New FDA guidance on interchangeable biosimilar labeling heads to White House for review

Regulatory Context: Biosimilars and Interchangeability

• The FDA was first authorized to develop a pathway for the approval of biosimilar products in 2010 under the Biologics Price Competition and Innovation (BPCI) Act. Biosimilars are biological products that are highly similar to a previously approved biological product and have “no clinically meaningful” differences relative to the original reference product. Because of the complexities involved in the production of biological products from living organisms, there are minor differences between a reference product and its biosimilars. Hence, they are similar, but not identical to, the reference product.
• Biosimilarity does not currently imply interchangeability for biological products. The FDA requires extensive testing to support the approval of a biosimilar product, including comparative clinical studies and other human research. For a biosimilar to be considered “interchangeable,” additional rigorous testing, which may include “switching” studies, is required.
• Interchangeable products are a subset of biosimilars that are demonstrated to produce the same clinical result as the reference product in any given patient. In practice, the biggest difference between interchangeable products and biosimilars are that pharmacists can substitute interchangeable biosimilars without consulting the prescriber (though different state laws may apply). Thus, switching studies must confirm that the biosimilar product is expected to produce the same clinical result as the reference product in any given patient, and that alternating or switching between the biosimilar and reference products will not cause any ill effects.
• The creation of a biosimilar pathway led to a new user fee program, known as the biosimilar user fee (BsUFA) program. BsUFA was first authorized in 2012, and BsUFA I ran from FY2013-2017. The most recent reauthorization, BsUFA III, extended the program for fiscal years 2023 through 2027, and was authorized at the end of 2022. That authorization followed the BsUFA III commitment letter, which was published in late 2021.
• FDA commitments under BsUFA III were varied and included a focus on “enhancing biosimilar and interchangeable biological product development and regulatory science.” This included investments that would bolster the regulatory processes for biosimilar products, and particularly, interchangeable biosimilars. The agency stated that it would “pilot a regulatory science program that focuses on advancing the development of interchangeable products and improving the efficiency of biosimilar product development.” [Read AgencyIQ’s full analysis of the BsUFA Commitment Letter here.]

Regulatory Context: Labeling for Biosimilar Products

• In 2018, the FDA released a guidance document entitled Labeling for Biosimilar Products. This guidance covered general expectations for biosimilar product labeling submissions, including the appropriate use of the proprietary, proper, and core names. It also clarified that the text is expected to be similar, but not identical, to the corresponding text in the reference product labeling. One possible deviation includes “information specific to the biosimilar product that is necessary to inform safe and effective use of the product, including administration, preparation, storage, or safety information which may differ from the reference product labeling.” Another anticipated deviation includes compliance with the FDA’s Physician Labeling Rule (PLR) and Pregnancy and Lactation Labeling Rule (PLLR), “regardless of the format of the reference product labeling.”
• In the 2018 biosimilar labeling guidance, the FDA provided specific language intended to define the biosimilar designation and clarify concerns related to immunogenicity. First, the product should declare itself as a biosimilar to the reference product near the top of the Highlights of Prescribing Information section, with an asterisk after “biosimilar”. At the end of the Highlights section, a specific statement explaining the meaning of “biosimilar” should be included. The exact text can be found in the guidance document and in an approved biosimilar product label. Also, within the Adverse Effects section, there should be a subsection for “Immunogenicity” which should provide language similar to that proposed by the agency in this guidance.
• The guidance also briefly explains how labeling will be handled for biosimilar products that are approved for fewer indications than the reference product. The FDA states that “certain text in the reference product labeling related to condition(s) of use for the reference product that are not licensed for the biosimilar product would generally not be included in the biosimilar product labeling.” However, it also notes that it may be necessary to mention uses for non-approved conditions in order to ensure safe use. In these cases, “such text should be written in a manner that does not imply” that the biosimilar product is licensed for these additional use(s).
• Two years later, FDA released a separate draft guidance document focused on labeling for interchangeable biosimilar products. The 2020 document, entitled Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act, clarified that, for the most part, labeling for interchangeable products should follow the same guidance proposed for other biosimilars. It also states that no biosimilar or interchangeable products should include a description of or data from clinical studies conducted to support a demonstration of biosimilarity or interchangeability. Additionally, it provides specific “Interchangeable Product (IP)” language to be used in place of the “biosimilar” explainer language provided in the 2018 guidance. [ Read AgencyIQ’s analysis of this guidance here.]
• As part of BsUFA III, FDA is required to release guidance on labeling for interchangeable biosimilar products by September 30, 2023. In the 2020 draft guidance, the FDA stated that it “intends to provide any additional recommendations for interchangeable biosimilar labeling in future guidance as the Agency gains more experience with interchangeable biosimilars.” Given there are just three interchangeable products approved so far (Semglee, Cimerli, and Cyltezo), it would seem that the FDA’s experience with these products remains limited.

Now, the FDA has submitted its draft guidance for labeling of biosimilar and interchangeable products to the White House for its review and (likely) clearance

• According to a new notice, a draft guidance document titled: “Labeling for Biosimilar and Interchangeable Biosimilar Products” was submitted to the White House’s Office of Information and Regulatory Affairs (OIRA) for review on August 16. OIRA is the federal management office tasked with internally reviewing federal documents before their publication to ensure consistency in the overall federal approach.
• The content of the guidance remains unclear, although there are specific areas that are expected to be addressed. While the new guidance is likely to incorporate much of the same information provided in the 2018 guidance, additional clarifications are needed. For example, manufacturers will be looking for finalized guidance on the language to use for interchangeable products, which may or may not mirror the language in the 2020 draft guidance. Other lingering questions are also expected to be addressed, including the preferred way to handle interchangeable products that are approved for fewer indications than the reference product.
• The new guidance will hopefully also contain additional examples to facilitate the application of the guidance. The 2018 guidance provided only limited examples on how to apply the labeling guidance, all of which were focused on the use of the proprietary, proper, and core names of the product. Notably, although the guidance mentions products that are approved for fewer indications than the reference product, the discussion is limited, and there are no example scenarios or solutions provided. Additionally, needs may differ for interchangeable products, for which further examples may be necessary.

What’s Next

• Once this new draft guidance is cleared by OIRA, it can be published by the FDA and opened for public comment. According to the BsUFA III commitment, the FDA will work towards the goal of publishing final guidance within 18 months after the close of the public comment period. However, if substantive changes are required, the FDA may instead issue an additional revised draft guidance within those 18 months. It will then be expected to publish a final guidance within 18 months of the close of the next comment period.
• Although almost three years have passed since the last draft guidance on this topic, few additional interchangeable products have entered the market. At the time that the 2020 draft guidance was published, only one interchangeable biosimilar, Semglee (insulin glargine-yfgn), was approved for sale. Since then, only two additional interchangeable products have been approved, Cimerli (ranibizumab-eqrn) and Cyltezo (adalimumab-adbm). Due to the limited experience with interchangeable products thus far, it is possible that this pending document may not provide thorough guidance across the full spectrum of labeling issues.
• Legislators also are currently considering a proposed bill that, if approved, would dramatically alter the landscape for interchangeable products, increasing the need for this labeling guidance. A bill introduced in July (Biosimilar Red Tape Elimination Act) would amend the federal code to state that all biosimilars, upon approval, shall be deemed interchangeable. According to this bill, if the FDA determines the need for a switching study, the agency would need to first brief lawmakers “to explain why such a study is necessary for the biological product” and why “alternatives are not sufficient.” [ Read AgencyIQ’s full analysis of this bill here.] Although the fate of this bill remains unclear, it would effectively flip the current regulatory pathway for interchangeable products, dramatically expanding the number of interchangeable products on the market and the need for clear labeling guidance.

Featuring previous research by Rachel Coe.
To contact the author of this item, please email Chelsey McIntyre ( cmcintyre@agencyiq.com).
To contact the editor of this item, please email Alexander Gaffney ( agaffney@agencyiq.com)

Key Documents and Dates

• Labeling for Biosimilar and Interchangeable Biosimilar Products; Draft Guidance