Part 2: Nick Mitrokostas on the Race for the First Interchangeable Biosimilar

The Center for Biosimilars^® (CfB): Hello, I'm Matthew Gavidia. Today on the MJH Life Sciences News Network, The Center for Biosimilars^® is pleased to welcome Nicholas K. Mitrokostas, an intellectual property law attorney with Goodwin Proctor in Boston and editor-in-chief of Big Molecule Watch. We haven’t gotten any interchangeable biosimilar designations from the FDA yet, but some states are allowing interchangeability and some hospitals and health care systems have reworked their pharmacy protocols to allow automatic substitution. Can you discuss this and touch on whether the FDA is falling behind the curve on this one?

Mitrokostas: Well, I think what we’re seeing is that the interchangeability designation is still a prize, so to speak, for biosimilar manufacturers because it requires not only that you demonstrate your product is highly similar to the reference product, but also that it’s going to provide the same clinical result and that switching between the reference product and the interchangeable product is not going to lead to any greater risk of adverse events or any differences in safety and efficacy. So, it requires additional studies, but of course, it leads to significant rewards, which is that automatic substitutions can happen at the pharmacy level by operational state law.

Now, you mentioned that some states are getting ahead of FDA and saying that they’re going to allow substitution for some products. And I think what really is going to be the issue here is how doctors prescribe products and what they choose to do. The Biosimilar Action Plan that Scott Gottlieb’s FDA released a couple years ago really focused on how to educate clinicians about biosimilar products and the fact that they have been approved by FDA to be highly similar to the reference product and, therefore, can be used in the approved indications for the reference product. But really whether or not those products get used is going to come down to how doctors operate in practice. Now, the interchangeable designation bypasses that in the sense that the doctor will write the brand or reference product name and then the pharmacy will just substitute it.

So, I suspect we will have a number of biosimilar manufacturers try to seek this interchangeability designation because the real value of that automatic substitution comes from FDA saying that additional studies have been done and that those studies demonstrated that there’s no increased risk switching between products.

Now, the second part of your question is has FDA fallen behind? I think FDA is trying to really facilitate the development of interchangeable products. I think that’s clear from the guidance they put out in May 2019 with respect to interchangeability. They made clear that they’re encouraging manufacturers of biosimilar products to really take a stepwise approach in the development of an interchangeable [product] and to evaluate in each stage of the development process if there is uncertainty about whether this [biosimilar] can be interchangeable. And if [there is], how can they demonstrate that [the biosimilar] is interchangeable and address any uncertainty.

[FDA] also made clear that structural and functional complexity will influence how difficult it will be for a manufacturer to get that interchangeability designation. So, something that has 1 target and has low complexity may be easier to be demonstrated as interchangeable than a product that has high complexity and maybe has multiple indications and multiple targets in the body that might require more studies and more work to demonstrate interchangeability. And this guidance really lays out for developers of biosimilar interchangeable products how to go about doing that.

The other thing that is a key piece from this FDA guidance is really in the switching study aspect. FDA indicated that switching studies aren’t going to be required for demonstrating that you can switch between the 2 products. It gave a lot of guidance on how the studies should be conducted in order to meet FDA requirements. And I think developers of biosimilar products seeking an interchangeable designation at least have sort of a roadmap to how to put together their development program in order to ensure timely and successful approval of their interchangeable products.

CfB: Can you describe the role of immunogenicity studies for biosimilars and insulins and tell us whether the latest FDA guidance makes it more or less likely that immunogenicity studies will be required?

Mitrokostas: Sure. So, just to take a step back for a minute, immunogenicity is, for those who are or not familiar with the concept, basically just the potential for a therapeutic protein to cause an immune response in the human body. And 1 of the key attributes of therapeutic proteins, like the ones that are approved as biologics and biosimilars, is that they have a high potential to lead to immunogenicity. And so, typically, immunogenicity is 1 of the main criteria that are evaluated in both the approval of a biologic and a biosimilar to ensure that the therapeutic protein or therapeutic molecule is not going to induce this immune response in the patient that could lead to serious adverse consequences.

Now, with respect to insulin, FDA put out a guidance late last year indicating that while insulin previously had been believed to have concerns with respect to immunogenicity, recent studies on insulin products over the last several decades have indicated that immunogenicity was less of a concern than originally anticipated. Therefore, what FDA was indicating to developers of [biosimilar] insulin products is that the [proof of the product being] highly similar [to the reference product] is really going to be the key attribute and leading to approval of a biosimilar. It’s not that there isn’t a concern for immunogenicity. A comparative clinical immunogenicity test may still be required in certain instances; [however,] FDA has said that it’s likely unnecessary for insulin products given all of the scientific evidence that has come to light with the use of insulin products.

So, developers of insulin products with this guidance in hand should seek out FDA’s views as they’re working through their file and their development program to determine whether, in the [developer’s] case, an immunogenicity study would be required. But it seems from all indications that FDA has given in this guidance that more often than not developers of insulin products will likely not be required to do the comparative clinical immunogenicity study.

CfB: With respect to promotions, labeling, and advertising, the FDA and Federal Trade Commission (FTC) have said they want to prevent anticompetitive messaging, but do they have the tools they need to stop this?

Mitrokostas: That’s a really good question. I think there’s sort of multiple considerations here. One is that FDA has been taking action in the sense of putting out guidance on labeling and promotional materials for biologics and biosimilars with this goal in mind, in my view. So, earlier this year they’ve released a draft guidance in the form of a Q&A that gives developers of biologics and biosimilars some examples of what would be misleading in the context of promotion and labeling. And I think that’s 1 tool that FDA has. Clearly, they don’t have as much of an arsenal as some of the other government agencies, but they can take action if someone is engaging in misleading and inappropriate labeling and promotional materials.

So, developers would be wise to look at the guidance and think about when they’re putting their label together and their promotional materials, what is going to be seen as not misleading. For example, the guidance talks about information like data from a clinical study that may be true in the sense that it’s accurate as representing the clinical study, but it can be presented in a way that’s misleading if it gives the impression that a biosimilar product is more or less safe than a reference product. Another example that’s in this guidance is when the biosimilar product is approved for fewer than all of the approved uses for the reference product. Would it be misleading to have a side-by-side column where you have the reference product is approved for 10 uses but the biosimilar only approved for 1 or 2? While that is truthful information, in essence, it can lead to the impression that 1 product is safer or more efficacious than another.

So, the guidance really does lay out a lot of concrete examples for developers. And I suspect that, to the extent that if companies don’t follow this guidance and do engage in misleading labeling and promotional materials, we’ll see action from FDA and potentially even from FTC. The second sort of consideration here is how receptive courts will be to claims made by third parties or government agencies with respect to labeling and promotional materials with misleading information.

CfB: And lastly, what does it mean if the FDA approves a biosimilar for fewer indications than the reference product?

Mitrokostas: Well, essentially, FDA has also put out guidance on this over the last year and said that a biosimilar applicant may seek approval for fewer than all of the indications. In the case of an interchangeable product, FDA said its preference would be for the applicant to seek approval for all of the approved indications for the reference product, but nothing precludes an applicant from seeking approval for just 1 of the approved indications. And what that essentially means is that for a particular biosimilar can only be used for that approved [indication].

Now, obviously, it really comes down to doctors’ prescribing preferences. So, doctors [who have a choice of multiple biologic products approved for the same indications] can choose which one they want to use. Doctors have freedom to prescribe products off label. At least in the small molecule context, we’ve seen the doctors have done that. In some instances, they have used products for uses that were not approved, so long as there was a clinical basis for the doctor to believe that they could use the product in that way. So, I suspect that in this space as well, we’ll see how it plays out in the market.

CfB: To learn more, visit our website at centerforbiosimilars.com. I’m Matthew Gavidia. Thanks for joining us.