FDA’s initial draft guidances for development of biosimilars specify that a sponsor will have to submit at least one clinical study comparing the immunogenicity of its proposed product with that of the reference biologic. A clinical study will also be required for a biosimilar to be considered interchangeable with the reference product.

The agency issued three guidance documents on Feb. 9 to assist the industry in developing products under the biosimilars abbreviated approval pathway. The long-awaited guidances come nearly two years after enactment of the Biologics Price Competition and Innovation (BPCI) Act establishing the pathway for approval of follow-on biologics.

The first guidance on scientific considerations describes the “totality-of-the-evidence” approach FDA will use in evaluating data submitted to support a determination of biosimilarity. A second guidance on quality considerations details the analytical factors that will be considered in assessing whether products are highly similar, and a third guidance addressing general questions uses a Q&A format to provide “answers to common questions from people interested in developing biosimilar products.”

In a media briefing, Rachel Sherman, director of the Office of Medical Policy in the Center for Drug Evaluation and Research, said the first draft guidance is the key document. “It lays out our expectations that a sponsor will squeeze out every bit of knowledge from the structure of their molecule and then decide the scope of animal and clinical testing,” she said.

Industry seemed to like – and expect – what they saw in the drafts, but players remain hungry for more practical details ([A#00120213028]).

The guidance, “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product,” advises companies to follow a “stepwise approach” in developing evidence to demonstrate biosimilarity. This approach would start with extensive structural and functional characterization of both the proposed product and the reference product. If these studies show minimal or no difference between the proposed product and the reference product, FDA said there would be stronger scientific justification for using a selective and targeted approach to animal and/or clinical testing to show biosimilarity.

“It may be useful to further quantify the similarity or differences between the two products using a meaningful fingerprint-like analysis algorithm that covers a large number of additional product attributes and their combinations with high sensitivity using orthogonal methods,” the guidance states.

The agency had laid out this approach to evaluating biosimilars in an article in the New England Journal of Medicine in August Also see "FDA's Biosimilar Strategy Will Rely On "Fingerprint" Technology To Limit Trials" - Pink Sheet, 4 August, 2011.. The guidance documents provide more details as to how the agency will implement this strategy.

Inability To Characterize Reference Product May Prevent Use Of Biosimilars Pathway

With regard to the analytics analysis, the first guidance says sponsors should conduct extensive structural characterization in multiple representative lots of the proposed product and the reference product to understand lot-to-lot variability. It recommends that sponsors also analyze the finished dosage form of multiple lots of both the proposed and reference product.

The scientific guidance also suggests that sponsors may be precluded from using the biosimilars pathway if they are unable to characterize the reference product.

“If the reference product cannot be adequately characterized with state-of-the-art technology, the sponsor should consult FDA for guidance on whether an application for such a protein product is appropriate for submission under section 351(k) of the PHS [Public Health Service] Act,” which provides for the biosimilars pathway.

The agency has already established something of a precedent for approving a biosimilar even though the reference product is not fully characterized. Sherman recently characterized the review that lead up to the 2010 approval of Momenta Pharmaceuticals Inc.’s ANDA for a generic version of Sanofi’s Lovenox (enoxaprin) “as complex as we expect our average biosimilar application to be” ([A#14120203007]). And that approval came even though enoxaprin was not fully characterized, a decision recently endorsed by a federal court Also see "Lovenox Generics: FDA’s Split Opinion On ANDA Approval Fully Supported By Court" - Pink Sheet, 7 February, 2012..

The enoxaprin ANDA was approved under a completely different statute (the FD&C Act), and the guidance seems to discourage applications using uncharacterized reference products, but it seems possible that a determined sponsor could get such an biosimilar through the agency.

Sherman said that sponsors must get their analytics in shape before having a meeting with FDA. At that point, she said, the agency will give advice on the scope of animal and human testing that would be required.

Rare Events May Require Postmarket Studies

The guidance also describes the studies needed to assess the differences in immune response between the proposed product and the reference product. It says that at least one clinical study comparing immunogenicity will generally be expected.

“If the immune response to the reference product is rare, two separate studies may be sufficient to evaluate immunogenicity: (1) a premarket study powered to detect major differences in immune responses between the two products and (2) a postmarket study designed to detect more subtle differences in immunogenicity,” the guidance states.

Sponsor Will Have To Supplement European Data

The Q&A draft guidance addresses whether a sponsor can use comparative animal or clinical data with a non-U.S.-licensed product. In certain studies, a sponsor may do so, the agency said.

“However,” the guidance says, “as a scientific matter, analytical studies and at least one clinical pharmacokinetic (PK) study, and, if appropriate, at least one pharmacodynamic (PD) study, intended to support a demonstration of biosimilarity must include an adequate comparison of the proposed biosimilar product directly with the U.S.-licensed reference product.”

The guidance says a sponsor should provide adequate data to establish an acceptable bridge to the U.S.-licensed reference product. Asked under what circumstances there would be an acceptable bridge, Sherman noted the agency’s desire to utilize Europe’s experience with biosimilars Also see "Biosimilar User Fee Agreement Allows For Reliance On Foreign Clinical Data, FDAer Says" - Pink Sheet, 14 December, 2011..

“We want badly to share clinical data with non-U.S. reference products,” FDA’s Sherman said. “We would like to the extent possible to bridge the European data.”

“We want badly to share clinical data with non-U.S. reference products,” she stated. “We would like to the extent possible to bridge the European data. We would try very hard to make that bridge.”

Sherman was also asked if the agency anticipated writing future guidances directed to a class of drugs – the approach taken by European regulators. She said that for now FDA wanted to expedite the development of these products but would look at drugs class by class if that is warranted.

Sherman noted that the agency will be holding another public meeting to discuss the three guidances and what else is needed going forward.

Data On One Condition Of Use May Be Extrapolated To Another

The Q&A guidance clarifies when clinical data intended to support a demonstration of biosimilarity in one condition of use can be extrapolated to support licensure of the biosimilar product in additional conditions of use. It says extrapolation could be made if the data demonstrates safety, purity and potency in an appropriate condition of use. “However,” the guidance states, “the applicant would need to provide sufficient scientific justification for extrapolating clinical data to support a determination of biosimilarity for each condition of use for which licensure is sought.”

In addition, the guidance says an applicant can seek licensure for fewer than all routes of administration, presentations and conditions of use than those for which the reference product is licensed.

The guidance also says that a proposed biosimilar may have a different formulation than the reference product and a different delivery device or container closure. It notes that a proposed biosimilar product in a delivery device will be considered a combination product and may, in some instances, require a separate application for the device.

The Q&A document also provides a definition of “protein.” The BPCI Act amended the definition of “biological product” to include a “protein (except any chemically synthesized polypeptide).” FDA said it has decided that “protein” does not include peptides and that it would distinguish the two based solely on size, i.e. the number of amino acids. The agency will deem any polymer composed of 40 or fewer amino acids to be a peptide.

Interchangeability Designation Will Require Switching Study

The agency also addressed the issue of interchangeability in the Q&A guidance. FDA said that it can make a determination of interchangeability in a 351(k) application or any supplement to the application. However, the document states that “at this time, it would be difficult as a scientific matter for a prospective biosimilar applicant to establish interchangeability in an original 351(k) application given the statutory standard for interchangeability and the sequential nature of that assessment.“

It added that FDA is continuing to consider the type of information sufficient for FDA to determine that a biological product is interchangeable with the reference product.

Sherman said she could not conceive of making such a determination without clinical data to know with certainty that switching back and forth between the biosimilar and reference product does not diminish the safety or affect the efficacy profile of the products.

FDA Biosimilars Guidances Address Immunogenicity Studies, European Bridge Data, Analytics

More from United States

More from North America