Considerations in Demonstrating Interchangeability With a Reference Product

Guidance for Industry:

By Rose Pagano and Suzanne M. Sensabaugh, MS, MBA


The purpose of this guidance is to aid sponsors by showcasing that a proposed therapeutic protein product can be exchanged with a reference product for the intentions of submitting a marketing application or supplement under section 351 (k) of the Public Health Service Act (PHS Act). The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) changed the PHS Act and other statues to generate an abbreviated licensure pathway in section 351 (k) of the PHS Act for biological products proven to be biosimilar to or interchangeable with an FDA-licensed biological reference product. Overall, this guidance focuses on therapeutic protein products and gives an overview of scientific guidelines to review when establishing that a proposed protein product can be used instead of the reference product.

Section 351 (k) of the PHS Act details the requirements for an application for a proposed biosimilar product and an application for a suggested interchangeable product. This allows the FDA to determine if there is enough information for a proposed product to serve as a substitute for the reference product. Section 351 (i) from this Act outlines that interchangeable means the biological product may be substituted for the reference product without additional interventions.

In this recently released guidance, the Agency details factors impacting the class of data and information necessary to establish interchangeability. One area to consider is product complexity. The product’s degree of structural and functional complexity could impact the amount of clinical data needed to prove interchangeability. This is dependent on the product.

Another factor to consider when attempting to establish interchangeability is product-specific immunogenicity risk. If a product has an established history of generating immune responses, this may require more data supporting interchangeability and establishing that immunogenicity does not influence clinical outcomes. An additional consideration to make is postmarketing data. Improved epidemiological approaches evaluating postmarketing exposures and outcomes have been shown to be helpful in determining the drug’s behavior.

The guidance also outlines data and information necessary to support interchangeability. For example, it is generally expected that a switching study or studies will be performed to show that the risk regarding safety or switching between use of the proposed interchangeable product and the reference product is not greater than the risk of using the reference product without such alternation or switch. This evaluates changes in treatment that result in two or more alternating exposures to the proposed interchangeable product and to the reference product. If the sponsor thinks that this is unnecessary, the FDA needs the sponsor to provide evidence for this claim.

The guidance also outlines some necessary components for a switch study. For example, the primary endpoint in a switching study needs to analyze the impact of alternating between the two products. These endpoints should be a comparison of pharmacokinetics and pharmacodynamics. The pharmacokinetic and sampling should entail intensive analysis at the final exposure period after at least three half-lives have elapsed after the final administration of the reference product in the switching arm. Additionally, the sample size of the switching study should be determined by pharmacokinetic considerations.

Ultimately, the guidance emphasized that robust postmarketing safety monitoring is important in ensuring the safety and effectiveness of biological products.


At HartmannWillner LLC we understand the regulatory requirements for development of biosimilar and interchangeable biological products through the PHS Act §351(k) and Biological License Application (BLA) process. We have assisted with the development of well over 25 biosimilar and interchangeable biological products. Contact us today to learn more about our services and how we can help you.

Suzanne M. Sensabaugh has advanced the development of over 130 biologics, biosimilars, and combination products since 2009. She can be reached at