for lower cost biologics with Peter Richardson of the European Medicines Agency, and Thomas Moore of Amgen. When we finished there, we were talking about Neupogen which is a first generation biotech product. But, really, I think the real excitement, and, of course, where Amgen's focused in biosimilars, is on the next generation, the next wave of products. And probably the most exciting thing -- interesting thing -- there are monoclonal antibodies.


Some of the companies that have announced monoclonal products seem to have some hiccups, or some setbacks lately, it's hard to tell, looking at it from the public information. But is it turning out to be more technically challenging than people had anticipated?


PETER RICHARDSON: Well, there are a range of monoclonals doing different things. So some are more complex than others. But in terms of the next wave of biosimilars coming, it's certainly what the future holds for biosimilars because we've had, let's say, in 2011, over 20 companies coming for specific scientific advice to the agency. And similar numbers, a little bit less, in subsequent years. So there's quite a potential for new products to come through the pipeline.


So we're looking forward to seeing that evolve. At the moment we have a transparency policy which allows us to state that we have two infliximab products under review at the present time. So those two biosimilars are in the pipeline. And in terms of the complexity of the biosimilars, it depends on, really, what the targets are. So it could be just a binding function, or if there are effector functions, it could be immunomodulator versus oncology indications. So all of these things add up to more or less complexity for the monoclonal.


And ultimately, again, as I said earlier, it comes down to the quality characterization, that we want to see a high level of definition of all of the quality attributes. And then that will let us decide a little bit more what we need to be asking for the clinical data.


So normally, we're balancing a single type of clinical study for these, like we did for the previous biosimilars. But that may need to be made a little bit more robust, depending on the particular case.


STEVE USDIN: So you've said there are two applications. And what's the timeline on that? When can we expect to see the first decision, either approval or rejection, of a biosimilar monoclonal antibody in Europe?


PETER RICHARDSON: Well, those are reasonably mature applications in the system, now. So it should be coming to decisions in the next few months, I would say.


STEVE USDIN: And Amgen has announced that you're pursuing a couple of monoclonal antibodies, right? Where do you see the opportunity there?


THOMAS MOORE: It's more than a couple that we've announced. So it's several.


STEVE USDIN: Several monoclonal antibodies? I'm sorry.


THOMAS MOORE: And primarily in two areas -- oncology and inflammation. That shouldn't surprise anyone. That's where the majority of the monoclonal antibodies, or MABs, are established in that space. And it would be good for the audience to be reminded, we currently have several innovative MABs in the space as well.


So we know how to do it. We think it is an interesting scientific endeavor to get engaged in the process of trying to clone existing products and bring them to the market. And we're learning things about biology in the process and getting very sound scientific advice as we go along.


STEVE USDIN: Well, that's an interesting thing, also. Do you think that developing biosimilars, and the innovative companies doing it, and companies that are more in the generic space doing that, is that going to lead to innovation that is going to flow back into other biologics manufacturing and development because you're looking for the cheapest, most efficient way to do it?


THOMAS MOORE: I mean, any time you're in a lab trying to determine why something is working the way it is, or isn't working the way you think it is, is a healthy exercise. The key with biosimilars is ensuring that there's some degree of clinical testing that's required before these products ever go to market, which Europe currently does, and the FDA, in its draft guidance, has said should be a requirement as well.


Because patient safety needs to be at the center of this. It can sound trite. It can sound self-serving, but biotech products are inherently complex. The variability could pose risks that no one could foresee without getting I tto the clinical space. So to answer your question, yes. And it's just important we stick to the guidelines and regulations that have been laid forth.


STEVE USDIN: We started off the show, I asked you whether biosimilars -- have there been any safety problems with them. But I also asked you if you'd even know it? That's one of the critical questions, what's called pharmacovigilance, in the technical term. Whether you have confidence you would know if there are problems. How are you doing that, and what are the issues going forward for it?


PETER RICHARDSON: Well, in Europe, there's recently been a fairly major upgrade of the legislation on pharmacovigilance, and that's become effective since 2012 -- July 2012. And that's making an effort across all areas to really upgrade the scrutiny and the robustness of the whole pharmacovigilance system.


The key things, I think, for biologicals that have come through from that are that we require that the biological is identified by its trade name. And if there's an adverse drug reaction report associated with a particular substance, then, also the batch number of the product is reported.


So I think the key thing from the European side is we're focusing on the product, trying to drill all the identification onto the product, maybe not quite so much at the substance level. So we are still using INNs that are proposed by --


STEVE USDIN: INNs are the international non-proprietary names. And so, for people who don't follow this all very closely, there's a lot of nuance here about the naming of the products, and what we would call the generic name for a small molecule. Tom, what's Amgen's position on what should be happening in Europe and in the United States?


THOMAS MOORE: I mean, our position, globally, is that we believe in having distinguishable names for all biologicals, including biosimilars because reliance on brand and batch number, as Peter was alluding to, could work, but we're seeing shortcomings in the system where it hasn't always worked. So for example, in Europe, because of austerity, you've had governments that have mandated that physicians start prescribing all medicines by that INN that's in the parentheses by a brand name --


STEVE USDIN: The non-proprietary name.


THOMAS MOORE: Regardless of what the medicine is. And so you have the potential for some form of substitution to occur if the products are sharing the same name. And then if there's suspected lack of efficacy or an adverse event that's reported by the healthcare practitioner, the pharmacist, or the patient, and the product was prescribed by INN, it's really a guess as to which medicine was given if there was some form of de facto substitution.


So it's not as tight as it could be. It's not the end of the world. But we would like to see it become a little more crisp with having distinguishable names.


STEVE USDIN: So it's interesting. Obviously, the people who are proposing the same names, the same INNs for biosimilars are doing it precisely because they want to encourage substitution or make it easier to do that.


THOMAS MOORE: I think, scientifically, they think the same name is warranted because of the chemical substance at the root of the product -- the biological substance, excuse me. But it probably does fit the generic paradigm, and their narrative, to have that happen.


STEVE USDIN: Well, thanks. Next, we're going to get some final thoughts about the future of biosimilars.


NARRATOR: BioCentury, named the 2012 Commentator of the Year by the European Mediscience Awards for excellence in communications and clear, concise, commentary.




STEVE USDIN: Before we go, let's get some final thoughts from Peter Richardson of the European Medicines Agency and Thomas Moore of Amgen.


Peter, I think one of the key things going forward for biosimilars is the extent to which there's going to be international harmonization, not only of the regulatory side, but of the ability to do clinical trials. One of the big questions for that is the EMA going to allow clinical trials for biosimilars using foreign reference products?


PETER RICHARDSON: Yeah, I think we talked a little bit about the biosimilar philosophy, trying to reduce the non-clinical and clinical requirements. So what we've had as the situation for a while is that in order to comply with the license or the authorization in the EU territory, we've required that the reference product comes from there. So it's forced a little bit that the clinical studies are done in Europe, let's say. But we're trying and we're working closely with FDA to evolve to a more open practice of where we actually do the clinical trial, whether it could be in the U.S. or in Europe, and that data would then be sufficient for the biosimilar application in the EU. So that's been a particular thing that we've tried to develop over time.


We've also worked closely with other delegations internationally, and with the WHO, to get quite a useful WHO guideline, which also talks about the philosophy of biosimilars and the fact that it's based on comparability assessment. So that's a critical thing. And that's, I think, a key message from an international audience.


STEVE USDIN: From Amgen's perspective, how important is it to be able to do global trials for biosimilars?


THOMAS MOORE: Well, if it's done right, it could help streamline operating expenses to do this. The key, of course, is seeing the details of the proposal, and then also making sure that any confidential data that the regulators might have in conjunction with approval of these products isn't shared with potential applicants to help streamline the process.


STEVE USDIN: So a quick question. You've just spent two years in Europe. You're coming back to the United States, you're working on biosimilars. In Europe, there was a relatively short period of time from when the regulations were unleashed to getting biosimilars on the market. Here, it's been three years since the law was passed, and there hasn't even been an application. Why do you think things are lagging in the United States?


THOMAS MOORE: It's a great question. First and foremost, I think Europe went first in this process because of discrepancies in patent time and patent life. So I don't think Europe was inherently altruistic and wanted these products on the market before the U.S. Patents of these products just expired there first.


So, the patents are beginning to expire now, and so I think there's a high degree of interest in making these medicines. But I think it's really hard, and companies that are getting into this business that aren't already established know it. And then also, they're trying to determine which pathway is the best way to come forth.


STEVE USDIN: Great. Well, thanks very much. That's this week's show. I'd like to thank Peter Richardson and Thomas Moore. Remember, you can share your thoughts about today's show on Twitter. Just use the hashtag #BioCenturyTV. I've Steve Usdin, and thanks for watching.