The US Food and Drug Administration (FDA) on Friday finalized a long-awaited guidance spelling out how biosimilars can achieve an interchangeable status, which means they may be substituted for the reference biologic without a prescriber intervening.

No interchangeable biosimilars have been approved in the US yet, and the number of companies seeking approval for an interchangeable has remained at just one, with Boehringer Ingelheim publicly disclosing that it’s begun an interchangeability study for its adalimumab biosimilar.

But former FDA Commissioner Scott Gottlieb said last month that interchangeable insulin products are likely coming to the US in the next couple of years. And final interchangeability guidance will provide sponsors with more certainty on how to develop interchangeable products.

Changes in Final Guidance

The final guidance is seven pages shorter than the draft and does not include two appendices that were included in the draft on comparative use human factors studies.

Commenters on the draft took issue with terms that needed further clarity, such as “residual uncertainty” and “fingerprint-like,” which is used in the draft to describe the similarity between the proposed interchangeable product and the reference product.

The final guidance, however, no longer uses the term “fingerprint-like” and whereas the draft includes almost 20 references to “residual uncertainty,” the final guidance includes only one. "The agency also considered the numerous comments on the draft interchangeability guidance and made changes to provide increased clarity to stakeholders," Acting Commissioner Ned Sharpless said.

Christine Simmon, executive director of the Biosimilars Council, applauded FDA’s "timely guidance on interchangeability for biosimilars, particularly its streamlined data and study design requirements that allow flexibility and the use of global comparator products to support applications."

Companies commenting on the draft also took issue with the requirement that they must use US-licensed reference product in a switching study (or studies). And FDA has altered this requirement in the final guidance and renamed that section of the guidance.

“If a sponsor seeks to use data derived from a switching study or studies comparing a proposed interchangeable product with a non-U.S.-licensed comparator product as part of the demonstration that the proposed interchangeable product meets the standard described in section 351(k)(4)(B) of the PHS Act, the sponsor should provide adequate data and information to establish a ‘bridge’ between the non-U.S.-licensed comparator and the U.S.-licensed reference product and thereby justify the relevance of the data obtained using the non-U.S.-licensed comparator to an evaluation of whether the requirements of section 351(k)(4)(B) have been met,” the final guidance says, explaining more about what the bridge would entail.

Otherwise, most of the draft version was carried over into the final guidance, including the requirement that companies use so-called "switching studies" to determine whether alternating between a biosimilar and its reference product impacts the safety or efficacy of the treatment.

Bernstein biotech analyst Ronny Gal added in a note to investors: "The main added requirement is a 2-arm switching trial where all patients start on the reference product. In one arm, the patients will remain on the reference product throughout. On the other, they will switch back and forth twice, ending on the biosimilar product. Critically, the main comparison is on PK/PD markers, not efficacy markers (which FDA considers less sensitive). This will materially lower costs of doing these trials."

He also said he expects this guidance will enable insulin interchangeables and allow for interchangeable versions of "some of the easier antibodies to replicate like Eylea." 

Considerations in Demonstrating Interchangeability With a Reference Product: Guidance for Industry

Editor's Note: Updated with comment from Bernstein's Gal.