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USFDA Guidance: Interchangeability: Considerations in Demonstrating Interchangeability With a Reference Product

The USFDA's updated guidance (21 June, 2024) on "Considerations in Demonstrating Interchangeability With a Reference Product" provides crucial information for stakeholders involved in developing interchangeable biologics. This guidance outlines the requirements, scientific considerations, and regulatory pathways for demonstrating interchangeability between a proposed biosimilar product and its reference product.

Interchangeability: The ability of a biosimilar to be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.

The requirements for biosimilarity include high similarity to the reference product and no clinically meaningful differences in safety, purity, and potency.

For a product to be considered interchangeable, it must produce the same clinical result as the reference product and pose no greater risk in safety or efficacy when switching between the products.

This draft guidance outlines considerations for a switching study or studies designed to demonstrate that a proposed therapeutic protein product is interchangeable with a reference product.

The main objective of this guidance is to update the scientific and regulatory considerations necessary to demonstrate that a biosimilar is interchangeable with its reference product. This update incorporates the latest scientific advancements and regulatory experiences.

The original guidance recommended including data from a switching study to ensure added assurance regarding immunogenicity risk when alternating between the reference product and the biosimilar. The FDA has gained further experience in evaluating potential analytical differences and their clinical impacts, supported by advanced analytical technologies that can structurally characterize therapeutic proteins and model in vivo functional effects.

Recommendations for Applicants

  • Applicants may choose to provide an assessment of why the comparative analytical and clinical data provided in the application or supplement support a showing that the 110 switching standard outlined in section 351(k)(4)(B) of the PHS Act has been met.

  • Applicants with a pending 351(k) BLA for a proposed biosimilar product may choose to submit an amendment to their pending BLA with the above-described assessment along with any additional data and/or information that they consider relevant to address the requirements in section 351(k)(4) of the PHS Act and request that their BLA be reviewed as a proposed interchangeable biosimilar.

For more detailed information, refer to the full guidance document available on the FDA website: Considerations in Demonstrating Interchangeability With a Reference Product: Update.

Also, there was another final guidance "Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection" released on 20th June, 2024 that covers facilities that are subject to drug or device inspection and guidance defines the types of behaviors (actions, inactions, and circumstances) that FDA considers constituting delaying, denying, or limiting inspection, or refusing to permit entry or inspection for the purposes of section 501(j) of the FD&C Act.


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