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  1. News & Events for Human Drugs

Switching Between Biosimilars and Their Reference Counterparts with Dr. Sarah Yim

Q&A with FDA Podcast | Transcript

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Dr. Roach: Welcome to “Q&A with FDA,” where we aim to answer some of the most frequently asked questions that we’ve received from the public.

My name is Dr. Sara Roach, and today we will be discussing biosimilar drug products, switching between biosimilars and their reference or brand name counterparts, and safety outcomes associated when switching.

Here with me today is Dr. Sarah Yim, Director of the Office of Therapeutic Biologics and Biosimilars in the FDA’s Center for Drug Evaluation and Research.

Welcome Dr. Yim, thank you for joining us today!

Dr. Yim: Thanks for having me.

Dr. Roach: Dr. Yim, we invited you to join us today to discuss a topic that is on the agenda it seems at every major healthcare professional conference. It’s been almost 10 years since the first biosimilar was FDA approved. How do you respond to health care professionals who are unfamiliar with biosimilar drug products, or who have reservations about prescribing a biosimilar drug product?

Dr. Yim: So yeah, it’s kind of unfortunate that there are marketplace related issues that have meant that not all healthcare professionals have had much access to or experience with FDA-approved biosimilars.

However, the number of approved biosimilars has been steadily growing, and as of the time of this recording, FDA has approved 50 biosimilars to 15 different biologic medicines, and these medicines treat conditions as wide ranging as macular degeneration, rheumatoid arthritis, multiple sclerosis, diabetes, inflammatory bowel disease, osteoporosis, and several cancers.

I expect as people have opportunity to use biosimilars and gain more experience with them, they’ll also gain more comfort with them, as has been the case with generic drugs.

Dr. Roach: For those who are listening to become more familiar with biosimilars, can you provide a quick background on these products?

Dr. Yim: Sure. Biosimilars are a type of biologic medicine, so let’s start there. Biologics are different than the historical small molecule, chemically derived drugs in that they are generally large, complex molecules, they’re typically proteins, and they’re made from living sources such as bacteria, yeast, and animal cells.

And because biologics are made by living organisms, even with the protein itself being reproduced identically from a genetic template for example, being made in cells inherently results in many slight variations from batch to batch. As a result, biologics are often more complicated to purify, process, and manufacture.

A biosimilar is a biologic drug that is highly similar to an FDA-approved reference biologic to which its compared, and it also does NOT have any clinically meaningful differences from the comparator biologic.

Dr. Roach: We sometimes use the analogy of generic drugs to explain the benefits of biosimilars to health care professionals. While not exactly the same, they do share some common benefits. Biosimilars, like generic drug products increase treatment options, and enhance market competition, which can lead to reduced drug costs.

Dr. Yim: Right, biosimilars are like generic drugs in some ways because biosimilars and generic drugs are compared to that reference or brand-name drug, and they have the same efficacy and safety profile of that reference drug.

The main difference between biosimilars and generic drugs is that the active ingredients of generic drugs are generally simpler and smaller, and more straightforward to copy.

Biologics generally can’t be copied exactly, because the products usually contain a mix of many slight variations of a protein, and this mix is never exactly the same in each dose or batch of the product.

For this reason, biosimilar manufacturers submit data showing that their product has similar variations as the comparator biologic product and that their product has no clinically meaningful differences in terms of safety or effectiveness.

Dr. Roach: You explained the differences between a biosimilar and a generic, however, what is an interchangeable biosimilar? When the concept of interchangeability is introduced, this is when healthcare professionals have even more questions. Can you elaborate on interchangeable products?

Dr. Yim: Sure. There is a lot of confusion about interchangeable biosimilars. And we’re the only country in the world that has this second specific category of interchangeability in our laws for biosimilars. That law specifies that an interchangeable biosimilar is a biosimilar that may be substituted for the reference product by the pharmacist without consulting the prescriber. In other words, the law sets out expectations related to the potential for automatic substitution.

In addition to the data that support biosimilarity, when a company requests approval as an interchangeable biosimilar, it has to provide information that would support its potential for automatic substitution at the pharmacy level. Of course, the ability to actually substitute is dependent on state laws.

Dr. Roach: Also, from my understanding, FDA does not approve a product as interchangeable unless a company specifically seeks an interchangeability determination. For the pharmacists listening, that is an important distinction.

Dr. Yim: That’s right. Companies must submit an application with adequate data to support an interchangeability determination. I also want to emphasize that interchangeables are not a higher level, quote unquote, of biosimilar. You don’t have to wait for a biosimilar product to be approved as interchangeable to prescribe that product to patients. And because the level of product quality and similarity, and of safety and efficacy is the same, biosimilars and interchangeables both can be used for patients.

In fact, all FDA approved biosimilars are as safe and effective as the reference product to which they are compared. It’s just that in certain states, that interchangeability status may allow pharmacists to substitute the biosimilar product for the reference product without first consulting the prescriber. Since many biosimilars are not dispensed at the pharmacy, and are physician administered, say in a hospital or in an outpatient facility, pharmacy level substitution may not really be relevant for those products.

Dr. Roach: So interchangeable biosimilar substitution is similar to how small molecule generic drug substitution occurs in pharmacies. I think our listeners would benefit in knowing more about how manufacturers demonstrate that a product is interchangeable with the reference biologic. Can you describe what the additional data includes?

Dr. Yim: To assess the safety of switching, manufacturers may conduct studies in which patients alternate between the reference product and the interchangeable biosimilar, and compare those to patients who did not alternate, and this is called a switching study.

The results must show no decrease in effectiveness and no increase in safety risk associated with switching.

Sometimes you can actually get information that supports that without an actual study, and in fact of nine of the approved interchangeable biosimilars, 6 of them did not need additional clinical data to support approval as an interchangeable. But no matter if there were additional studies or not, it’s really important to emphasize that an interchangeable is not safer or more effective than a biosimilar that hasn’t gone through that process.

Dr. Roach: Some pharmacists may then ask if patients need to have been treated with the reference product before receiving a biosimilar?

Dr. Yim: No. I mean, biosimilars can be prescribed for patients who have previously been treated with the reference product, as well as for patients who have not previously received the reference product. Either case, the biosimilar’s able to be used in place of the reference product.

Dr. Roach: We recognize that some health care providers continue to have reservations about switching a patient to a biosimilar when a condition is stable on the reference product. What do you say to dispel the myth that switching a patient to a biosimilar will destabilize their condition?

Dr. Yim: We understand that a lot of patients go through many medications before finding the right one, and that causes a fair amount of anxiety about switching to a biosimilar. For that reason, FDA investigators conducted a systematic review and meta-analysis to determine whether there were differences in safety outcomes between individuals who switched between a biosimilar and a reference product, and individuals who did not switch.

In particular, the research was focused on identifying any statistically significant differences in the number of deaths, non-fatal serious adverse events, and study discontinuations due to an adverse event. Immunogenicity events, such as the development of antidrug antibodies and neutralizing antibodies, were also examined and compared following switching.

Dr. Roach: And what were the findings?

Dr. Yim: In the meta-analyses, the researchers found zero difference in the risk of death, serious adverse events, and treatment discontinuations between participants who switched, and participants who did not switch.

Immunogenicity data also showed a similar incidence of antidrug antibodies and neutralizing antibodies. And immune-related adverse events such as anaphylaxis, hypersensitivity reactions, and injections site reactions were also similar between the groups.

Based on these data, the researchers concluded that there were no statistically significant differences in the risk of death, serious adverse events, or treatment discontinuations between the switch and no-switch arms. And these results were not affected by the reference product class, the direction of the switch (for example, going from the reference product to biosimilar or vice versa), or the number of switches.

Dr. Roach: What has been the reaction of the health care community to these findings?

Dr. Yim: We hope that people are reassured. We know health care providers want to do what’s best for their patients, and these findings hopefully provide additional evidence to reassure them and be able to tell their patients that switching between biosimilars and their reference product is not associated with any major safety concerns.

Dr. Roach: Are there any final thoughts you want to share with our audience?

Dr. Yim: Just that I want health care providers to feel confident that FDA’s rigorous approval process means that biosimilars provide the same treatment benefits as their respective reference products.

The take home message is that the availability of FDA-approved biosimilars including interchangeable biosimilars can provide more treatment options for patients, increase access to lifesaving medications, and potentially lower health care costs through competition.

Dr. Roach: Thanks for listening to “Q&A with FDA”. The full podcast and a transcript of this recording is available at fda.gov/qawithfda. Many of our episodes offer continuing education credits for health care professionals, so be sure to visit this webpage for more details. If you are looking for additional learning or continuing education credit opportunities, including live and home study webinars, you’ll also want to check out fda.gov/CDERLearn and fda.gov/DDIWebinars. And if you have questions about this episode, or anything drug-related, email us at druginfo@fda.hhs.gov.

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