Biosimilarity, Manufacturing Changes, and Comparability

Gillian Woollett, MA, DPhil: So, comparability is an issue that’s raised in the context of biosimilars. Comparability is a regulatory tool developed in 1996 whereby manufacturing changes can be made to an existing biologic. Then it was adopted internationally in 2005 and under so-called [ International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH]. Now, comparability—you can make a manufacturing change to an existing biologic as long as you show that the critical product quality attributes, including immunogenicity, haven’t changed. That’s been used extensively for many products including, I believe, infliximab—it’s published; it’s been used over 50 times since the product was approved.

Now, I say in general and shorthand, that makes every originator biologic essentially a biosimilar to itself. It’s been subject to changes, but the important point is, the clinical outcomes are no different. In the US, it’s an entirely confidential trade secret when comparabilities occurred, and most physicians, most providers, and patients—they don’t know that’s happened to their existing medicine because the label on the product doesn’t change.

Carlos Sattler, MD: And because there’s no difference in the clinical performance.

Gillian Woollett, MA, DPhil: You could say that comparability is already the standard for extrapolation between indications and even interchangeability. So from a manufacturing perspective, does it matter? Is it important for physicians to know about these changes in the US in order for them to be more comfortable about biosimilarity? How much do you think education goes back to these fundamentals, understanding the variations of biologics both batch to batch, pre— and post–manufacturing change? But fundamentally, to this citizen petition that the clinical outcomes are unchanged—that’s the important other part of both comparability and both biosimilarity.

So, Carlos, do you find, as a manufacturer, there’s any understanding? Is there interest? Where are we on this fundamental understanding of biosimilarity and comparability being the same as a scientific asset?

Carlos Sattler, MD: So, manufacturing changes, as you mentioned, occur frequently, and they’re there for very good reasons—for example, if there’s a scale-up in the manufacturing process that represents a change or there’s a change from one manufacturing line or facility to another or if there’s an improvement in the process. All of these are good justifications for manufacturing changes. But they do introduce potential variability in the product from an analytical perspective, from a characterization perspective. And again, as you mentioned, the pre—manufacturing change product and the post–manufacturing change product have to be shown to have the same clinical efficacy, safety, and no difference, no change in immunogenicity.

This is not well known. This is not well known among providers. In fact, when you describe this manufacturing change and the fact that it does result potentially in a change to the product, they’re not aware. But I think what’s critical is also what you mentioned. These changes occur frequently. They occur for good reasons, but there must be a demonstration that there’s no clinical impact. And they can happen multiple times, as they do, and you mentioned the example of infliximab. It’s been available now for a long time and has undergone many manufacturing changes, some of which are relatively minor; others may be somewhat less minor.

But as long the pre— and post–change product is shown to not have any change in the clinical effect, then the product remains on the market. There’s no change in the label. And I believe in that case, it’s interesting to make that known, because it provides some insight into biosimilarity because you’re absolutely right—the scientific concept between the comparability exercise of manufacturing changes and the biosimilarity exercise in demonstrating that a biosimilar is highly similar to the reference product is essentially the same. And you get a lot of “ah-has” from prescribers, even more so when you mention, then, that it is conceivable that a reference product is a, quote, unquote, “biosimilar of itself” over time—that also raises an ah-hah moment. And I believe that for products that have been on the market for many, many years, a product that was first launched compared to a product that’s currently available in the market is probably a different product from an analytical perspective, but, again, the efficacy—the clinical performance—has to be the same.

Gillian Woollett, MA, DPhil: So basically, what we know, then—and FDA did lead the world in 1996 with comparability protocols as the basis of manufacturing changes—is that the FDA knows how to do this. That’s 22 years of experience, by definition, with the very biologics that are the referenced products for biosimilars.

So, Julie, we talked about the experience in Europe. The European regulators have been absolutely explicit that biosimilarity and comparability are the same. Do you think we need that from the FDA too? Is that an opportunity—again, in terms of a primary source of educational materials—for FDA to add to this clarity? That doesn’t mean they have expose for individual products when comparability is being used, because in the US, that’s a trade secret; in Europe, it’s public. But would it help for the FDA to articulate some of these primary principles and, quite frankly, laud their experience on successful use of comparability?

Juliana Reed: Thanks, Gillian. And yes, I think it would be supportive and helpful if the FDA was to clarify this. But I think—and I go back to what Carlos said—it’s important to understand that both Pfizer and Novartis Sandoz are innovator companies and biosimilar companies, as well. And I think if the FDA could clarify this but also clarify that the standards for biosimilar and its innovator biologic or its reference product are not different…So, I think those are very important as far as manufacturing changes, comparability, the data, and everything else goes. So we need to simplify that message. The FDA should take the lead on that and then continue to provide…

Gillian Woollett, MA, DPhil: This is not anything new we’re asking really at the FDA.

Juliana Reed: No.

Gillian Woollett, MA, DPhil: In fact, they’ve got everything on their website, which I personally find phenomenal, because there’s so much stuff there.

Juliana Reed: You need to know to look for it there.

Gillian Woollett, MA, DPhil: But you need to know for it look for it, so we’re essentially asking simple summaries.

Carlos Sattler, MD: What Juliana is asking is the basics, right? Just understanding some of the basics would clarify some of these misconceptions. For example, the quality standards and requirements of biosimilar manufacturers and reference part of manufacturers are exactly the same. As Juliana mentioned, at Novartis, for example, we manufacture our original, originator biologics and biosimilars in the same manufacturing facility. So the standards are the same, and this is the same in the [European Medicines Agency, EMA] as it is in the FDA. There’s this perception that somehow the standard and the requirements for biosimilars are lower than the referenced products, and that’s just not true.