BioRationality: A Dr Sarfaraz Niazi Column—US Senate Considers Nixing Interchangeability for Biosimilars

Only the United States has 2 classes of biosimilars, one that has no clinically meaningful difference with the reference product and the other interchangeable biosimilar that undergo additional extensive testing. Both are tested the same way yet get awarded different statuses, a practice that has greatly damaged the adoption of biosimilars in the US.[1] (Figure 1).

Removing interchangeability is supported by several arguments:[2]

• Logic. Testing for clinical efficacy and safety differences by switching and alternating 3 times is not a clinical possibility. So, why would a clinician go back and forth? According to the FDA, "Biosimilars and interchangeable biosimilars are expected to have the same kind and amount of immunogenic response as their reference product. For example, if a patient does not respond to the reference product or lost their response because of anti-drug antibodies, then using a biosimilar or interchangeable biosimilar to that reference product would not likely be helpful."
• Scope: Interchangeable status applies only to self-administered biosimilars; professionals can select a biosimilar in place of the reference product; the payers may mandate such selection.
• Statistics: Statistical modeling tells us that it will take thousands of patients tested to conclude if there is a difference upon switching or alternating; to know if a biosimilar is 5% different from the reference product with a 30% clinical response variability will require 1200 patients. As a result, studies with fewer patients are least likely to fail.
• Politics: According to the FDA, "FDA-approved interchangeable biosimilars may be substituted for the reference product without the intervention of the prescribing health care provider, subject to state laws. State laws that address substitution of biological products (also called biologics) at the pharmacy level vary; therefore, prescribers and pharmacists need to understand the pharmacy practices in their state." Unfortunately, long before the FDA approved the first interchangeable product, every state and Puerto Rico formulated their policies on substitution, some promoting other blocking.
• Exclusivity: According to the Biologics Price Competition and Innovation Act (BPCIA), a 1-year exclusivity period is granted to the first interchangeable product. It is also possible for multiple interchangeable biosimilars to share a period of the first interchangeable exclusivity if they are approved on the same day and otherwise qualify for exclusivity. In addition, FDA can tentatively approve a subsequent interchangeable biosimilar while the first interchangeable product’s exclusivity period is pending. Such statements by the FDA have created more confusion than clarification.
• Perception: FDA requires developers to ask for interchangeable status and does not award this status by default. The FDA approved 2 interchangeable insulin products and 1 ranibizumab product as interchangeable[3] without requiring switching or alternating studies. It is obvious to assume that the interchangeable products will be presumed to be of "higher" quality. Insulins have been switched and alternated for decades; there is no reason for a special request to be made to the FDA to declare them interchangeable.

To remove the interchangeability status, Senator Lee has introduced a bill in the Senate that modifies the language in the BPCIA. The passage of this bill will bring the FDA in concordance with the rest of the regulatory agencies, remove misconceptions about biosimilars and expedite the adoption of biosimilars. In addition, biosimilars can also be switched with other biosimilars, and both the European Medicines Agency[4] and the United Kingdom’s Medicines and Healthcare products Regulatory Agency[5] have issued specific clarifications removing all interchangeable designations. No other global regulatory agency offers interchangeability; it is treated like any other drug, where the prescriber decides whether to substitute.

I invite my colleagues and stakeholders to write to me to add to or question the conclusions drawn in this article at niazi@niazi.com.

References

[1] Biosimilar info sheet. FDA. Accessed December 13, 2022. https://www.fda.gov/media/154917/download

[2] Niazi SK. No two classes of biosimilars: urgent advice to the US Congress and the FDA. J Clin Pharm Ther. 2022;47(9):1352-1361. doi:10.1111/jcpt.13743

[3] Biosimilar product information. FDA. Updated December 7, 2022. Accessed December 13, 2022. https://www.fda.gov/drugs/biosimilars/biosimilar-product-information

[4] Biosimilar medicines can be interchanged. EMA. September 19, 2022. Accessed December 13, 2022. https://www.ema.europa.eu/en/news/biosimilar-medicines-can-be-interchanged

[5] Guidance on the licensing of biosimilar products. United Kingdom’s MHRA. November 7, 2022. Accessed December 13, 2022. https://www.gov.uk/government/publications/guidance-on-the-licensing-of-biosimilar-products/guidance-on-the-licensing-of-biosimilar-products