FLEXIBILITY IN APPROACH
BioPharm International asked Levine whether he thought developers would be able to be fairly flexible in how they characterize biosimilars, or whether,
as a result of the new guidance, they would be pigeon-holed into a standard set of analytics that FDA would like to see. "No,"
he said, "This is not really any different than the requirement for characterization of a new product—except, of course, one
must demonstrate comparability or similarity to an existing reference product, rather than simply providing the characterization
data for a new product. I think FDA will, once again, rely on their standard case-by-case approach as far as what analytical
characterization is required. Obviously, they will be looking to have as extensive a characterization of the molecule as possible,
using the most up-to-date state-of-the-art techniques that are currently available."
Levine says the biggest challenge for developers, from a technical standpoint, is demonstrating biosimilarity from a biochemical
and biophysical perspective. "One expects that there will be minor differences in, for example, glycosylation patterns or
the extent of deamidation in a monoclonal antibody product. One expects that there will be slight differences between the
biosimilar and the innovator product. The question is, how large a difference will be acceptable for the product to still
be deemed biosimilar?"
The other challenges for developing biosimilars in the US are not necessarily technical challenges, says Levine, but rather
more commercial and regulatory. "First of all, there is the 12-year data exclusivity period which means that a biosimilar
product in the US cannot come to market until 12 years after the reference product or innovator product was first approved.
This generally isn't a problem because the patents usually extend beyond that 12-year period, but it could be a problem in
a case where a patent may expire earlier than this 12-year exclusivity period. The biosimilar company would be precluded from
selling their product until the end of that 12-year period."
He notes that the second commercial or legal challenge for biosimilar companies is the requirement that the biosimilar company
must disclose their entire dossier to the reference product company to review. Levine believes this could prompt very frequent
and lengthy patent and intellectual property litigation, which could be very costly and could, in the long run, hold up the
approval of biosimilar products.
When asked about the new guidance and the challenges in demonstrating interchangeability, Levine pointed out that, "First
of all, other than saying that FDA will consider interchangeability after one has demonstrated biosimilarity, there really
is no discussion as to what the requirements for demonstrating interchangeability might be." He added that if one looks back
to the original BPCI Act, the bar for interchangeability is extremely high and may actually be impossible to meet because
the BPCI Act actually says that in order to achieve interchangeability, one has to ensure that the molecule will behave the
same as the innovator product in every patient. "Achieving that from a scientific perspective may actually be difficult,
if not impossible."
Levine says that the development of biosimilars in the US will depend on how quickly it takes for the FDA draft guidance to
become finalized. "FDA, by their own releases, has said they've already had discussions with, I believe, nine companies regarding
biosimilar applications. They have several other meetings pending. There's obviously been a lot of activity behind the scenes
of companies approaching FDA even before the guidelines were published."
Levine thinks that the first wave of biosimilars in the US will most likely be those products that are already on the market
as biosimilars in Europe. He points out that the clinical-trial requirements for biosimilar under the new guidance allow for
a non-US reference product—meaning that companies should be able to submit their clinical and postmarket data against that
European reference standard and it should be acceptable in a submission to FDA.
"What that means is compiling the data and putting together the appropriate application and submitting the application without
actually having to run new clinical trials," he explains. "So those will probably be the first products I would expect to
see approved, probably within the first year after the guidance is finalized. And then, beyond that, we'll begin to see new
biosimilars that are not yet on the market in Europe."
"It will also be interesting to see what, if any, changes there are in the guidance between this current draft and the final
version," says Levine. The guidance documents were open for public comment through Apr. 16, 2012, followed by a public hearing
on May 11, 2012. "The question is really, how long will it take them to compile all those comments and revise and update the
draft before they release it as final?"
A podcast of the full interview with Levine can be found at