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FDA Guidance on Biosimilars: The Two Minute Version

If you are in the business of developing biosimilar products—or thinking about it—then you have to read all three guidance documents published by FDA on February 9, 2012. They provide essential (but not complete) instructions for how to construct and implement a biosimilar development plan.


For everyone else, FDA Matters is providing the short version. Why take an interest? Because over the next 5 to 15 years, biosimilars are going to dramatically transform the marketplacefor biological products, creating new winners and losers. Also, these new rules are going to lead to new, groundbreaking medicines…and not just less expensive versions of old ones.


Nearly two years ago, Congress passed the “Biologics Price Competition and Innovation Act” (BPCIA) to create an abbreviated approval pathway for biosimilars, which are highly-similar copies of already marketed, complex, large molecule biological products. This is a distinct from making exact copies (generics) of relatively simple, small molecule drug products, whose abbreviated pathway to market was created in 1984 (under the Hatch-Waxman legislation).


Even without FDA formal guidance, companies have begun the process of entering the biosimilars market in the US. Thus far, FDA has received early-stage meeting requests for 35 proposed biosimilars that would relate to 11 reference products (innovator biologic products that are already on the market). About 60% of those meetings have been held and 9 investigational new drug (IND) applications have been received.


The three FDA guidance documents, described in this FDA Fact Sheet, are:

• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

• Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product

• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009


As FDA Matters envisioned when the BPCIA was passed, FDA will handle every biosimilar application on a product-specific basis. Two major concepts embody this approach:

  • The agency expects sponsors to take a “step-wise approach,” starting with the structural and functional characterization of the biosimilar and reference molecules, then determine “the residual uncertainty about the biosimilarity of the proposed product and identify next steps to try to address that uncertainty.” The strength of the analytic proof of similarity and the degree of uncertainty will determine the required amount and type of animal and human testing.
  • The agency plans to look at the “totality of the evidence” presented by each sponsor.  Every application must include certain elements–structural and functional characterization of the molecule, nonclinical evaluation, human PK and PD data, clinical immunogenicity data, and clinical safety and effectiveness data—but they will be weighed by the overall degree to which they support similarity, rather than by any pre-determined formula.

The law also allows for biosimilars to be deemed “interchangeable” with the reference product. In these guidance documents, FDA has effectively said that sponsors must establish biosimilarity first, and then present additional evidence of interchangeability.


In sum, the guidance documents lay out a daunting, but still feasible pathway for approval of a biosimilar. The first approvals will come slowly over the next 2 or 3 years, and then accelerate after FDA and sponsor companies have more experience.


What about the part where the FDA guidance documents on biosimilars eventually result in new, groundbreaking medicines? The key to approval of a biosimilar is to be able to characterize the structure and function of specific biological molecules and, also, to define the conditions under which the human body is likely to reject a large molecule biologic as a foreign substance (immunogenicity).  


These requirements are forcing companies to invest hundreds of millions of dollars in order to better understand human biology and therapeutic biological products. That knowledge is going to make it possible to find and create wholly new therapies, as well as develop significantly better versions of existing medicines.


We are likely to have biosimilars approved long before this impact hits. However, in about six to ten years, we should see the start of a wave of groundbreaking new medicines that emerge from knowledge that was gained as a by-product of creating biosimilars.   



For a longer commentary on the new biosimilar guidances, I recommend: First Bio-Similars Guidance Issued by FDA by James Czaban at the Wiley, Rein law firm.

One Response to “FDA Guidance on Biosimilars: The Two Minute Version”

  1. emaggio says:

    Great resource – thank you for making this available. A key issue that will be increasingly highlighted as a concern by the FDA is the use of the polysorbate excipients, Tween-80 and Tween-20. They are used in nearly all bio-therapeutic formulations to prevent protein aggregation which leads to increased immunogenicity and reduced efficacy. The polysorbates auto-oxidize to produce peroxides which are the agents that cause the actual damage to proteins. Alternative surfactants need to be identified that work as well to prevent aggregation but do not cause oxidative damage. One such group of surfactants are the patented ProTek alkylsaccharide excipients which are non-toxic molecules similar or identical to surfactants approved for food and cosmetic use. These have already been licensed by one major player in the monoclonal antibody/biotherapeutics field (Roche/Genentech) and are under evaluation by two of the other major players in this field at present.

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