Last month, the FDA released four new guidance documents providing insight on the FDA’s interpretation of provisions of the Biologics Price Competition and Innovation Act (“BPCIA”), as it amends the Public Health Service Act (“PHS Act”) and the Patient Protection and Affordable Care Act (“ACA”), among other statutes. Two of the documents relate to the “Deemed to be a License” provision in section 7002(e) of the BPCIA, and are covered in a separate post. The remaining two documents, which will be discussed here, address recommended practices for biosimilar development and meeting the application requirements for biosimilar and interchangeable products.[1]

The Questions and Answers on Biosimilar Development and the BPCI Act (Revision 1) guidance document is intended to enhance transparency of the FDA’s interpretation of the BPCIA by providing responses to common questions from prospective applicants and interested parties. The content is largely pulled from two of the FDA’s prior draft guidance documents issued in April 2015 and May 2015, respectively, with some updates and revisions.

In particular, the Q&A addresses questions regarding the permissible differences between a proposed biosimilar product and a reference product, as related to formulation and delivery device and the number of routes of administration, presentations (e.g., strengths or delivery devices), and conditions of use. One noteworthy change from the earlier drafts that spans several of the questions is the reference to a new January 2017 guidance document entitled “Considerations in Demonstrating Interchangeability With a Reference Product.” While the 2015 drafts included brief explanations about the FDA’s review process for interchangeable products as relevant to each question, the revised responses now direct applicants to the comprehensive 30-page guidance, which provides detailed suggestions for the development of and applications for a proposed interchangeable product specifically.

Other relevant differences between the drafts include: a change in the recommended length of time to retain reserve samples of the products used in comparative clinical studies intended to support a 351(k) application (now for at least 5 years following the date on which the 351(k) application is licensed, or, if such application is not licensed, at least 5 years following the date of completion of the studies); removal of the recommendations related specifically to retaining samples from multi-site studies and products intended for multi-dose administration; and an expanded definition of “publicly-available information” in relation to FDA’s previous determination that the reference product is safe, pure, and potent to include in a 351(k) application (the definition now includes “FDA-approved labeling for the reference product,” in addition to the types of information found in the “action package” for a Biologics License Application (“BLA”)). Lastly, while some Q&As were withdrawn and moved to the companion draft guidance document (addressed below), one  question relating to the permissibility of extrapolated clinical data was withdrawn entirely, and instead refers applicants with questions about the standards for clinical data to another guidance from April 2015, entitled “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product.”

The companion document to Questions and Answers on Biosimilar Development and the BPCI Act (Revision 1) is New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2), which includes additional Q&As that address the requirements for pediatric assessments or investigations under the Pediatric Research Equity Act (“PREA”), the suggested support for post-approval manufacturing changes for a licensed biosimilar product, and the definition of “protein” in section 351(i)(1) of the PHS Act. Notably, the document also clarifies that a 351(k) application is not the appropriate vehicle to seek approval for routes of administration, dosage forms, strengths, or conditions of use that differ from those of the reference product, implying that sponsors must instead utilize the regular, unabbreviated pathway for licensure in those instances.

A new topic that the FDA addresses in this second guidance is the issue of when a reference product holder refuses to sell a product to a prospective applicant that is seeking to conduct studies to support approval of a biosimilar product, based on a belief that supplying the product for that purpose would violate the risk evaluation and mitigation strategy (REMS) with elements to assure safe use (ETASU) for the reference product. Noting that such incidents have occurred, the FDA proposes a solution where the prospective applicant may submit study protocols to the FDA and request a letter from the FDA stating that the proposed studies contain safety protections that would comply with the REMS. If the FDA finds that the safety protections are comparable to those in the REMS, the FDA would then notify the reference product holder with a separate letter indicating that the Agency would not consider the supply of the reference product to the prospective applicant for the required testing to be a violation of the REMS. The FDA hopes that this solution will help facilitate a prospective applicant’s access to the reference product for purposes of supporting the license application.

[1] The FDA clarifies that a “biosimilar” or “biosimilar product” refers to a product that the FDA has determined to be biosimilar to the reference product under sections 351(i)(2) and 351(k)(2) of the PHS Act, and that an “interchangeable biosimilar” or “interchangeable product” refers to a biosimilar product that the FDA has determined to be interchangeable with the reference product under sections 351(i)(3) and 351(k)(4) of the PHS Act.