Biosimilars are biologic agents that are biologically similar to a reference product that’s already been approved for a specific purpose. These are large molecules that are made in living cells, and there’s a complex process to their production that includes a bunch of things being added on to it—postproduction modifications such as adding sugars and things on to the agent. For this reason, there has been a lot of discussion about how you would ever make an agent that wasn’t the original reference product or the original branded product for that biologic agent. In the spirit of competition, in trying to make additional agents available after the patent life runs out on a particular biologic agent, the concept of biosimilars arose. These are biologic agents made in living cells that are similar but not identical to the original reference product. These agents are defined as having no clinically significant or meaningful differences in efficacy or safety, along with multiple other factors that have to be similar and safe.

A biosimilar has to have the same or similar route of administration, storage conditions, and strengths as the reference product. The manufacturers have to show that these conditions are similar during the development program of the drug, before it can be approved.

The difference between generics and biosimilars is easily understood if you imagine how they are being produced. Although generic medicines are usually chemically produced and can easily be reproduced because of the chemical formula that you have, there is no big effort to get these approved. You don’t need large clinical trials. However, biosimilars are being produced by living cells. Every batch differs, to a certain extent, from the other. If there is no change in activity of the substance—no issue&mdash;and it is being tolerated by the agencies’ responses before the approval of the drug, it is necessary to do a lot of preclinical analysis and clinical trials to see that there is, based on the totality of evidence of these experiments in preclinical and clinical studies, a highly similar product available. This can lead to the approval of the drug. However, it is much more complex than just producing a generic compound.

Generics are usually small molecules. I always make the example of aspirin or ibuprofen, where you have a small molecule. It’s a chemical structure. You make an identical chemical structure and show that there are no major differences in pharmacokinetics or purity in an initial small trial in healthy people. And once you’ve done that, the agent can be marketed as a generic. The chemical structure just needs to be shown to be the same. For some of these, you just need to show that there are no differences in animal models, in terms of the pharmacokinetics or impurities. You have to show that it doesn’t have impurities in it. 

But that leads to a lot of different generics out on the market. They are made in different countries with different binders, etc, but they are the same chemical structure. They’re thought to be the same, in terms of their clinical effect. If you’re looking for ibuprofen, whether you get one that is a generic or a branded name, it shouldn’t have a difference in activity based on this long-standing definition and approval process. 

But biologics are different. These are very large molecules and are usually monoclonal antibodies. They’re made, as we’ve discussed, in living cells, and there are different processes that are involved in creating a biologic agent than a simple chemical structure. You have to have the antibody, but there are modifications to the antibody—glycosylation, or adding sugars on. You have to make sure that the drug doesn’t cause antibodies. It’s an antibody itself, so some of these can be immunogenic. So there are a lot of different ways of looking at biologic agents that are completely different from the way that we look at generics or small chemicals and small chemical products.

You want to make sure that it is similar in terms of its structure and in vitro measures of efficacy, none of which are perfect for biologics. You also want to make sure that it’s similar clinically, as well, and that’s where you get the whole concept of biosimilars. There’s a very different, very complicated process for demonstrating that these are similar to the referenced product. 

Comparison of Biologics to Biosimilars Versus Generics

The whole concept of generics and having a patent run out on an agent is, of course, old. Once a patent runs out and the company no longer owns single rights to a drug, any company anywhere could make the same chemical. They can show that it’s reasonably pure and doesn’t cause problems in animals and can put it on a shelf and market it. That can happen all over the world, and it’s a huge market. 

But when biologics became a part of successful treatment for rheumatologic diseases and cancer, the whole concept that came about was, how could we ever have a generic for a biologic? It’s not a simple chemical, so you could never do anything that was a generic. That’s where the whole concept of biosimilars came into play. 

The Biologics Price Competition and Innovation Act tried to address the idea that we have a lot of innovative products. The patent life will eventually expire on these drugs, although that’s a whole other area of controversy—in regard to what defines the patent’s life. When that patent life runs out, how will there ever be any competition unless people have a path to develop agents that are biosimilar? In other words, similar to a biologic agent. 

That would result in competition and price lowering and more accessibility throughout the world. This is really important. And so, that was actually developed as an act and was put into law—that you could have these biologic similar agents and have competitive pricing, etc. A lot of organizations, including the United States FDA, European Medicines Agency, and World Health Organization, have a great interest in these biosimilar products, because competition with pricing is really important in order to expand the accessibility of potentially lifesaving agents around the world. That’s what really led to the act and sort of paved the way for the beginning of the field of biosimilars, now some time ago.

Each extra substance being developed is being issued a so-called INN [international nonproprietary name] by the World Health Organization. In 2015, the FDA suggested a naming procedure where this INN—for example, for filgrastim&mdash;would be followed by 4 lowercase letters, which could be introduced or suggested by the manufacturer. Then the FDA would choose, out of several suggestions, the naming for this particular compound. 

This is an important issue, with regard to safety of the patients and pharmacovigilance. If a patient experiences adverse effects during the course of treatment, it is possible to know what kind of compound this particular patient has received. Physicians have to monitor the therapy and then, if such adverse events occur, report them to regulatory agencies. This makes it possible to see, after marketing of the product, whether there are any safety issues. In this regard, this unique naming helps a lot.

For example, if filgrastim was produced by Sandoz, it was named filgrastim-sndz. I suppose this is because of the producer of the drug, but there’s not necessarily a meaning out of these 4 letters.

The BPCIA and the Naming of Biosimilars

The approval process for biosimilars is really interesting. People usually show a slide that has a triangle that is upside down, so there’s a point, and the big part of the triangle is at the top. It’s like an upside-down triangle. The bottom sort of represents that you’re developing the biologic agent and are doing some purification processes. Of course, that takes a lot. It looks like it’s the plane of a triangle, but it’s a huge amount of work, right?

Then you go to the meat of the whole matter, which is showing that these agents are safe and effective in a clinical setting. Not only do you have to show your original clinical setting, but then you have to test it in other settings. A nice example of that is with trastuzumab. It took a long time to develop trastuzumab and show that it was safe. You started doing clinical trials. You gave it in 1 trial with 1 combination. Another showed that the survival was better. You moved it into early-stage cancer and gave it in combination with different targeted agents. We’re still using trastuzumab as a backbone for studies looking at ways to expand on treatment options and improve outcomes for patients with [human epidermal growth factor receptor 2, 

So the clinical part is the biggest part of the triangle, because it lasts for a long time. The drug is tested in many different ways. That’s a reference biologic. 

When you get to the biosimilar, the triangle is reversed. That reference biologic has done all of the work at the top of the triangle. The biosimilar is really showing that it’s biologically similar. So the triangle is reversed. You need to show that it’s clinically similar. Here, it’s really sitting on top of a much bigger weight of evidence that shows that it’s similar in the laboratory, as well as biologically. 

You have to show that it has a similar structure, which is a complicated process, because these are antibodies made in living cells. You have to show that there is similar biologic characterization. The caveat to that is that we know that any biologic test that you do in vitro doesn’t correlate very well with what the agent does in vivo, in a patient. There are still tests that are done. One example is that antibody-dependent cell-mediated cytotoxicity, or ADCC, is something that can be done in a laboratory. You can use that as a way to compare and contrast the reference and the proposed biosimilar to see if there are major differences, but you know that’s not the end-all, by any means.

Then you look at a lot of other structural characteristics. You look to see, for example, if there’s a difference in the number of sugars. It turns out that the differences are mostly in the amount of glycosylation, which doesn’t seem to make a big difference, actually. In animal models, you look at pharmacokinetics, pharmacodynamics, and immunogenicity. You can imagine that the bottom of the triangle is really the big part where you’re doing lots and lots of studies—many more than the number that were required for the reference biologic to show that it’s biologically similar. 

And then at the very top of the triangle are clinical studies. The idea here, as defined by the different regulatory agencies and the World Health Organization, is to show that there are no biologically meaningful or clinically meaningful differences between the reference product and the proposed biosimilar. You have to have shown all of that sort of prework, such as working in the laboratory or clinic. 

What’s interesting is that through the initial work of figuring out how to do the clinical study, an idea came about: If the reference biologic was made in the United States versus in Europe, did you need to show whether or not they were different products?

It turns out that when you move the production of a reference biologic or you simply change the production process, you can change the reference biologic enough so that it is actually as much changed as a biosimilar would be. Where you make the biologic and how you make it really makes a very big difference when you’re making something in living cells.

One of the things that needed to be done, for example, for the biosimilar trastuzumab—not in people with cancer but in healthy subjects&mdash;was that you had to show that the pharmacokinetics and pharmacodynamics were similar. Obviously, through very short exposure, they compared the proposed biosimilar with the European and United States trastuzumab because the 2 of them could be different. This is very, very interesting because we hadn’t thought about that. Before there were biosimilars in the clinic, we never thought about that.

There’s also been some really interesting work that has shown that the potency of ADCCs may vary. We don’t know if it affects the clinical efficacy, but from lot to lot of produced trastuzumab, there were variations in ADCC and the reference biologic, which is also quite interesting. It has been looked at in some of the reference biologics used as a control in the biosimilar trial, so that’s quite intriguing. Basically, you have to show that all of these things that are in the preclinical area and in healthy individuals are the same.

Then you get to the actual efficacy and safety in patients. The regulations have noted that you want to study your biosimilar in a clinically sensitive area. For example, you would go back and look at the development of that reference biologic and you would say, “Where have we seen a big, reproducible impact from that agent that we would trust to actually tell us that the agent worked?” 

That’s brought about some controversies. It’s differed based on the agent, etc. But in general, you pick a sensitive area—the indication for the drug. Then you have to pick an endpoint. For most of these reference biologics, when they got approved, they need to show an endpoint of disease control and, for many of them, overall survival, if they’re cancer drugs. Things are a bit different in the rheumatologic area and for supportive care, where we also have biologics.

We talk about cancer drugs. They’ve really been showing efficacy. Many of the reference biologics have actually shown survival differences. If you made the proposed biosimilar do the exact same thing, you would never get them on the market. That’s part of this whole idea of competition. You want to use a short-term clinical endpoint that correlates with the long-term end point, and you want to use that for your approval. 

Response rate has been used as a short-term clinical endpoint with the idea that, in most cases, although you’re not obliged by regulatory guidelines, you would look at the longer-term endpoints over time, if you’re able to. But every time you extend out your study you add cost, right? So if you’re going to follow people for 10 years, that’s going to be a big cost added to the development of that agent.

Then you have the potential approval, right? You’ve done your clinical study. You’ve shown that your short-term end point is similar. Maybe it’s the response rate, for example, for a cancer agent like trastuzumab in the neoadjuvant setting or in the first-line metastatic setting. Then the question is, what do you do with that data? That brings up 2 other areas where the regulators have had comments, and 1 is interchangeability and extrapolation. 

We talk about extrapolation as the idea that if these biologic agents worked just as well in combination with different chemotherapy drugs, hormone agents, other antibodies, or different oral biologic targeted agents like tyrosine kinase inhibitors, you could extrapolate from your approval to all of these different combinations. If it worked just as well in the metastatic and early-stage settings, you could also extrapolate freely between the 2 settings. And then, lastly, if it works for more than 1 disease, like trastuzumab for breast cancer or gastric cancer, you could extrapolate between those indications, as well. 

So that is the entire approval process, from beginning to end. And right now, in terms of what’s been approved so far, the United States FDA and [European Medicines Agency, EMA] have approved these agents with the idea that extrapolation will be used.

The Approval Process for Biosimilars

Generic drugs are usually small molecules that are produced chemically and can easily be copied or reproduced. Therefore, if you have an active ingredient that you can chemically synthesize, there is no need for major clinical trials. However, for biosimilars, which are complex molecules of a much larger size, it is necessary not only to have the physical chemical analysis and preclinical data but also to show that due to the effect of these large molecules, which can have a certain amount of immunogenicity—meaning there are antibodies against the drug that is being developed&mdash;it is necessary to do clinical trials, such as a phase 1 trial, where you can show pharmacokinetic and, if possible, pharmacodynamic issues and attributes of the compound. And then, depending on the results of the phase 1 trial, you can do a phase 3 trial in a sensitive disease model, where you can show the similarity of the biosimilar to the reference product based on the so-called totality of evidence. Regulatory agencies such as the FDA and the [European Medicines Agency, EMA] decide whether this leads to the approval of a biosimilar.

In comparison with generic drugs, where it is possible to just chemically reproduce the originator product, the biosimilar production is different. We have large, complex molecules that you can’t copy in the sense of what you would usually want. There are certain differences between the reference and the embellishing of the product. To a certain degree, this is allowed by the regulatory agencies. Based on the data and from preclinical and clinical investigations, it has to be highly similar without quality differences to the reference product in order to be approved as a biosimilar.

As you can imagine, because of the fact that biosimilars are being produced by living cells, there is no complete equality to the reference product. Even the reference product, if you have several batches, might contain minor differences as long as the protein structure and certain parts of the manufacturing quality that is being asked for by the regulatory agencies is long. Differences can be considered for biosimilars. For example, posttranslational changes might lead to differences in efficacy of the drug later on or to increased immunogenicity. With these quality assurances, as a manufacturer, you ensure that this is not going to happen.

One of the things that happens when these agents go for regulatory approval is that the regulatory agencies go to where they’re produced. They want the production companies to fit into very strict guidelines and want the reproducibility to show where the agents are made. This requires an enormous number of criteria. The regulatory agencies may go back—they have been known to go back and to say “You need to fix this process or that process.” They can go back in and reevaluate over time. In addition to that, they’ve put in this pharmacovigilance where the companies are obliged to continue to track any differences, toxicities, or unusual events over time. The information can be reported for long-term follow-up of these agents once they’re approved. 

In terms of the clinical approval, they have to have no clinically meaningful differences in terms of short-term clinically sensitive endpoints, no differences in safety that are clinically meaningful, and no differences in immunogenicity. You have to be able to look at antidrug antibodies, as well as the common safety—both short and long term&mdash;and the short-term efficacy end point, as well.

Regulatory agencies don’t require that you look at longer-term efficacy end points. For example, if you do a neoadjuvant trial, you don’t have to show that survival is similar in the long term, because you have to follow those patients for a very long time. But they do like to have enough exposure to feel comfortable about safety. 

In terms of the lot release, there may be variations in glycosylation and sometimes in activity in vitro between different lots that are released. And so, for every few lots, they have to end testing sporadically throughout a lot. You have to show that you’ve maintained your similarity throughout and that any changes that occur—any shift over time&mdash;is not clinically meaningful.

Considerations for Approving Generics Versus Biosimilars 

Interchangeability is an interesting area. Extrapolation is much easier because that means that you’ve got a biosimilar that was approved in the neoadjuvant or metastatic setting and can use it, alternatively, in the other setting. For example, if you’re testing a biologic growth factor like filgrastim or pegfilgrastim, if it worked in 1 setting, it’s going to work across other settings. I think that everybody’s been able to embrace that much more easily compared to the drugs that are being used for therapeutic purposes to treat cancers. 

There’s growing acceptance that this extrapolation is reasonable, but interchangeability is different. You can switch from the reference to the biosimilar at any time. Interchangeable means that there is little difference. The pharmacist who’s filling the prescription can decide which one they’re going to provide you, based on the criteria—what the insurance requests, what’s cheaper, what they bargained for, et cetera&mdash;to get a better group price.

So that would be interchangeability. They don’t have to come back to the provider and say, “You ordered the branded trastuzumab. Can I give this biosimilar instead?” If it’s an interchangeable product, the pharmacist can change.

As described by the regulatory agencies, interchangeability is complex because it requires studies that show that you can switch from one to the other and then back again without changing immunogenicity or safety. Obviously you’re not going to be able to look at efficacy well in that setting. It really hasn’t been studied in any appreciable way for the therapeutic anticancer drugs, and I don’t know that it really will be something that happens in the community. In the United States, pharmacists will generally have to ask, “Can we use the biosimilar?” Much of that will be decided by insurers and by negotiations between our infusion centers and drug providers, in terms of which agent is being provided at a lower cost.

Manufacturers go to the regulatory agents when they start production of these biosimilars and ask for guidance either by the FDA or [European Medicines Agency, EMA]. Part of this guidance, after the physical chemical analyses and safety and purity issues, and then based on phase 1 and phase 3 data in patients, is that the manufacturer has to present thorough pharmacovigilance and a safety program that takes place after approval of the drug. As a manufacturer, you have to assure that the production is not being changed because then, in a way, you produce your own biosimilar of what you have produced before and you have to follow certain guidelines to assure that the quality is not changing.

Interchangeability and Postmarketing Pharmacovigilance of Biosimilars

I feel very comfortable using biosimilars. In Europe, we have more than 10 years of experience using biosimilars. Filgrastim was developed in the early years of the new century and was actually approved in Europe in 2006. In 2007, filgrastim came to the market. I feel comfortable because I know how to develop such a drug. This occurs through a very thorough development plan issued by regulatory agencies, such as the FDA or [the European Medicines Agency, EMA]. Some people might argue that there is little data available in comparison to the reference product. In my opinion, this is not the issue with biosimilars. Due to a very extensive preclinical problem and a phase 1 study, you have a phase 3 study—a sensitive disease model. There is also a clear postmarketing plan for pharmacovigilance. Therefore, I consider this to be a safe group of drugs to use.

In many situations, there is no issue. In patients who have a short period of drug exposure—for example, in the adjuvant setting of HER2/neu-positive breast cancer, where you have a year of adjuvant treatment&mdash;one could argue that there’s much more data on the originator product, so far. This could be an argument, but in most of the cases, I don’t see an issue when choosing a biosimilar. In Germany, the decision is not based upon the physician alone. The pharmacists and regulatory agencies, on the state and on the national level, are also a part of this decision process.

Biosimilars, in my opinion, are a major advancement not only in the field of cancer treatment but also in rheumatology and gastroenterology, where we have a couple of antibodies that have been used successfully for quite a while. In highly developed countries, as in the United States or in many European countries, you have access to these drugs through your health care plan or insurance coverage. But there are many countries in the world where this isn’t the case. For example, Herceptin, the originator trastuzumab, was not available due to its high cost. I hope that the development of these biosimilars, through recent technology, will enable us to treat more patients worldwide with these complex, expensive compounds.

Extrapolation of indications means that a biosimilar can be used for all indications that the reference product has been used and approved for. However, for biosimilar development, it is usually enough to have 1 sensitive disease model where you show, in a phase III trial, that it’s similar to the reference product. Regulatory agencies have clear-cut conditions when extrapolation can be done. These differ a bit between the FDA requirements and the EMA. One of the issues, for example, is that it is clear that the mode of action of the biosimilar is the same in the different diseases for which the indication is granted for. Therefore, due to the thorough regulatory process, extrapolation, in my opinion, is something that can be done. I don’t have a problem using filgrastim in breast cancer, where most of the studies were performed and led to an approval of biosimilars, or in other diseases where neutropenia is an issue.

In clinical use, filgrastim has been on the market for more than 10 years in Germany. The market share is approximately 75% to 80% of prescriptions, on average, over the whole country, which shows the acceptance of this drug. And, in addition to that, monoclonal antibodies recently became available as biosimilars. For example, we have replaced part of our rituximab administration to patients with biosimilars without seeing any difference in efficacy or side effects. The same was true with filgrastim.

I wouldn’t have a lot of compunction for switching a patient from a reference biologic to the proposed biosimilar. For people who are on the drug for a very long time, where there’s a cost issue, we might switch. Or, for example, if the university is saying “This is the agent we’re giving,” we would switch. Otherwise, I think it’ll be more of an issue in people who start new on HER2-targeted therapy. In those situations, I would certainly feel comfortable using a biosimilar. In the United States, we’re often driven by what insurers want and what the pricing structure of the university is.

Experience Prescribing Biosimilars Versus Biologics

We’re very hopeful that access will improve worldwide. In the United States, I think most people have access to biologic therapies. That’s changing with the very expensive immunotherapies that patients stay on, but the immunotherapies are so new and biosimilars are a long way away. Biosimilars play the biggest role, in terms of access, internationally, where people pay out-of-pocket for these agents. And so, many people are not able to afford to use trastuzumab when they have curable HER2-positive breast cancer.

I see this making a huge impact because there are a number of, for example, trastuzumab biosimilars out there. That helps with competition. It’s going to really make people want to make these contracts and drive down the price. Then, hopefully, it will mean that people who previously couldn’t get any HER2-targeted therapies will have access.

The competition, we don’t really know a lot about it yet. I think that the companies that are making these biologic agents, the reference products, are trying new delivery methods and new combinations to try to get around the biosimilar market. So, I don’t know exactly how that competition is going to play out over time. I have seen that the reference biologic companies are going to the regulatory agencies to say, “Hey, we should be able to extend our patent because we got approval in this setting” or “with that combination.”

They first started working on trying to extend their patent and are now looking more at trying to have novel delivery mechanisms or some new combination that’ll make them competitive. For example, I mentioned that pegfilgrastim now has a novel delivery system where you put the patch on and trigger it. The next day, it delivers the growth factor and you peel it off and throw it out, right? That’s a great method of competition. Not having to come back means that you’re going to treat people. They’re going to want to get that drug instead of the one that they have to come back for. So, there are a number of different ways that you can compete with the agents.

The financial impact of the development of biosimilars to the health care system is not yet completely clear. In the United States, there have been 2 agents registered over the past years in supportive care.* The first biosimilar antibodies may come this year or next year. Therefore, there’s not much experience. In Europe, there has been much more experience over the past 10 years. If you consider biologics being a major part of the health care system, which was, for example, analyzed in the United States in 2009, approximately 32% of the budget went into biologics for Medicare. In 2014, this was approximately $9.5 billion. Nine years later, it was approximately double the amount in percentages and approximately $26 billion. You can see what an impact cheaper biologics might have on the entire system.

Therefore, I consider the development of biosimilars a big chance for the health care system if the prices of biosimilars will be marketing lower than the reference products. This should be seen by analyzing the health care costs in different countries. If you look, for example, in Germany, we now have a market share for the biosimilar filgrastim of approximately 75% to 80% of the prescriptions being done. The price range shows that the biosimilars are approximately 30% less cost intensive versus the reference products. We should see a major reduction in costs due to biosimilars. This money can be spent on the development of new drugs and to help more people become insured, for example, in the United States.

The Impact of Access to Biosimilars

The pricing of biosimilars is an important issue. Everybody, of course, hopes that costs can be saved by using biosimilars. On the other hand, to consider that, the production process of a biosimilar should be equal to the reference product. What has been seen over the past is that if the price reduction is in a low percentage, the likelihood of changing to or using a biosimilar is not as high as if you have a bigger price difference. This has been seen for antibodies in rheumatology, and I’ve heard that with trastuzumab, which is going to be marketed sometime this year, there might be a difference of 30%, for example, to the reference product. If price is an issue in the health care system, and if the trastuzumab biosimilar is, pricewise, cheaper than the reference product, it might actually enter the market more easily than if you had a small margin. However, I think you have to take into consideration that there are different systems in different countries.

Rebates are being made for using the reference product. I think this whole decision-making process needs to be understood to actually value the chances for cost reduction by using biosimilars. If there is a price difference between Europe and the United States, for example, from 30% to 15% by using biosimilars, the likelihood of using biosimilars might be higher in Europe than in the United States. However, the reimbursement of drug costs needs to be taken into consideration because this is different between countries. It may even be different between states and health insurers. Therefore, to have a complete picture, you have to have this information.

The United States has a funny market in this because insurers pay for biologics and pay for patients to receive biologics for years and years based on the studies that we have. People may have private insurance and other insurance that allows for that process. In other countries, insurance may be owned by a government. The government sets forth guidelines, and you can only get the drug through those means, unless you have other means of paying for it. 

In Europe, there’s more chance for cost savings because people are going to contract broadly and push to get a bigger cost decrease. In the United States, insurers don’t contract directly with the companies in order to get the drugs, and there aren’t those same kinds of restrictions based on the cost of the government paying for your health care. So, we have a different situation. 

The cost savings have been estimated to be about 15% to 30%, overall. My guess is that, just like many drugs that are marketed for much higher prices in the United States versus other countries, the same will be true of the biosimilars. The cost will be lower than the reference product, but it will still be more than we would like it to be. It’s not going to be rock bottom because insurers will still cover it. There will still be a discount.

Then it depends on people making deals. The reference biologic stakeholders may say “Only buy our product and we’ll give you this amount of discount.” The biosimilar stakeholders might say something very similar.

In Europe, there are countries like Germany or Great Britain where you have a high-impact of use of biosimilars. In Great Britain, this is partly driven by the advice of [the National Institute for Health and Care Excellence, NICE] as an institution—it’s involvement in drug costs and use. There are other countries with much less market share, also in Europe. In other regions, like in South America, biosimilars have been taken up quickly because originator products like trastuzumab, for example, are not available. I think the use of biosimilars, at reasonable costs, will catch up in the market.

In Germany, insurance companies are not the ones that decide whether to use a biosimilar or reference product. If there is an indication—a patient has a certain disease and the drug is approved&mdash;it’s up to the physicians, together with pharmacists, to decide which drug to use. Furthermore, in Germany, on the national and regional levels, there are certain institutions that play a part in the decision-making process, whether or not to use a biosimilar. I think the high rates of the use of a filgrastim biosimilar in Germany is partly due to the fact that these institutions are a part of the process.

I don’t think that the difference in the cost of the drug will change the copay. For some people, certainly those with Medicare plans where you’re paying for some parts of the drug, or whatever it is, if the drug is less expensive, the patient will pay less. If they have a lifetime cap, they’ll have less money. There are a lot of important points.

The issue of copays, to my knowledge, doesn’t play a role in Germany because insurance pays if the drug is indicated. If you are outside an indication for a drug, you have to ask whether cost reimbursement is being granted. If not, the patient has to pay for it on his or her own. The likelihood is low, but this does happen. I think it’s different in the United States.

My experience, over the past 10-plus years, is that many people don’t really have an idea of what we are talking about when we talk about biosimilars. I think a major issue is educating prescribers, but also nurses, on what it means to produce a biosimilar. They need to understand the approval process and what types of studies are needed to address issues related to treatment. Few patients are being treated with a biosimilar and still this drug has been approved. Prescribers need to understand how it came to approval.

Also very important to prescribers, in my opinion, is this postmarketing strategy for biosimilars. You have these pharmacovigilance and safety plans. After the drug is on the market, they need to recognize how to react when a patient has an adverse event to a biosimilar or the reference product. It should be as easy as possible to track what kind of drug this patient has received.

US and EU Biosimilar Pricing and Stakeholder Education

Will a health plan approve a biosimilar or not? If there are 5 trastuzumab biosimilars approved in the United States, or 3 filgrastims, how do you decide? My guess is that health plans will just contract with different companies. Or they’ll say, “You can use any biosimilar.” It won’t really matter because they’re all going to be about the same price point lower. So I don’t know that there will be a key factor, other than approval by a regulatory agency and a price difference.

In the hospital, we have a commission for the use of pharmacologic agents. It is led by a physician, and his deputy is the hospital pharmacist. To get into a hospital from the outside, as a manufacturer, you have to convince the physician that this drug is good to use. And then gastroenterologists or rheumatologists or oncologists, together with the pharmacist and the physician, can determine the pros and cons of using these drugs. Then it’s decided. Of course, having 3 or 4 different drugs with the same compound is not wanted. And so this has to be decided on. This is how it’s being handled here. I know that in practices outside hospitals, these regulatory agencies, on the national and regional levels, are a part of this decision making because they actually ask for certain amounts of use of biosimilars.

Whether biosimilars will be a first-line, first-tier biologic or not is an interesting question. If you’ve shown that an agent is similar and that there are no clinically meaningful differences, we can consider that a first-tier biologic. It can be the first one you take off the shelf when you’re treating your patient in early-stage disease. So much care is taken with the production and assessment of these agents that we can be very certain that they’re safe and [very certain] of their clinical endpoints, at least the short-term clinical endpoints.

I think we can feel secure in using these drugs. It’s not like we’re going to save them for the incurable patient, you know? We can feel safe in using these agents with curative intent. I’m speaking primarily about therapeutic agents for cancer, particularly trastuzumab, but many others will be coming down the pike. I think the rheumatologic area is sort of a separate case that we’re not really involved with. We certainly have been embracing the supportive care drugs, and I don’t think any of us have seen any appreciable differences there, as were shown in clinical trials as well.

People are always a bit nervous about it, and it’s going to take a while to percolate in, but with the cost savings and the availability, I think it is an inevitable shift over time, and a very important one in our competitive atmosphere. The cost savings can be translated into spending money on drug development and spending money on giving patients newer drugs that are not yet biosimilars. New immunotherapies are a fortune of cancer therapy at the moment. So by ratcheting down some, by moving on to the biosimilars, we’re really improving things.

To get access to biosimilars in Germany, it is important that the physician know about it. If there’s more experience in the use of biosimilars in rheumatology, for example, where they have been used longer than other antibodies in oncology or hematology, I think this information needs to be spread.

It’s difficult to know what the payer challenges are, but I think some of it is going to be deciding how to contract for these drugs. Are they going to say that you’re obliged to get the biosimilar if there’s a biosimilar available for your insurance plan?

Biosimilars are intravenous drugs, so you have to get approval. As providers, our offices send in approval. “I want to get trastuzumab for my patient.” The insurer could come back and say, “Yes, you can use trastuzumab, but you need to use a biosimilar.” It’s going to be a fascinating thing. Let’s say that my institution contracts with 1 biosimilar. We usually contract to get delivery of specific agents, right? We can’t just give a different one because the company says, “I want you to use Company X’s biosimilar.” Why should they care whether a physician uses Company X’s or Z’s biosimilar? They’re not going to specifically contract with that company. So it’s interesting. With so many people jumping into the biosimilar market, will the insurers simply say, “We will only pay for a biosimilar, but we don’t care whose it is”? Will the cost differentials be big? My guess is no. The whole field will see this big shift and price down, but there are a lot of interesting challenges ahead.

Substitution means that the pharmacist can distribute a biosimilar or the reference product no matter what the physician has prescribed. It is important that there is contact between the physician and the pharmacist. If the physician does not want substitution, it’s important that it’s not performed. However, legislation is not yet clear-cut. For example, in the European Union, to my knowledge, it’s a matter of the national institutions rather than of Europe or the [European Medicines Agency, EMA]. In the following years, I think we will see how this is going to happen. Substitution for other drugs outside biologics is something that happens on a regular basis. With biologics, I think it’s a more complex issue. What needs to be assured is that there is knowledge to the physician and the patient as to whether he or she receives what has been prescribed.

Formulary Approval and Challenges for Payers

It’s an interesting one. We first sort of dealt with the challenge of talking to patients about filgrastim. “You’ve been getting this brand of filgrastim, but now our institution is switching to this other one, which is a biosimilar. It’s been tested in the laboratory and in the clinic, and it looks to be the same.” Patients did not care. They didn’t even blink an eye. And meanwhile, they don’t like generic ibuprofen. They say that the pink one isn’t as good as the white one, right? Or, “That gave me a headache” or “a rash” or whatever else. So I think that there is more attention paid to that than there is to the switch. 

Growth factors may be different when we start looking at the therapeutic drugs, particularly in the curable setting, like trastuzumab. Will patients feel differently and feel anxious about switching? We don’t really know. So the question is, in an area where the insurance is paying for the drug, will we transition patients who are already on the reference biologic? Probably not because what’s the push? If you’re going for your 6-month approval and the insurer says, “I’m only going to pay for this,” then we’re going to transition them.

For naïve patients, when we’re starting a drug, if we have that drug and it’s less expensive and we look at the data and the FDA has looked at the data and feels that they meet the criteria for a biosimilar, I think it would be fine to use the biosimilar instead.

For patient education, it’s interesting. I show Google images to patients all the time to show them the transdermal delivery system for pegfilgrastim, for example. I show them what a port looks like. I show them some unusual finding that was mentioned in their radiology report. I can often show it on Google better than I can show them their own X-ray images. In terms of patient education, I think that helps a lot.

I do think that educational tools for patients will be very helpful in understanding what biosimilars are. You can show the small molecule and the big antibody and the difference between the generic and the biosimilar. You can also show them those triangles and how you really assess them. You can show them the kind of robust evaluation that has gone on, as well as the regulatory guidance that has been given, that people have agreed on internationally. I think that those points are all very comforting for patients, as well as the fact that they don’t cause antibodies, and, if anything, are very, very well studied, in terms of safety.

Manufacturers provide patients with information in a variety of ways, such as through printed materials, webcasts, and other learning devices. In addition to that, they put in a lot of effort, for example, at clinical conferences such as the [American Society of Clinical Oncology, ASCO] and the European Society of Medical Oncology annual meetings, to educate physicians and patients on the use of biosimilars.

I think that the biosimilar companies are going to be doing work in patient and physician education—provider education. Both of these areas are really important. In terms of patients, it’s about understanding the basics behind biosimilars. I’ve seen some of these companies sort of start to look at how we’re going to tell patients what these are or how much of a role patients have in making that decision about treatment. Do we let them know, or do they get to decide yes or no? If the insurer says, “I’m only paying for 80% of the reference biologic but will pay for all of the biosimilar,” how will we sort of make that decision? That remains to be seen. I’m not even sure the insurers know yet. I know that the insurers want to support the biosimilar filgrastim versus the branded product, in many cases.

Prescribing Biosimilars and Educating Patients and Physicians 

Filgrastim and pegfilgrastim are the first 2 biosimilar drugs in supportive care that got approval in the United States. Filgrastim has been approved in Europe for quite a while, and pegfilgrastim is expected to follow soon. I think that both are major advancements, as were the reference products because of the lower risk of neutropenia associated with using these drugs. They already have had a huge impact. In Germany, for example, the market share of the biosimilar filgrastim is in the range of 75% to 80% over the average with regard to prescriptions. So the biosimilar market has sped up quite a bit over the past few years.

In addition to these 2 biosimilars, filgrastim derivatives and monoclonal antibodies, such as rituximab, came to the market. The market share for the rituximab biosimilar, after the first 7 months, rose to around 10% of the prescribed rituximab product overall. Because of the cost savings, this will increase even more in other countries. I consider this similar. 

Trastuzumab biosimilars and bevacizumab biosimilars that are in development could be available within the next year or so. We will see how this will impact the treatment of solid tumors differently from the filgrastim derivatives for supportive care. With these antibodies, we have direct cancer treatment. The results of the clinical trials are quite promising because biosimilarity could be shown for several of these compounds.

In Western countries, I don’t consider it necessary to change. Because of the healthcare systems, the availability for the reference product, as in the United States, is comparable, I think. However, in third-world countries or poorer countries, this will definitely change the treatment plan. In certain areas, such as in Eastern Europe, drugs such as trastuzumab have not been available for HER2/neu-positive patients, which is something we can hardly imagine. Because these drugs are going to become available, I think it will change the treatment for these patients.

I believe that the availability of biosimilars will change the treatment plans for many patients in poorer countries or third-world countries where biologics are not available, mostly because they have been too expensive for the healthcare system. I hope that having the chance to use biosimilar compounds such as filgrastim, pegfilgrastim, and monoclonal antibodies will provide availability in these countries. The outcomes of treatment will improve, and the likelihood of dying from cancer, in certain situations, can be decreased with the use of these drugs.

The likelihood of patients’ having neutropenia has been decreased with the use of filgrastim and pegfilgrastim. But if you don’t have it available and get intensive chemotherapy—because certain diseases can only be treated intensively&mdash;the likelihood of higher morbidity and mortality is pretty clear and can be lowered with these therapies. For example, for HER2/neu-positive breast cancer, the clear message is that the use of HER2/neu-directed antibodies leads to a better prognosis for these patients. If you can treat them with a drug that was not possible before, it will lead to better outcomes.

The Influence of Biosimilars in Cancer Care

The whole idea of drug development is a little dry. The biggest challenge we have is in making this very exciting or interesting. It’s something that’s really at hand. Starting with education a couple of years before the first therapeutic entered the market, which we hope will be next year, has been 1 way to do that. It’s kind of interesting. Through nobody’s plan, we started with agents that were used for supportive care. Everybody is a lot more comfortable in that scenario versus when you’re treating somebody with curative intent in the early-stage cancer setting. 

Starting with filgrastim and pegfilgrastim will give people experience and make them feel more comfortable with using these agents. And then, as these agents get out into practice, it’s really important to make sure that people understand how we’re using them, what extrapolation means, and what the clinical evidence means. Comparing the different biosimilars is going to be extremely difficult because they all have very good data that support their use as biosimilars. So that’s helpful. I think understanding the lack of immunogenicity is particularly helpful.

Another challenge that providers face is understanding what pharmacovigilance means. One other thing that’s required by the regulatory agencies is that there is very careful pharmacovigilance. You have to look at safety and efficacy in different indications. You have to report, based on this little 4-letter abbreviation after the “tra,” any safety issues that come up. So who’s responsible for pharmacovigilance? How is it reported? Is it done easily? This is something we still need to understand. 

In the United States, we currently have 11 approved biosimilars and more than 20 in the pipeline, which will come during the next months or years. This is good news for patients. For physicians, this is a challenge. If you have several biosimilars for the same reference product, you need to know the data. You need to know whether there are any differences. In the end, what is good news for everybody is that because several manufacturers are producing biosimilars for the same reference product, there’s price competition. As it is with other goods you produce, if you have more than 1 company offering this compound, the likelihood that the price will be lower is rather high. I think this is good news. 

As I said, the fact that you have several biosimilars for the same reference product might cause more discussion regarding which one to use. At our hospital, we discuss which biosimilars to choose. From time to time, we discuss whether we should change anything. The likelihood to have the reference product and 2 or 3 biosimilars in stock for the same reference product, for example, is not being considered by many institutions. It needs to be rediscussed with pharmacists and this commission—the use of drugs within the hospitals. Of course, the price issue is something that the pharmacists and the regional and national agencies will be a part of.

I don’t think it really changes our management, but it changes the management worldwide. In many countries, for example, you’re only allowed access to 9 weeks of trastuzumab. Or you have to pay for every bit of trastuzumab you receive out of your own pocket. And so having a less expensive drug will completely change access around the world. Because we know these are agents that can cure patients, they can have a really big impact on disease management. 

It’s also our hope that having a lower-cost option for drugs that can be given for a long time will free up money for drug development and other drugs that are also lifesaving—for example, the new area of immunotherapy, which adds a huge additional layer of cost and complexity in patient care, particularly for our patients with the most aggressive diseases that stand to benefit most.

We continue trastuzumab forever, right? People in other countries always say, “What?” They stopped because it’s so expensive that they can’t continue it. But if I have a patient who has metastatic HER2-positive breast cancer and she goes on trastuzumab—maybe now with pertuzumab&mdash;and she gets chemotherapy, has a great response, and they stop the chemotherapy, if she’s sitting on those 2 antibodies, she can stay on those 2 antibodies forever. At some point, usually at 10 years, I’ll say “OK, you’ve been on therapy for 10 years. Let’s stop the therapy.” Of course, the patient is very anxious about that. Still, they’ve stayed on it for 10 years.

Many other countries, probably most, don’t do that because they can’t afford the drugs. With the significant cost savings—not 15%; it would have to be a lot more than that&mdash;people will be able to stay on the drug longer and will potentially have better survival as well. So I think that there is a potential impact on patient outcomes by having the drugs become more accessible, just not so much in the United States.

In the future, the availability of biosimilars and biologics will change the way of treatment in countries that are not in the situation to be able to afford these drugs so far. I think there will be a major change for treatment. The use of filgrastim or monoclonal antibodies, for example, will lead to better outcomes in patients with cancer. Therefore, it is to the benefit of patients being treated there. In the Western countries, the availability of the reference product as well as the biosimilars did not change the use of these compounds very much overall. Here the situation, with regard to quality of treatment, is not really affected.

Biosimilars in the Pipeline and Disease Management

If the current biosimilars should fail to actually lead to cost reduction in the healthcare system, it will be interesting to see what will happen. For a manufacturer, it is necessary to get the money out of the development of such a drug afterward. If this is not the case, you may need to reconsider. I am skeptical that this is going to happen. I am very optimistic, actually, that the use of biosimilars will lead to cost reductions and that the money being saved can be used on new, innovative products.

What happens with cost? That’s one of the issues that has come up a lot. With a 15% savings, is it worth it? Does it make a big difference to us? Does it need to be 30%? Does it need to be 70%? In some countries, to really make an impact on how accessible drugs are to the population, it probably needs to be a 70% reduction.

I think that the competition between the different biosimilars that are out there will allow for substantial pricing differentials. If they say, “If you say you’re going to only use our drug, we’re going to give it to you at a 40% discount,” that kind of competition can really allow for much greater cost savings. So I think that we will see cost savings. I don’t really see that the market will collapse because we didn’t see any cost savings. 

If my predictions are wrong and nobody uses biosimilars, that whole area will collapse. In the general approach of pharmaceuticals and cancer care, the competition has been a really important part of drug development. It has really benefited our patients. I hope that’s still the case.

I believe that in rheumatology or gastroenterology, as well as in oncology, the progress being made in the development of biosimilars will lead to quality care for these patients. One could imagine that, for example, inCrohn disease or ulcerative colitis, the use of these monoclonal antibodies, because of the reduced costs, may lead to an earlier use of these drugs throughout the course of the disease. 

However, this is speculative. I think clinical trials need to be performed before one can consider this true. I think this is an option in countries where there’s not such a high budget in healthcare. In all 3 areas, the availability will lead to better treatment results because of more use of these drugs.

You can basically group these into rheumatologic diseases and cancer. As agents go off patent, we’re largely going to be replacing those agents with biosimilars. Or the reference biologic products are going to just match the pricing of the biosimilars. 

We’re going to see that shift over time, but we keep entering new biologics into the area, right? We just got immunotherapy. We have new antibodies that are HER2-targeted. We have a lot of other agents that target different biologic pathways. We’re always going to have agents starting the patent process while other agents come to the end of their patent life. This is going to be an ongoing change where we will see different options available around the world, in terms of the costs of agents and better access. 

I think that the whole area of biosimilars is a nice example of the interplay between regulatory bodies, pharmaceutical companies, and patient access in drug competition. Overall, I think there are some feelings against some regulations and regulatory bodies and how they sort of control different ways of using agents. 

In the United States, we’ve largely believed that’s a way to protect patient safety. Now we’re seeing that the regulatory agencies are also helping to create a competitive environment that will improve access, reduce cost, and free up some of the money for the additional development of new agents and access to novel agents.

To me, it has really been a fascinating time to see that go into play—to see our first approvals of therapeutic biosimilars in the United States and Europe. To some degree, I think we’ve seen it in India, but I hope we’ll see it around the world&mdash;in the long term, this can provide access for patients who can’t afford lifesaving drugs or don’t have access because of the competition of biosimilars. I think that is a really big step. This is important progress. Even though our patients in the United States have access to biologic agents, this can only move our ability to care for our patients better forward, in a positive way.

Global Perspective on the Effect of Biosimilars

EP 1: Comparison of Biologics to Biosimilars Versus Generics

EP 2: The BPCIA and the Naming of Biosimilars

EP 3: The Approval Process for Biosimilars

EP 4: Considerations for Approving Generics Versus Biosimilars

EP 5: Interchangeability and Postmarketing Pharmacovigilance of Biosimilars

EP 6: Experience Prescribing Biosimilars Versus Biologics

EP 7: The Impact of Access to Biosimilars

EP 8: US and EU Biosimilar Pricing and Stakeholder Education

EP 9: Formulary Approval and Challenges for Payers

EP 10: Prescribing Biosimilars and Educating Patients and Physicians

EP 11: The Influence of Biosimilars in Cancer Care

EP 12: Biosimilars in the Pipeline and Disease Management

EP 13: Outlook on the Future of Biosimilars