New Paper Seeks to Clarify the US Position on Interchangeability

A new paper, published this week in Current Medical Research and Opinion, seeks to clarify the US definition of interchangeability and differentiate it from the separate concepts of automatic substitution and physician-mediated switching.
Kelly Davio
January 18, 2019
When the Biologics Price Competition and Innovation Act (BPCIA) was passed into law as part of the Affordable Care Act, Congress put forth a statutory definition of interchangeability of biologic products. The fact that interchangeability is not a legal concept but a medical one in other parts of the world has sown a great deal of confusion over the nature of interchangeability in the United States. In fact, some US stakeholders, including payers, view interchangeability as a critical factor in whether they will adopt biosimilars, a fact that could be hampering uptake.

A new paper, published this week in Current Medical Research and Opinion, seeks to clarify the US definition of interchangeability and differentiate it from the separate concepts of automatic substitution and physician-mediated switching.

According to the BPCIA, an interchangeable product may be substituted for the reference without the intervention of the prescriber. In order to be declared interchangeable, a product must be approved as a biosimilar to its reference, and it must also be expected to produce the same clinical result as the reference in any given patient. Furthermore, the risk—in terms of safety or diminished efficacy—of alternating or switching between the biosimilar and its reference must not be greater than the risk of using the reference product without any alternation or switching in a product that is administered more than once to a given patient.

According to current draft guidance, the FDA expects that data from a clinical switching study that involves 2 or more alternating switches will be provided to the agency. The study’s primary end point should assess the impact of switching between the biosimilar and the reference, and the FDA considers pharmacokinetic (PK) end points as generally the most sensitive to assess the development of clinically important immunogenicity. Separate assessments of immunogenicity and safety are also expected to be provided.

The paper’s authors emphasize the fact that interchangeability does not relate to product quality or degree of similarity between the biosimilar and its reference. “Rather, this designation signifies that the interchangeable biological product sponsor has provided the FDA with the additional data and information necessary to meet the statutory standard for substitution,” they write.

Substitution, a separate but related concept, is governed by state laws. Where local laws permit the practice, a product that has been granted interchangeable status may be substituted at the pharmacy without consulting the prescriber.

Physician-mediated switching is yet another separate matter; biosimilars that have not been granted interchangeable status must be specifically prescribed, and they cannot be substituted at the pharmacy level. Physician-mediated switching, therefore, describes a prescribing decision made by a physician to change a patient’s treatment to a different product. There is no statutory standard for this decision, which may be undertaken as a part of usual medical practice.

The authors conclude that “physicians’ confidence in prescribing biosimilars to their patients, including and where appropriate to patients already receiving the reference product, should not be impacted by whether the product has been deemed interchangeable by the FDA.” They add that “Whether a product is biosimilar to or interchangeable with a reference product, patients and physicians should be assured that the product has met the FDA’s rigorous approval standards for quality, safety and efficacy.”

McKinley L, Kelton JM, Popovian R. Sowing confusion in the field: the interchangeable use of biosimilar terminology [published online January 17, 2019]. Curr Med Res Opin. doi: 10.1080/03007995.2018.1560223.


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