Understanding “Biosimilars,” with Gary H. Lyman, MD, MPH, FASCO, FRCP

February 14, 2018
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Research into new forms of biologic therapy, such as immunotherapy or targeted therapy, have made dramatic advances in treating and managing cancer, but these therapies can be very expensive. You may be familiar with generic drugs, which are identical copies of brand-name drugs, and are often much cheaper. However, the manufacturing process for biologic therapies is so complex, it is not possible for a different manufacturer to make an identical copy. In this podcast, Dr. Gary Lyman discusses biosimilar agents, which are similar, but not identical, copies of these drugs. 



ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

Research into new forms of biologic therapy, such as immunotherapy or targeted therapy, have made dramatic advances in treating and managing cancer, but these therapies can be very expensive. You may be familiar with generic drugs, which are identical copies of brand-name drugs, and are often much cheaper. However, the manufacturing process for biologic therapies is so complex, it is not possible for a different manufacturer to make an identical copy. 

In this podcast, Dr. Gary Lyman discusses biosimilar agents, which are similar, but not identical, copies of these drugs. Dr. Lyman discusses some of the differences in manufacturing biosimilar agents, the criteria that are used to ensure they are as effective as the original drug, and some of the ways that biosimilars can help reduce the cost of cancer care.

Dr. Lyman is the Co-Director of the Hutchinson Institute for Cancer Outcomes Research at the Fred Hutchinson Cancer Research Center, and Professor of Medicine, Public Health, and Pharmacy at the University of Washington School of Medicine.

ASCO would like to thank Dr. Lyman for discussing this topic.

Dr. Lyman: Hello, this is Dr. Gary Lyman, from the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, Washington, and I'd like to discuss the forthcoming issue related to biosimilars. This has gained a great deal of attention and resulted in a recent statement from the American Society of Clinical Oncology on this topic, and it has a potential for a broad impact on both cancer patients and providers that care for cancer patients.

So first of all, what are biosimilars? These are formally defined by the US Food and Drug Administration as being biologic substances or drugs that are highly similar to the original biologic product or treatment, what we refer to as the reference product. And these reference products, these biologic therapies like monoclonal antibodies, have gained a great deal of attention in recent years because of dramatic improvements in the treatment of many types of cancers, including common cancers like breast cancer, or colon cancer, even now lung cancer. Biologic therapies, which are products that are produced in living cells that are different from more traditional medications that are synthesized chemically in test tubes, in a laboratory. Biologic therapies and these highly similar biosimilars are produced within living systems, and therefore it is impossible to replicate them identically like you would with a generic form of a common medication.

So this adds a layer of complexity. So not only do we have these exciting new therapies that have dramatically changed the treatment and outcomes for many cancer patients, but now as the patents expire on these original biologic products, things like the common supportive care drugs, filgrastim or pegfilgrastim, now we have biosimilar forms of some of the direct cancer therapies like trastuzumab or Herceptin and bevacizumab which is Avastin. These are used broadly in cancer therapies but have come with a considerable cost.

So one of the challenges that these new biosimilars are trying to address is this rising and unsustainable rise in healthcare costs. And much of that increase over the last decade or so has related to these new biologic therapies. Again, they're very exciting drugs. They target specific targets within cancer cells to be more selective, often with fewer side effects than the traditional cancer therapies, chemotherapy. But because they're so complicated to develop and produce, and all the clinical trials that have to be done to demonstrate the original product, the reference product, they are often priced at extremely high rates, not infrequently being as high now as 10 to 20 thousand dollars per month for these types of treatments.

So 1 of the strategies to rein in the rising costs of these cancer therapies is as the patents expire—the limitations that are imposed by the regulators on someone duplicating these agents—as these patents expire, companies are increasingly saying, "Well, we want to develop the same product." And again, it's impossible to develop exactly the same product, but they can produce very similar. And if they meet certain criteria based on preclinical studies, meaning things like the molecular structure is the same, the work in animals shows these are highly similar in terms of their effect and side effects, and then with some clinical data—but not as much as the original product required, otherwise one would not be able to reduce the cost of development of these new biosimilar agents—they meet the FDA criteria for being highly similar.

So they have to replicate the purity, the potency, and the safety of the original biologic to reach the level that's acceptable to the FDA for approval. But as of the last few years, we now have biosimilar versions of these proteins, these biologic therapies, available in the United States. Again, one of the aims here is to have competition in the marketplace so that the cost of these exciting but costly drugs comes down, and with increasing use of the biosimilars that healthcare costs might be constrained and we all benefit. There will be broader access to these exciting new therapies because patients can now afford them or their insurance companies can afford to pay for them and so forth. So this is 1 of the goals here, that we have competition in the marketplace driving down the price or at least blunting the continual rise in pricing of cancer therapies.

So there are a number of aspects of biosimilars that are confusing, not only to patients but to clinicians, to providers. So we're in a broad effort, through the American Society of Clinical Oncology, to try to better inform our colleagues, clinicians, others who care for cancer patients, as well as the patient community, about what these biosimilars represent and why they are developed and regulated the way they are. One of the things that is different, that is requiring a bit of a leap of faith among the practice community, is that often the original biologic was approved for several different indications, either for treatment of different types of cancer or for treatment of different types of problems within the cancer population, and the original product needed to produce clinical trial data for each of these conditions. So the approval of the original biologic for several indications, different diseases or different variations on the condition, required individual, separate clinical trials to support their approval there. Once granted, of course, the biologic was permitted to be used for any of these conditions. For the biosimilar, the decision was made that if the regulators, the FDA, required the same number of trials for each of the various conditions for the biosimilar, that the cost of developing them would be probably as high, or could even be higher, than the original biologic cost. And therefore this goal of constraining the cost of these agents would be very limited.

So a decision was made that if a developer of a biosimilar demonstrated, provided compelling evidence, that the biosimilar was highly similar to the original biologic product for one indication, unless there was some reason to be concerned otherwise, that the FDA could extrapolate approval to the other indications without additional supporting clinical trial data. This would allow development of these biosimilars with much less cost for development, and the reasoning being that extrapolation has been shown now for several years in Europe, where these agents have been out, to be a safe and effective approach to approval. And based on our early experience in the United States, largely around supportive care of biologic treatments, that extrapolation seems to be not only an important but a safe way to broaden the indications and to allow these new biosimilars to compete against the original biologic and drive down the cost of care.

But this extrapolation, of course, is a leap of faith as I said, because it's asking the provider and the patient to accept that these agents work in conditions, in settings, where there has not been a lot of clinical trial supporting data provided for the biosimilar, even though that was provided for the original indication. So the key principles for extrapolation, it has to have the same mechanism of action in the body and all of the evidence that's provided by the developer has to show that there's probable cause for there to be a comparability to the original biologic and the safety profile.

And particularly an issue that's called immunogenicity has demonstrated safety. So what is immunogenicity? The fact that these biologics, including biosimilars, are proteins. They're, again, produced in living systems like any protein, and it can be immunogenic. That is, it can cause an allergic reaction, or it can cause the development of antibodies to the product, which can both cause some safety problems and also could neutralize or counter the beneficial effects of the biologic. So one of the things is that the biosimilars need to show, just like the original biologic product, is that these proteins don't show evidence of causing immunogenicity or the production of these neutralizing antibodies.

There are a number of new features here and 1 final 1 that really does raise concern, and why we're educating and having programs at the Annual Meeting of the American Society, as well as in other forms, is the fact that because these are biologic products produced in living systems, as there are minor changes in the manufacturing product—maybe a new plant opens or some new substrate is used for the growing of the cells that produce these proteins—there's variability that can be introduced into the production of these substances: minor changes that hopefully don't change the ultimate effectiveness and safety of the drug. And over time, what we call drift, there may be minor changes in the product, in the drug, of both the original biologic. So we've shown that some of the biologics we've had now for up to a decade over time may change a bit because of, again, minor differences in manufacturing. Well, the same is true of biosimilars. So what the FDA is likely to impose—they already have indicated they will—is something called pharmacovigilance. And this is even after a biosimilar has been shown to be as effective and safe, and highly similar to the original biologic, and is approved and put on the market so it's available to treat patients, they will not stop monitoring the effectiveness and safety of that drug. So in the post-approval period that is after the drug is on the market available for doctors to use in treatment, there will be continual monitoring of the effectiveness and safety of these biosimilars, in case there was some rare side effect that wasn't shown with the original studies or some delayed side effect that only appears years later. So this is a critical part of biosimilars, is that we don't stop monitoring these or looking at these the day it is approved by the FDA. But for a period, unquestionably at least years after it's introduced into the care of patients in this country, there will be a continual monitoring for side effects, toxicities, this drift in changes in the product that might change the effectiveness and safety. All this will be continued to be monitored over time.

There is one final issue, and this has become quite contentious. And that is, there is, under consideration at the FDA, a new criteria that has not yet reached the marketplace, called interchangeability. There's a proposal by the FDA, that if a biosimilar has shown that the efficacy and safety does not change when a patient is switched between the biosimilar and the original product—maybe they start with the original product at one institution, they go to another institution, get put on a biosimilar, or vice versa—that there's no meaningful difference in the effectiveness and safety by switching back and forth between these. If a biosimilar in the future is approved to be interchangeable, that's a higher standard than just being granted approval as a biosimilar.

The concern is that that could lead to switching from one to the other without the patient or the doctor being notified. That is automatically substituting one for the other. And again, since these are not identical products, they're similar, there's concerns that, again, there could be toxicities, antibodies, or some loss of effectiveness, and yet you wouldn't know because there's been a substitution and a lack of notification. So now, well over half of the states in the United States have passed laws preempting whatever the final decision is at the federal level that would require a notification of physicians when a patient has been switched from an original biologic that used for years to one of the new biosimilars. And I think, as a oncologist, I agree fully that the physician and the patient need to know when these switches have occurred.

These new biosimilars, we think, are going to be highly effective and safe. They're very similar to the original product. These are amongst the most exciting therapies for the management of cancer today. Their costs have become unsustainable and this is, again, a mechanism for reining in that cost. But we need transparency. We need to know which product the patient is receiving, whether there's any unexpected side effects or lack of benefit in the management of their disease. So I think if we all understand the benefits, but the safeguards that are necessary for the use of these products, biosimilars offer a tremendous opportunity for us to move the field forward, improve the quality of patient care safely and effectively, and hopefully in the long run, make the treatment of cancer more affordable, accessible to everyone that needs it. And we can all continue to benefit from this revolution of biologic therapies that we've seen enter the field of oncology and many other disciplines in medicine today. And this is 1 big step towards all of those goals.

I want to thank you for your attention, and I hope if there are other questions that come up, you'll take advantage of the information available on the ASCO website and other sources that are available. And very importantly, have a conversation with your physician if you're a patient receiving one of these treatments. It's very important to continue to ask questions, and have your physician and yourself engaged in the decision on how to proceed with these therapies and what to look for. Thank you again for your attention. Good day.

ASCO: Thank you, Dr. Lyman. Learn more about how cancer is treated at www.cancer.net/treatment. And for more expert interviews and stories from people living with cancer, visit the Cancer.Net Blog at www.cancer.net/blog.

Cancer.Net is supported by the Conquer Cancer Foundation of ASCO, which is working to create a world free from the fear of cancer by funding breakthrough research, sharing knowledge with physicians and patients worldwide, and supporting initiatives to ensure that all people have access to high-quality cancer care. Thank you for listening to this Cancer.Net Podcast.