On February 9, 2012, almost two years after the Biologics Price Competition and Innovation Act was passed, FDA released draft guidelines concerning the regulatory path for biosimilars. Amy Ritter, Scientific Editor at BioPharm International, spoke with Dr. Howard Levine, President and Principal Consultant of BioProcess Technology Consultants, about what these guidelines mean for developers of biosimilars. Dr. Levine is based in Woburn, Massachusetts, in the U.S.
“These guidelines have been anxiously awaited by industry for almost a year now, so it’s nice to see them finally come out,” says Dr. Levine. “They’re a very positive and big step forward for development of biosimilar products in the U.S.
Dr. Levine says there was nothing necessarily new or surprising about the guidelines. “I think the FDA has been telegraphing what was going to be in these guidelines for some time now. They’ve been making presentations throughout last year 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 Dr. Levine, is the FDA’s totality of evidence approach. “The 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 the 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.
Similarities between US and EU Guidelines
Dr. Levine sees a similarity between the new FDA guidelines and the current guidelines in Europe. “They follow very closely along the lines of the EU law,” he says. Levine notes however that there are a few differences between the US guidance and the current EU regulations, 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. “The so-called 351(k) pathway, which is the biosimilar application, offers both advantages and disadvantages over the current guidelines for biosimilar development in the EU.”
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.”
Flexibility in Approach
BioPharm International asked Dr. Levine whether he thought developers would be able to be fairly flexible in how they characterize or whether, as a result of the new guidelines, they would be pigeon-holed into a standard set of analytics that the 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 biosimilar similarity to an existing reference product, rather than simply providing the characterization data for a new product. So I think the 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 the 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 deamination 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 IP litigation, which could be very costly and could, in the long run, hold up the approval of biosimilar products.
BioPharm International asked Dr. Levine whether he thought the new FDA guidelines presented challenges for interchangeability. “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.” Levine says 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, you have 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.”