Transcript:Hope S. Rugo, MD: 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.
Cornelius F. Waller, MD: 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—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.
Hope S. Rugo, MD: 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.