The Biologics Price Competition and Innovation Act (“BPCIA”) created an abbreviated approval pathway for biological products shown to be “highly similar” to already FDA-approved biological products.  By permitting the sponsor of a biological product to rely on data submitted by the holder of an FDA-approved biological product, the BPCIA is somewhat similar in concept to the abbreviated approval pathway for small molecule pharmaceuticals, commonly referred to as the Hatch-Waxman Act.  Just as there are important differences in biologics and small molecule pharmaceuticals, there are also important differences in the approval pathway of biologics under the BPCIA and the ANDA approval pathway of small molecule pharmaceuticals under Hatch-Waxman.

One important distinction between the two approval pathways in that under the BPCIA there are two different biological product classifications — those products that are “biosimilar” and those that are “interchangeable” to the reference drug product. As defined by the BPCIA, a “biosimilar” product is one in which “the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components,” and “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”  42 U.S.C. §262(i)(2).  In contrast, an “interchangeable” product is one in which “the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”  42 U.S.C. §262(i)(3).

The difference between the two classifications is significant because current federal law does not permit a pharmacist to simply substitute a biosimilar product with the reference product.  Therefore, in order for a patient to receive a biosimilar product, a medical professional must actually prescribe the biosimilar product in place of the reference product.  That is not the case, however, if the biological product is classified as “interchangeable.”  Indeed, a pharmacist may freely substitute the interchangeable biological product for the reference product, absent express direction to the contrary.  Accordingly, the “interchangeable” classification for a biological product provides an enormous competitive advantage to any sponsor that is able to meet the standard.  In that regard, it is of note that of the four biosimilar products that have been approved in the United States by FDA, none has been classified as interchangeable.

To understand why no biologics have yet been classified as “interchangeable” to the reference product, it is helpful to understand why there are two classifications of biological products in the first place.  The answer has to do with the inherent complexity of biological products.  Unlike a small molecule “generic” pharmaceutical, the structure of a biological product may differ somewhat from the structure of the reference product.  Such differences may arise for a number of reasons, e.g., an amino acid substitution in the primary amino acid sequence, or because of the particular expression system used to produce the protein.  Although the FDA recognizes that differences between a biological product and the reference product may not adversely affect the safety or efficacy of the biological product (as evidenced by the approval of four biosimilar products to date), it remains leery of permitting wholesale substitution of the reference product with the biological product absent a more thorough vetting process.   However, the industry remained in the dark regarding the details of that vetting process until recently when the FDA released its “Draft Guidance – Considerations in Demonstrating Interchangeability with a Reference Product” (“Interchangeability Guidance”) on January 17, 2017.

Statutory Requirements for Interchangeability

The Interchangeability Guidance set forth the FDA’s current thinking on the scientific criteria it expects a sponsor seeking approval for an interchangeable biological product to meet.  The Interchangeability Guidance explains that under the statute three conditions must be met: (1) the biological product must be biosimilar, (2) it must produce the same clinical result as the reference product in a patient, and (3) if the biological product is administered more than once, it must be shown that the risk of switching between the biological product and the reference product must not be greater than if the reference product was used without such switching.


With respect to the biosimilarity requirement, the FDA acknowledges that if the biological product had previously been approved as a biosimilar, then that same data may be used to satisfy the “biosimilarity” statutory criteria.  However, such data may not be sufficient to satisfy the “same clinical result” or the “risk of switching” criteria.

“Same Clinical Result”

The Interchangeability Guidance indicates that for a biological product to be approved as interchangeable, FDA expects to see data sufficient to show that the proposed biological product provides the “same clinical result” in all of the reference product’s licensed conditions for use.  This is important because the FDA has previously explained that a biosimilar product applicant is free to seek approval for less than all of the indications for which the reference product has been approved.  See Draft Guidance – Labeling for Biosimilar Products at §IV (March 2016).  Thus, although a sponsor may submit an application seeking approval for less than all of a reference product’s approved indications, it will not be possible for the sponsor’s product to be deemed interchangeable for the reference product without providing data effectively proving that it could be approved for all indications.  The result is that additional clinical studies may be required to show that a proposed biological product produces a “highly similar” clinical result in treating a disorder for which the applicant ultimately has no interest in pursuing approval.

“Risk of Switching”

The third criteria that must be met for interchangeability under the statue is that “risk of switching” for the proposed biological product must be shown to be no greater than the risk associated with using the reference product alone.  The Interchangeability Guidelines explain that  the “FDA expects that applications generally will include data from a switching study or studies,” and goes into some detail as to the relevant design considerations, including appropriate study endpoints, study populations, analysis, etc.

In terms of the study design, the FDA suggests either a dedicated switching study or an integrated study.   The dedicated study is one that only examines the effect of switching between the reference and proposed product.  In contrast, the integrated study is intended to be a single study that the sponsor will use to support a finding of no clinically meaningful differences between the proposed and reference products (i.e., for purposes of biosimilarity) and that evaluates the impact of switching between the reference product and the proposed product (i.e., for purposes of interchangeability).  In either case, the switching arm of the study will be expected to incorporate at least three switches with each switch crossing over to the alternate product.

If the reference product has been approved for multiple indications, the FDA recommends selecting an indication that “would be adequately sensitive” to evaluate the risk associated with switching between products for other indications.  Presumably, a sponsor would actively seek consultation with the FDA prior to proceeding with such a study to ensure the FDA agrees the selected indication is “adequately sensitive.”   Regardless, the sponsor will then have to provide scientific justification explaining how the data it has collected may be extrapolated to justify the interchangeability classification for other indications which were not expressly tested in a switching study.

The Influence of Patents on Interchangeability

Given the FDA’s interpretation that the statute requires a sponsor show the same clinical result is achieved for all approved indications, as well as potential difficulties in extrapolating data from a switching study looking at one indication to another, unexamined indication, one may wonder why a sponsor would ever seek approval for less than all of the approved indications.  In other words, why would a sponsor conduct all of that work and then voluntarily drop an indication that the data otherwise supports?  Although there may be several potential reasons, the patent landscape may provide the most significant answer to that question.

Imagine a scenario where a reference product has been approved for two distinct indications that are each covered by a different patent family.  A sponsor may be confident of its non-infringement and/or invalidity defenses for the patent(s) covering one indication, but less so in its defenses for patents covering the other.  Thus, the sponsor could reasonably make the decision to pursue approval for one indication, and design appropriate studies to show that its proposed biological product produces the same clinical result as the reference product for only that single indication.  However, in view of the new Interchangeability Guidelines, in making that decision, the sponsor will apparently forego any chance of FDA approval of its proposed product as interchangeable, as well as the financial gains that such a status confers.

This situation creates an interesting dilemma for the sponsor.  Should one go through the time and expense required to demonstrate the same clinical result is achieved for both indications (even though one will only seek approval for a single indication) in an attempt to be approved as an interchangeable product?  Or should one defer the cost of those studies until such time as the patent landscape is more favorable, and seek only approval as a biosimilar in the interim?  And those are only two of the myriad of considerations that a sponsor will have to face when wrestling with the decision of whether and how to pursue the interchangeable classification when faced with a potentially unfavorable patent landscape. It will be interesting to find out how the various stakeholders resolve this dilemma in the coming years.

You can read the full guidance here.