At long last, FDA Issues Guidance on Biosimilar Interchangeability

January 17, 2017By Sara W. Koblitz & Kurt R. Karst

After months of promises and postponements, FDA has finally published its long-awaited draft guidance on biological product interchangeability, Considerations in Demonstrating Interchangeability With a Reference Product, under the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”).  While FDA had originally promised the guidance in 2016, FDA’s biosimilar user fee reauthorization commitment letter pushed its goal to December 31, 2017. Imagine our delight when we saw that FDA released the guidance so early in 2017!  (And just days after the U.S. Supreme Court granted certiorari in a case concerning two important provisions of the BPCIA – see our previous post here.)

FDA’s draft interchangeability guidance is incredibly important for biosimilar and reference product manufacturers alike. As of now, only four biosimilar products have been approved, and none of them are considered interchangeable. While these products are “highly similar” to their respective reference product counterparts, as shown by a “B” rating in the Purple Book, only interchangeable products (shown in the Purple Book with an “I” rating) can be substituted for the reference product by a pharmacist without the intervention of a health care provider. “Interchangeable” is obviously a coveted status for biosimilar manufacturers and a source of anxiety for reference product manufacturers. As such, the entire biologics industry has anxiously awaited this guidance.

As explained in the draft guidance, FDA requires interchangeable biologics to be biosimilar to the reference product in addition to other criteria. An interchangeable product is expected to produce the same clinical result as the reference product in any given patient. Also, if the product is administered more than once to an individual, the sponsor must demonstrate that the safety and efficacy risks of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using only the reference product. FDA expects clinical data to demonstrate this in all of the reference product’s licensed conditions of use.

As with generic versions of small molecule drugs, the data and information to support an interchangeable biosimilar application will vary based on the nature of the proposed product. To that end, FDA reiterates the Agency’s “totality of the evidence” and “reduction of residual uncertainty” approaches first expressed by the Agency in the biosimilars world in the context of demonstrating biosimilarity (see our previous post here).  The potential interchangeable product will first need to provide all of the information necessary to demonstrate biosimilarity (i.e., analyses of critical quality attributes and mechanisms of action for each condition of use for which the reference product is licensed; PK and biodistribution of the product in different patient patients; and differences in toxicities in each condition of use and patient population). These data likely will also suffice to support a showing that the proposed interchangeable product can be expected to produce the same clinical result as the reference product in any given patient. However, other elements of interchangeability will require additional testing.

FDA anticipates that interchangeable applications will include data from a switching study or studies in one or more appropriate conditions of use. The guidance outlines considerations for the design of these studies and stipulates that only the U.S. version of the reference product should be used in these studies. If the product is not designed to be administered more than once, a sponsor should provide justification for the omission of a switching study in the interchangeable application.

Importantly, the guidance notes that postmarketing data collected from products first licensed and marketed as a biosimilar, without corresponding data from an appropriate switching study, is not sufficient to demonstrate interchangeability. While postmarketing data may be helpful to determine what data is necessary to support interchangeability, the data itself are not enough. This means that even already-approved biosimilar products may be able to obtain interchangeable status if sponsors provide switching study data.  In addition, the draft guidance notes that while a non-U.S.-licensed comparator may be used for purposes of demonstrating biosimilarity, for switching studies intended to demonstrate interchangeability “using a non-U.S.-licensed comparator product generally would not be appropriate” for various reasons.

Finally, the draft guidance emphasizes that the presentation and design attributes of the proposed interchangeable product should be the same as the reference product in an effort to simplify substitution. This reasoning applies to container closure systems and delivery devices, as well.

The guidance rates to be a handy tool for sponsors, but FDA encourages sponsors to consult FDA early and often rather than relying on the guidance alone. And remember, this is just FDA’s first attempt at outlining interchangeability requirements, so there is likely room for other approaches.