FDA publishes biosimilar interchangeability guidance

The US Food and Drug Administration (FDA) has issued draft guidance on demonstrating biosimilar interchangeability.

The guidance recommends that companies looking to get a biosimilar approved as interchangeable with its reference product conduct at least one studies showing that patients can switch between the two products with the same clinical effect.

The draft guidance discusses study design and analysis, and makes recommendations on the data and information required to support interchangeability but it noted by the agency that its exact requirements will vary from product to product. The FDA discusses a number of considerations including study endpoints, study design and analysis, study population, condition(s) of use, and routes of administration. The agency says that sponsors should consider all factors including product complexity, extent of characterisation and product-specific immunogenicity risk.

Additionally, FDA advises sponsors consider the “totality of factors” for their product to determine the amount and type of data that will be needed to demonstrate interchangeability, and gives the following two examples:

  • “Product A has relatively low structural complexity, has been demonstrated to have meaningful fingerprint-like analytical similarity to the reference product as part of demonstrating biosimilarity, and has a low incidence of serious adverse events related to immunogenicity. Here, data derived from an appropriately designed switching study … may be sufficient to support a demonstration of interchangeability.
  • Product B has high structural complexity, has been demonstrated to be highly similar to the reference product as part of demonstrating biosimilarity but has no demonstration of meaningful fingerprint-like analytical similarity, and has known serious adverse events related to immunogenicity. Here, post-marketing data for the product as a licensed biosimilar, in addition to an appropriately designed switching study … may provide additional data and information necessary to support a demonstration of interchangeability.”


Switching studies should be designed to determine whether alternating between a biosimilar and its reference product two or more times impacts the safety or efficacy of the treatment course. Generally, such a study should not be needed for a single dose product, but FDA will require a justification for this.

FDA are clear that if a difference in immune response or adverse events is noticed between the switching and non-switching arms of the study, this would raise concerns as to whether the biosimilar is interchangeable with the reference product, regardless of what caused the difference. FDA therefore advises sponsors intending to develop a proposed interchangeable product to meet with them to discuss the proposed product development plan.

FDA says that sponsors may use extrapolated data to support interchangeability for multiple indications if a sponsor is able to provide adequate scientific justification for doing so. The agency says that sponsors should address any differences in relevant factors (mechanism of action, pharmacokinetics, pharmacodynamics, biodistribution, immunogenicity, toxicity) in their justification.

FDA recommends using a US-licensed reference product in switching studies. The agency says that subtle differences between biological products licensed in different regions could have an effect on patients’ immune response. These differences would create uncertainty as to whether the results of a switching study using a non-US-licensed reference product would be applicable to a US-licensed reference product.

The guidance recognises that differences in product presentation, including the delivery device and container closure system, may affect FDA’s determination of interchangeability. In general, FDA advises against trying to get an interchangeable biosimilar approved with a different type of presentation than the reference product. FDA advises that sponsors wishing to develop a different presentation should discuss doing so with FDA early on. However, the agency says that not all differences in product presentation will have an impact on a product’s use, and the draft provides sponsors with recommendations for conducting a threshold analysis for assessing the differences.

To access the draft guidance, please click here.