EditorialPublication Exclusive

Given high stakes of cancer care, biosimilar debate requires an open mind

In the last few months, I have followed the emerging debate about the use of biosimilars at a distance, but they have not impacted my clinical practice even after the introduction of the first biosimilars in the U.S.

Until very recently, biosimilars had not been on my radar screen as a subject I needed to better understand. That has changed in the past few weeks.

Two events have changed my mind. The first was attendance at an advisory board to discuss a new biosimilar. The second was a visit to India, where biosimilar use appears to be expanding rapidly, but in the context of a very different health care and regulatory environment than the U.S.

John Sweetenham

My own opinions about these agents have rapidly shifted.

I started from a position of ignorance — or, a kind of benign denial of their existence. From there, I moved to skepticism that these drugs would get much use in the absence of large-scale prospective randomized trials.

Now, my opinion has matured into uncertainty as I ponder value in health care, the potential societal benefits of the agents, and the possible impact on research and innovation. I decided I would share my thoughts on this subject in the hope that some of you might be convinced that uncertainty is the appropriate position to take on these agents for now.

Reference product vs. biosimilar

Without getting into the intricacies of biosimilar definition, they are biologic drugs that are similar to an established biologic — known as the reference or innovator drug — that can be manufactured and considered for licensing once the patent on the innovator drug expires.

The gate opened for production of these agents with the Affordable Care Act, which created a shortened pathway to licensure for products demonstrated to be “biosimilar to” or “interchangeable with” an existing FDA-approved biologic.

The FDA doesn’t yet appear to have accepted the concept of interchangeability, primarily because these compounds are not like generic drugs. Although generics typically are structurally identical to their reference compound, the production of biosimilars relies mostly on biological systems in which absolute identity with the reference molecule is unlikely. In fact, I have subsequently learned that different batches of reference drugs are rarely completely identical.

Manufacturers of these drugs are required to provide analytical data that show their molecule is highly similar to the reference compound; animal studies that include toxicity data; and data from clinical studies that demonstrate safety, purity and potency in at least one condition for which the reference product has a license.

They can then get approval without further extensive clinical trials or direct head-to-head comparisons with the innovator product. In fact, they can extrapolate the results from the reference compound to their own product.

As I started to grasp these details, my initial reaction was that whatever the FDA might think, as oncologists, we are not likely to have confidence in a product that has not been extensively evaluated against the standard of care in a randomized clinical trial. For our patients, the stakes are too high to be messing around with a cheap “knock-off” drug of uncertain efficacy.

However, if the molecule is highly similar to the original compound and there are clinical data for one disease entity confirming its efficacy, why not extrapolate these data into other conditions? The fact is, we do it all the time.

Many of us, for example, give maintenance rituximab (Rituxan; Genentech, Biogen Idec) to patients with follicular lymphoma after bendamustine (Treanda, Teva)/rituximab induction — an extrapolation of R-CHOP induction data. If randomized clinical trials were required for these agents for every indication, they would probably never be done. Apart from the expense of these studies, how many patients would sign up for a randomized study in which they are being offered, at best, the same outcome on both arms?

Further, these drugs are not cheap knock-offs. The major driver for biosimilar production is to reduce costs. Although these drugs undoubtedly save money compared with the reference compound, estimates of how much savings these drugs will bring to the health care system and to our patients vary widely, with a current consensus of only around 10% to 20%.

Value of biosimilars

Although my own comfort level with the concept of these drugs is increasing, it bothers me that major companies will spend millions of dollars developing anticancer drugs that are, for the most part, no better than an existing compound. As an advocate for my patients, I have to think that those dollars might be better spent on research into new targets and new anticancer drugs rather than offering patients the status quo.

The bigger picture, however, is the potential societal benefits of these agents. If the advent of biosimilars drives down the cost of these agents through competition, then health care systems, insurance companies and — most importantly — patients stand to win.

I witnessed this on my recent trip to India, where there are seven versions of rituximab available, including the reference compound. This has undoubtedly improved access to this drug in a resource-limited health care system and may have saved lives. Although we may have reservations about the regulatory environment that has allowed these agents onto the market very quickly, this does provide an extreme example of how these agents might deliver direct benefit to patients.

From our own perspective, as the march toward value in oncology care continues, these agents clearly have the potential to improve value by reducing cost. This will make them attractive to all stakeholders as long as they provide equivalent efficacy; although, there are even suggestions that some of these agents could turn out to be more effective than their innovator compounds — so-called “biobetters.” Health care systems and insurance companies are likely to drive purchasing decisions for these agents, and unless the FDA’s position changes, we can expect to see these drugs gain in use in coming years.

In the short term, the potential advantages of biosimilars from a health care perspective seem clear. Concerns have been expressed by many about the potential long-term consequences of an expedited pathway to licensing of these drugs. This could stifle research and innovation if a company could invest many millions of dollars into a new agent only to have it ripped off by a competitor at a lower cost a few years later.

Another concern is whether these agents could generate a two-tier system. I have heard a senior figure from one insurance company describe the concept of “economy-class cancer care.” His idea was that payers might take a closer look at guidelines — such as the emerging National Comprehensive Cancer Network guidelines for resource-limited areas — and see whether they could be applied in the United States, saving costs for the patient (and the payer) while maintaining outcome.

Could we get to a point where biosimilars were used in the economy class while the innovator compound is reserved for business class patients? In that situation, economy class might turn out to be a very good deal, but the idea of a tiered system makes me uncomfortable.

Overall, my mind has been opened to the possibility that biosimilars will benefit our patients in the short term, although the long term is less certain. What’s for sure is that they are not going away. We will need to be vigilant about the risks to innovation, and to how use of these drugs is driven by payers, but we should keep an open mind for now.

Reference:

FDA. Information for Consumers (Biosimilars). Available at: www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm241718.htm. Accessed Nov. 11, 2015.

For more information:

John Sweetenham, MD, is HemOnc Today’s Chief Medical Editor for Hematology. He also is senior director of clinical affairs and executive medical director at Huntsman Cancer Institute at University of Utah. He can be reached at john.sweetenham@hci.utah.edu.

Disclosure: Sweetenham reports no relevant financial disclosures.

In the last few months, I have followed the emerging debate about the use of biosimilars at a distance, but they have not impacted my clinical practice even after the introduction of the first biosimilars in the U.S.

Until very recently, biosimilars had not been on my radar screen as a subject I needed to better understand. That has changed in the past few weeks.

Two events have changed my mind. The first was attendance at an advisory board to discuss a new biosimilar. The second was a visit to India, where biosimilar use appears to be expanding rapidly, but in the context of a very different health care and regulatory environment than the U.S.

John Sweetenham

My own opinions about these agents have rapidly shifted.

I started from a position of ignorance — or, a kind of benign denial of their existence. From there, I moved to skepticism that these drugs would get much use in the absence of large-scale prospective randomized trials.

Now, my opinion has matured into uncertainty as I ponder value in health care, the potential societal benefits of the agents, and the possible impact on research and innovation. I decided I would share my thoughts on this subject in the hope that some of you might be convinced that uncertainty is the appropriate position to take on these agents for now.

Reference product vs. biosimilar

Without getting into the intricacies of biosimilar definition, they are biologic drugs that are similar to an established biologic — known as the reference or innovator drug — that can be manufactured and considered for licensing once the patent on the innovator drug expires.

The gate opened for production of these agents with the Affordable Care Act, which created a shortened pathway to licensure for products demonstrated to be “biosimilar to” or “interchangeable with” an existing FDA-approved biologic.

The FDA doesn’t yet appear to have accepted the concept of interchangeability, primarily because these compounds are not like generic drugs. Although generics typically are structurally identical to their reference compound, the production of biosimilars relies mostly on biological systems in which absolute identity with the reference molecule is unlikely. In fact, I have subsequently learned that different batches of reference drugs are rarely completely identical.

Manufacturers of these drugs are required to provide analytical data that show their molecule is highly similar to the reference compound; animal studies that include toxicity data; and data from clinical studies that demonstrate safety, purity and potency in at least one condition for which the reference product has a license.

They can then get approval without further extensive clinical trials or direct head-to-head comparisons with the innovator product. In fact, they can extrapolate the results from the reference compound to their own product.

As I started to grasp these details, my initial reaction was that whatever the FDA might think, as oncologists, we are not likely to have confidence in a product that has not been extensively evaluated against the standard of care in a randomized clinical trial. For our patients, the stakes are too high to be messing around with a cheap “knock-off” drug of uncertain efficacy.

However, if the molecule is highly similar to the original compound and there are clinical data for one disease entity confirming its efficacy, why not extrapolate these data into other conditions? The fact is, we do it all the time.

Many of us, for example, give maintenance rituximab (Rituxan; Genentech, Biogen Idec) to patients with follicular lymphoma after bendamustine (Treanda, Teva)/rituximab induction — an extrapolation of R-CHOP induction data. If randomized clinical trials were required for these agents for every indication, they would probably never be done. Apart from the expense of these studies, how many patients would sign up for a randomized study in which they are being offered, at best, the same outcome on both arms?

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Further, these drugs are not cheap knock-offs. The major driver for biosimilar production is to reduce costs. Although these drugs undoubtedly save money compared with the reference compound, estimates of how much savings these drugs will bring to the health care system and to our patients vary widely, with a current consensus of only around 10% to 20%.

Value of biosimilars

Although my own comfort level with the concept of these drugs is increasing, it bothers me that major companies will spend millions of dollars developing anticancer drugs that are, for the most part, no better than an existing compound. As an advocate for my patients, I have to think that those dollars might be better spent on research into new targets and new anticancer drugs rather than offering patients the status quo.

The bigger picture, however, is the potential societal benefits of these agents. If the advent of biosimilars drives down the cost of these agents through competition, then health care systems, insurance companies and — most importantly — patients stand to win.

I witnessed this on my recent trip to India, where there are seven versions of rituximab available, including the reference compound. This has undoubtedly improved access to this drug in a resource-limited health care system and may have saved lives. Although we may have reservations about the regulatory environment that has allowed these agents onto the market very quickly, this does provide an extreme example of how these agents might deliver direct benefit to patients.

From our own perspective, as the march toward value in oncology care continues, these agents clearly have the potential to improve value by reducing cost. This will make them attractive to all stakeholders as long as they provide equivalent efficacy; although, there are even suggestions that some of these agents could turn out to be more effective than their innovator compounds — so-called “biobetters.” Health care systems and insurance companies are likely to drive purchasing decisions for these agents, and unless the FDA’s position changes, we can expect to see these drugs gain in use in coming years.

In the short term, the potential advantages of biosimilars from a health care perspective seem clear. Concerns have been expressed by many about the potential long-term consequences of an expedited pathway to licensing of these drugs. This could stifle research and innovation if a company could invest many millions of dollars into a new agent only to have it ripped off by a competitor at a lower cost a few years later.

Another concern is whether these agents could generate a two-tier system. I have heard a senior figure from one insurance company describe the concept of “economy-class cancer care.” His idea was that payers might take a closer look at guidelines — such as the emerging National Comprehensive Cancer Network guidelines for resource-limited areas — and see whether they could be applied in the United States, saving costs for the patient (and the payer) while maintaining outcome.

Could we get to a point where biosimilars were used in the economy class while the innovator compound is reserved for business class patients? In that situation, economy class might turn out to be a very good deal, but the idea of a tiered system makes me uncomfortable.

Overall, my mind has been opened to the possibility that biosimilars will benefit our patients in the short term, although the long term is less certain. What’s for sure is that they are not going away. We will need to be vigilant about the risks to innovation, and to how use of these drugs is driven by payers, but we should keep an open mind for now.

Reference:

FDA. Information for Consumers (Biosimilars). Available at: www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm241718.htm. Accessed Nov. 11, 2015.

For more information:

John Sweetenham, MD, is HemOnc Today’s Chief Medical Editor for Hematology. He also is senior director of clinical affairs and executive medical director at Huntsman Cancer Institute at University of Utah. He can be reached at john.sweetenham@hci.utah.edu.

Disclosure: Sweetenham reports no relevant financial disclosures.