The FDA Approval of Biosimilars

Ali McBride, PharmD, MS, BCOP, FAzPA, FASHP: There are numerous pathways or steps that we have to address from either a biologic standpoint under a BLA [Biologics License Application] pathway, or a biosimilar pathway, which is approved through the 351(k) pathway if I’m not mistaken. And that occurred through the Affordable Care Act, ACA.

When we’re taking a look at any type of product, regardless of whether it’s a biologic or a small-molecule entity, they always have to go through fidelity checks. That means we have to check that it’s the right product—no fidelity issues. That the actual biologic agent doesn’t have any changes in terms of maybe a pH change or structural change and certain post-translational modifications as well. The FDA does a great job validating those checks across the board with the company. In addition, you know, if there are any variations, they’ll look mostly at the, again, preclinical data set to see if there are any changes throughout the structure pieces for the originator biologic.

When we take a look at a biosimilar, we do the same steps as well. But again, now we’re looking at this from the perspective of approval. When the FDA reviews the actual package for FDA processing, they’ll first check again the preclinical studies, which I think we did a good job discussing, but also the phase 1 and phase 3 studies as well. That whole package has developed.

As time goes on, maybe a manufacturing change can occur. Variations can occur in terms of the actual production line; therefore increasing the capacity of that biologic for use. We’ve seen it before with some biologic therapies early on because of increased utilization and increased need to the patient population. In those cases, there will actually be a consistent discussion with the FDA and the pharmaceutical company to make sure those checks are in balance and in validation of the product.

In the EMA [European Medicines Agency], in the European Union, they’ll actually have very transparent processes. Therefore, anytime a post-translation modification change occurs, manufacturing change, or other variations—which may include a cell molecule or the variations for buffers or solubility—those all are provided to EMA in a much more transparent manner. And so we utilize some of those guidelines and information pieces to address and check the biologic pattern for the biologic or biosimilar as well. In a nutshell, we have several different checkpoints across the board that have worked with the manufacturer, but also the FDA is aware and compliant with those informational pieces.

The definition of extrapolation, the understanding of it, is very interesting. When we’re taking a look at it for different disease states, and we can go from everything from a rheumatology disease state, as we’ve seen with infliximab, to those of other therapies. In oncology we can see the extrapolation vary based on indication. For example, if you have Neulasta, you have only 1 indication, so really there is no need for extrapolation. When we start taking a look at oncology, the extrapolation for the FDA-approved indications makes sense as we’re looking at those patient populations. Because again, we’re really addressing the fact that we may have 1 or 2 sets of populations in these cases, and then you extrapolate those indications.

That does make sense; it’s actually understanding that by utilizing extrapolation, we reduce the overall number of clinical studies needed to get the approval. If we mimic every single clinical study out there, we’d increase the cost of that biosimilar because you have to do more studies, which means you have to do more of an analytical piece, more clinical studies for patient populations. Therefore, there is increase in the cost. The question also comes up whether you extrapolate for off-label indications. I think that’s an unknown.

In fact, in many cases where you may not have extrapolation to all indications, due to the patent litigations, or to patent issues in regard to that, that will also be another unknown. So we still have some unknown areas of development, which can include patent-based issues for certain types of off-label indications or labeled indications—the former being more of an important piece. If you have something called the “skinny label,” for example, you have 6 indications due to some patent pieces, and the actual biosimilar carries only 4 of those, what do you do with those other 2? What does that off-label piece mean? How do you address it? That’s an unknown right now.

With the current approval of some biosimilars with the pending approval of the actual rituximab, Truxima, being released, I think we’ll have a better understanding how the payers define that. Because really when it comes to off-label, it’s all dependent upon the payers. Again, it’s kind of a point in question, do we consider a skinny label with missing indications to be off-label if the brand-name biologic has it in its full patent inclusion?

I think that’s going to be a question for that piece. In addition, will the extrapolation occur there? We don’t know. Will payers define that extrapolation to include all and, therefore, have a variance on the next extrapolation piece too? We don’t know. I still think we’re kind of in that neophyte, nascent area for biosimilars and also what those patents include.

In Europe they have a very different type of regulation with patent inclusions, but in the US we have some variations. We have that interpretation of the extrapolation for skinny label—based indications will be a very important piece. In addition, if we have certain therapies that have a very large off-label inclusion, having many different types of off-label therapeutic indications. What I mean by that is there may be phase 2 data, but there was never an actual inclusion of the FDA indication. We use it very often off-label. Will that also carry forward too? We don’t know. Hopefully it does, and the extrapolation piece for those indicated FDA pieces are still being realized. For the off-label, I think that will also be in discussion.