On Friday, FDA published the final guidance, “Considerations in Demonstrating Interchangeability With a Reference Product,” which is intended to assist sponsors in demonstrating that a biosimilar product is interchangeable with a reference product. Even as some of the details remain to be hashed out, the guidance makes clear FDA’s desire to minimize the burdens of obtaining a determination of interchangeability. The guidance summarizes the important scientific considerations for demonstrating interchangeability, including:

  • The data and information recommended to support a demonstration of interchangeability
  • Considerations for the design and analysis of a switching study or studies to support a demonstration of interchangeability
  • Considerations regarding the comparator product in a switching study or studies
  • High-level overview of considerations for developing presentations, e.g., packaging and delivery systems, for proposed interchangeable products

The finalized version of the guidance maintains the principles and structure of the January 2017 draft version, which we discussed here. In general, it provides a flexible framework that emphasizes the “totality of the evidence” in a given case, with interchangeability determinations guided by product-specific assessment of immunogenicity risks and other factors.

Switching studies

The final guidance makes clear that, for products that will be used more than once in a given patient, FDA generally will expect sponsors to conduct “switching studies,” i.e., clinical trials that switch patients back and forth between the reference biologic and the biosimilar. If the switching study is intended to support a finding of interchangeability for an already-licensed biosimilar, FDA says, existing postmarketing data for the biosimilar might be harnessed to support the interchangeability finding. If a interchangeability finding is requested with an initial biosimilar application, the agency contemplates that the switching study could be “integrated” with the study required to show biosimilarity. The final guidance also confirms that the primary endpoints for switching studies can be pharmacokinetic (PK) and/or pharmacodynamics (PD) markets, not clinical efficacy. Additionally, FDA generally will permit extrapolation of data from one condition of use to another.

The final guidance contains two notable changes from the draft: it permits switching studies to use non-U.S. versions of the reference product, and suggests flexibility regarding healthy subjects being used in switching studies. Additionally, the final guidance is much more general about the requirement to demonstrate interchangeability regarding the biosimilar and reference products’ presentation. In cutting much of the detail in the draft guidance, FDA has said it will issue a separate guidance to “provide more detailed recommendations on the data and information recommended to support the proposed interchangeable product’s presentation, container closure systems, and delivery device constituent parts and related issues.”

Encouraging interchangeable biosimilars

In a statement announcing the guidance, Acting FDA Commissioner Ned Sharpless emphasized FDA’s commitment to advancing the regulatory approval pathway for biosimilar and interchangeable products, citing agency plans to provide greater clarity for applicants and other stakeholders that are outlined in its Biosimilars Action Plan, which we discussed here. By way of example, Dr. Sharpless noted that there are no approved generic insulin products that can be substituted for branded products, but suggested that would change in March 2020, when insulin products approved under NDAs will be deemed to be licensed via BLAs, which may lead to biosimilar and interchangeable biosimilar insulin products. This guidance will help that happen, Dr. Sharpless said.