FDA Approval Process of Biosimilars


A review of the steps of the FDA approval process for biosimilars and a discussion on immunogenicity and quality assurance for biosimilars.


  • Comparison of Biosimilars vs Biologic Agents

Anthony Mato, MD, MSCE: Why don’t we talk a little about how these drugs are approved. I think we have a good sense of how a new drug may go through the regulatory process through the FDA. But from my own knowledge base, there are some potential differences in the way that a biosimilar might be approved by the FDA, for example. Would you be willing to touch on that for us, Bhavesh?

Bhavesh Shah, RPh, BCOP: Absolutely. I think the whole goal of having a biosimilar is that you’re actually bypassing all the phase III randomized controlled trials you have to do for every single indication. It’s a shortened pathway, and that makes it more attractive and increases the availability of the molecule much faster. There are drugs that are currently approved biosimilars that have been approved based on just healthy subjects. They haven’t even been done in the indications that the FDA has for the reference product.

There’s a pathway that’s much shorter. It is heavily involved with analytics, where you’re basically comparing the primary structure, the secondary structure, and a lot of the tertiary structure, which has to do with glycosylation, fucosylation—which really targets the ADCC [antibody-dependent cell-mediated cytotoxicity] and CDC [complement dependent cytotoxicity] assays. Once those analytic studies are done, it then moves on to animal studies. Actually, nowadays, the FDA doesn’t really require much animal studies for biosimilars. It can just move directly to PK [pharmacokinetic] and pharmacodynamic studies. The FDA chooses which indication you would do this in, so sometimes it may be not ethical to do some studies in patients who actually have healthy subjects with a specific drug.

For example, for rituximab, it was not ethical to do studies in healthy subjects for pharmacokinetics and pharmacodynamics. The FDA chose a specific indication where it would be appropriate to do the studies. Of course, the phase III is decided based on all the evidence that they have, analytics and pharmacokinetics to identify if they need to go to phase III, and which indication needs to be studied that is the most sensitive indication. That’s the overall process of the pathway.

Anthony Mato, MD, MSCE: I want to push a little more on this, because I think we all have a sense of what a generic drug is. In my mind I know what a brand acetaminophen is, what the generic is, and what they should be. But what does it mean to you when something has to be required to be “highly similar”? What does that mean from a drug design perspective and an approval perspective?

Bhavesh Shah, RPh, BCOP: To me, as a pharmacist, from an analytic perspective, I’m looking at the structural similarities. I think the structural similarities are the key to driving the mechanism of action of the drug. Having that being appropriately designed would be important, and then the pharmacokinetics and dynamics also need to be similar between the reference product and the biosimilars. If you see the data that are actually been utilized and published, most of these pharmacokinetics and dynamics are superimposable graphs of the serum concentrations—the Cmax, the AUC [area under the curve], even the pharmacodynamics of the drug. So, there’s definitely the high similarity of the structure and the function. That’s what I think of as a biosimilar.

Anthony Mato, MD, MSCE: Do you guys have anything you would add to that?

Tim Peterson, PharmD, BCOP: I think another interesting part of the approval process for the biosimilars is that they are going to specifically look at the immunogenicity of these agents too. It’s something that we’ve come to know with biologic agents, that they have different levels of immunogenicity depending on glycosylation and these different minor variations in the structure—even in the processing of these agents. The FDA does require immunogenicity testing, too, to have a comparator between the reference and biosimilar. This is because if we can have increased rates of immunogenicity being elicited in these patients with biosimilars, that could lead to neutralizing antibodies. That could reduce efficacy. It could lead to allergic and anaphylactic reactions, serum sickness, autoimmune disorders, and those types of things developing. That’s an important consideration as well within the development pathway too.

Anthony Mato, MD, MSCE: It does sound like the quality assurance process is quite rigorous. Have there been any questions or concerns with biosimilars in terms of quality assurance once they’ve been approved, to your knowledge? Is there anything we should be thinking about?

Bhavesh Shah, RPh, BCOP: I have not been aware of anything. I think it’s a very heavily regulated process where there are critical quality attributes that every single manufacturer has to meet based on the standards that have been set by the reference product. If that is out of range, then of course the FDA is not going to allow that product to go into distribution. There’s a rigorous process that the FDA has developed, so I haven’t heard of any concerns after we have over 20 plus biosimilars approved in the market.

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