Challenges and Opportunities for Biosimilars Developers

Published on: 
BioPharm International, BioPharm International-09-01-2012, Volume 25, Issue 9
Pages: 40–45

Howard Levine of BioProcess Technology Consultants talks about what industry needs to know to enter the biosimilars game in the US.

On Feb. 9, 2012, almost two years after the Biologics Price Competition and Innovation (BPCI) Act was passed, FDA released its draft guidance documents for the regulatory path for biosimilars. BioPharm International spoke with Howard Levine, PhD, president and principal consultant at BioProcess Technology Consultants in Woburn, Massachusetts, about what the guidance means for developers of biosimilars.

Howard Levine, PhD

"These guidelines have been anxiously awaited by industry for almost a year now, so it's nice to see them finally come out," says Levine. "They're a very positive and big step forward for development of biosimilar products in the US."

Levine says there was nothing necessarily new or surprising about the guidelines. "I think FDA has been telegraphing what was going to be in these guidelines for some time now. They made presentations throughout 2010 and 2011 at various industry conferences and they've published several articles over the last year that talked about their approach to the development of guidelines for biosimilars." One of the most positive aspects of the new guidelines, according to Levine, is FDA's totality-of-evidence approach. "FDA has been talking about this approach for awhile, meaning they'll look at the approval of biosimilars as a compilation of all of the evidence and characterization that a company has developed for a particular molecule. What this means is that there will, obviously, be extensive characterization of the biosimilar product using what FDA refers to as state-of-the-art analytical techniques." Levine adds that human clinical trials will always be required for a biosimilar, however. Even with the detailed biochemical and biophysical characterization, there may still be a need for animal studies in some cases.



Levine sees similarities between the new FDA guidance and the current guideance in Europe. "They follow very closely along the lines of the European Union law," he says. Levine notes, however, that there are a few differences between the two, some of which are favorable to developers of biosimilars in the US and some of which actually are much less favorable than the EU law.

Levine continues, "I think one of the biggest advantages of the new guidance is the allowance of a non-US reference standard for clinical trials. In the EU, the reference standard that's used to compare a biosimilar must be an EU-approved product. What FDA has done has allowed the use, for example, of European reference standards for approval of a biosimilar in the US. This is really very, very good news for companies developing biosimilars, because if they have clinical trials already underway in Europe, for example, using a European reference standard, those clinical trials don't necessarily have to be repeated—provided they can show that the reference standard is an acceptable one for the US submission. Likewise, companies which haven't started their clinical development can put together a clinical program that encompasses both the EU and the US, again, by incorporating an EU reference standard."


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