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Approval Process for Biosimilars


Peter L. Salgo, MD: There are the bioequivalence data from the Biologics Price Competition Innovation Act. Help me here. What on earth is that? Is that a different way of approving biologicals versus biosimilars?

Vibeke Strand, MD: It’s part of the Affordable Care Act, which is very interesting, because if that gets repealed, I don’t know how the FDA will actually be able to regulate biosimilars. But, essentially, what it’s saying is that a biosimilar must be highly similar to the reference product (based on a totality of the evidence). That means the structural characterization and functional characterization—so, physical, chemical, and biologic characterization.

There’s some limited preclinical data, usually based on what was done with the reference product, and then, finally, the clinical trials. There’s a human PK/PD [pharmacokinetics/pharmacodynamics] study, and then usually 1 or maybe 2 studies, maybe, in 1 or 2 indications to show that, in fact, the product behaves clinically no differently from the reference product.

Peter L. Salgo, MD: This is the standard that was used to approve Renflexis and Inflectra?

Vibeke Strand, MD: Right. And etanercept, right?

Peter L. Salgo, MD: Right. So, that’s the standard they’re using?

Allan Gibofsky, MD: Yes, it’s an abbreviated pathway.

Vibeke Strand, MD: And adalimumab.

Allan Gibofsky, MD: But the point is, it’s an abbreviated pathway. The totality of the evidence says, as Vibeke correctly points out, it relates, lately, to the analytical, the preclinical, and the pharmacokinetics and pharmacodynamics. The clinical experience is really the tip of the iceberg for a biosimilar. For a bio-originator, for each indication, the manufacturer has to conduct 2 replicate trials for each thing they want to market it for. For a biosimilar, that’s not the case.

Peter L. Salgo, MD: Again, let’s come back to this difference. Generic drugs have got to be the same drug, right?

Vibeke Strand, MD: Right. But based only on bioequivalence data (only on PK and, if you have it, PD—pharmacodynamics). So, that’s all you have to do, which is probably why we’ve seen, with generic pills, that some of them don’t behave as well as the originator.

Gary R. Lichtenstein, MD: And, Peter, one other point to note is that there are differences. Administration in a generic is oral, typically, whereas that as a biologic is often parenteral. Another thing, as well, is the mechanism of action. A small molecule that is a generic, if you would, is going to be an enzyme inhibitor, whereas this is a biologic blocking agent, per se.

Peter L. Salgo, MD: You did mention something. I want to circle back. There’s the PK/PD that you mentioned in terms of these drugs. These are biologicals. Is there a formal PK and a formal PD for these drugs? They get in and they go to work. Do they wash out?

Gary R. Lichtenstein, MD: For infliximab, it’s linear pharmacokinetics, and it’s well established. In the area of inflammatory bowel disease, we do therapeutic trough monitoring. And a level of 5 to 10 (that trough) is classically associated with remission, whereas a level of 11 (for example) or higher has been shown to correlate with fistula healing, and a level of 10 or higher, mucosal healing, based on the recent data that we’ve elucidated in the gastrointestinal arena, if you would.

Peter L. Salgo, MD: My view of these drugs (and clearly it’s wrong, based on what you’re telling me) was that you put these drugs in, and it’s like these little molecules are creeping along and doing stuff and changing stuff. They’re effective when they’re there, and when they go away, they’re not effective.

Gary R. Lichtenstein, MD: One of the key things to recognize, as well, is that albumin is one of the best predictors. Serum albumin is the best predictor of response, pharmacokinetically, to a biologic (infliximab).

Peter L. Salgo, MD: Why is that?

Gary R. Lichtenstein, MD: It’s a reflection of what’s going on in the gastrointestinal world in the bowel. You lose albumin in the bowel when you have active inflammation. And actually, levels of infliximab have been measured in the stool of patients. It’s not a fun job to do, but it’s been measured and recognized that they’re higher in patients who have active disease.

Allan Gibofsky, MD: This is as good a time as any to recognize that there are differences in our specialties in what we use and how we use it. Concepts of antidrug antibodies, concepts of trough levels, and concepts of albumin levels are really not used in rheumatology or, as far as I’m aware, in dermatology, either. They seemed to be unique to gastroenterology.

Vibeke Strand, MD: I think they’re not used because we don’t have protein-losing enteropathy in our diseases. We’ve been treating our patients so effectively that they don’t have hypoalbuminemia any longer. So, in fact, a monoclonal or soluble receptor will have the same PK in any of our diseases. It will be different in gastroenterology for the reasons that we talked about, but it will be the same in, for instance, psoriasis.

Peter L. Salgo, MD: Now, I also read that you’ve got preclinical studies that these biosimilars are forced to meet. Animal data—it’s got to show at least some animal data, right? Is that fair?

Allan Gibofsky, MD: Yes.

Vibeke Strand, MD: Yes.

Peter L. Salgo, MD: OK. And then there are clinical studies that are post-marketing pharmacovigilance in addition to PK/PD. How do you do that?

Allan Gibofsky, MD: No, no.

Vibeke Strand, MD: There is no post-marketing.

Peter L. Salgo, MD: There’s no post-marketing?

Allan Gibofsky, MD: No.

Vibeke Strand, MD: No. Although there’s a lot of interest in it, particularly in Europe where it is mandated and we have been able to see a lot of information based on those mandates, in the US, once a biosimilar is approved as a biosimilar, we consider that the post-marketing surveillance from the reference product would be more than sufficient.

Peter L. Salgo, MD: Really? OK, so let’s get this very clear. Once they’ve established that a biosimilar is similar, they can turn around and say, “Well, we did that part. And by extension, we can use the post-marketing data on the original drug as monitoring for the similar drug.”

Vibeke Strand, MD: Well, it’s not that they can use it. It’s that the post-marketing requirement for the reference product has already been completed, and thus, there really isn’t a need for further studying. We do want to have people report if there are adverse events that are significant, but it’s not the same thing as having to do a formal type of a registry study.

Allan Gibofsky, MD: But to be specific, if there’s no post-marketing requirement on the bio-originator, there will be no post-marketing requirements on the biosimilar. The package insert of the biosimilar will be identical to the package insert for the biosimilar. The only thing that we’re particularly interested in, and we’ll get into this in a few minutes, is, how do we differentiate between the use of a biosimilar and the use of a bio-originator? And that gets to the scheme of some concocted 4-letter suffix that seems to bear no relationship to the manufacturer.

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