FDA’s New Draft Guidance Regarding Biosimilarity and Interchangeability

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On November 20, 2020, the U.S. Food & Drug Administration (“FDA”) released a Q&A-format draft guidance to address four questions regarding the submission of biologics license applications (BLAs) and labeling for interchangeable biosimilar products. 85 FR 74345 (“Draft Guidance”). The Q&As in the Draft Guidance will be finalized by adding them as a revision to the final guidance document, Questions and Answers on Biosimilar Development and the BPCI Act. A biosimilar product is one that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. Section 351(i)(2) of the Public Health Service Action (“PHS Act”). An interchangeable product is one that is shown to meet the standards described in section 351(k)(4), means that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. Section 351(i)(3). To date, the only known BLA under review for a proposed interchangeable biosimilar product is Boehringer Ingelheim’s BLA for an Adalimumab to be interchangeable with Abbvie’s Humira®. As more applicants file interchangeability BLAs and the FDA gains more experience with interchangeable biosimilars, the FDA intends to provide additional recommendations in future guidance documents.

The four Q&As addressed in the Draft Guidance are summarized as follows:

  1. How may the applicant seek FDA review for licensure for an interchangeable biosimilar, and how does FDA intend to review the application?

To seek FDA review for licensure for an interchangeable biosimilar, the applicant must submit a BLA under section 351(k) of the PHS Act with an affirmative statement in the cover letter indicating that the product meets the standards described in section 351(k)(4) for licensure as an interchangeable biosimilar or clearly requesting “INTERCHANGEABLE-ONLY REVIEW.”

If an applicant includes a statement for 351(k)(4) licensure, the FDA will evaluate the BLA as both an application for licensure of a biosimilar product and an application for licensure of an interchangeable biosimilar. If the application then only supports licensure of the product as a biosimilar product but not an interchangeable biosimilar, the FDA will split the action for administrative purposes. By splitting the action, the FDA could license the product as a biosimilar product and then convey any deficiencies in the application for licensure as an interchangeable biosimilar. The FDA could then make a later determination of interchangeability for the product upon submission of a supplement of additional data.

If the applicant requests interchangeable-only review, the FDA’s complete response letter will address any deficiencies of both interchangeability and biosimilarity because biosimilarity is a condition necessary for approval of a 351(k) BLA as an interchangeable product. However, the response letter will not address whether the application is sufficient to support a demonstration of licensure as a biosimilar product alone, as per the applicant’s request. If the application can support biosimilarity, but not interchangeability, the applicant may choose to amend and resubmit the application to address the deficiencies to support a demonstration of interchangeability or to amend and resubmit the BLA seeking licensure as a biosimilar product.

  1. How should a 351(a) BLA holder proceed if it seeks licensure of its biological product under section 351(k) as biosimilar to or interchangeable with another biological product licensed under section 351(a) (a “reference product”)?

For licensure of a proposed biological product as a biosimilar product, the applicant should submit an original application under section 351(k) of the PHS Act. For licensure of a proposed biological product as an interchangeable biosimilar product, the applicant should submit either an original application under section 351(k) of the PHS Act or a supplement to an approved application submitted under section 351(k) of the PHS Act. An applicant may, however, support a demonstration of biosimilarity or interchangeability under section 351(k) using relevant data and information from the applicant’s own 351(a) BLA for the reference product.

The Draft Guidance clarifies that it is not necessary for the holder of a 351(a) BLA for a biological product licensed or deemed licensed under section 351(a) to seek revocation of its 351(a) license in order to submit a 351(k) application. The 351(a) BLA holder may continue to market the reference product licensed or deemed licensed under section 351(a) while the 351(k) BLA is pending and after licensure of the biological product under section 351(k).

  1. Does FDA have recommendations for labeling of interchangeable biosimilars at this time?

Yes – the Draft Guidance explains that certain principles outlined in the FDA’s July 2018 Guidance for Industry: Labeling for Biosimilar Products (“Biosimilar Labeling Guidance”) also pertain to interchangeable biosimilar products.

Specifically, interchangeable biosimilar product labeling, like biosimilar product labeling, should incorporate relevant data and information from the reference product labeling, including clinical data that supported the FDA’s finding of safety and effectiveness of the reference product. As explained in the Biosimilar Labeling Guidance, labeling should not include a description of or data from clinical studies conducted to support a demonstration of biosimilarity or interchangeability because such studies would typically not be expected to facilitate an understanding of product safety and effectiveness.

Interchangeable biosimilar labeling should meet the content and format requirements of the physician labeling rule (PLR) as described in 21 CFR 201.56(d) and 201.57, as well as the final pregnancy and lactation labeling rule (PLLR) as described in 21 CFR 201.57(c)(9)(i)-(iii). Interchangeable biosimilar labeling should also follow the Biosimilar Labeling Guidance for revising biosimilar product labeling and submitting initial and revised labeling.

The Draft Guidance highlights certain differences between interchangeable biosimilar and reference product labeling. For example, interchangeable biosimilar product labeling conforming to PLR and/or PLLR may deviate from reference product labeling because the reference product labeling may not be required to conform to those requirements at the time of licensure of the interchangeable biosimilar. The interchangeable biosimilar product labeling may also differ from the reference product labeling if an applicant choses to seek licensure of the interchangeable biosimilar for fewer than all of the reference product’s licensed conditions of use.

  1. Does FDA recommend that the BLA-holder of an approved interchangeable biosimilar include a labeling statement on interchangeability?

Yes – a statement should be placed on the line immediately beneath the Initial U.S. Approval in the Highlights of Prescribing Information stating that the product is interchangeable with the reference product.

By addressing these questions, the FDA hopes to “enhance transparency and facilitate the development and approval of biosimilar and interchangeable products.” Comments and suggestions regarding the Draft Guidance should be submitted to the FDA by January 19, 2021.

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

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