The US Food and Drug Administration (FDA) has issued a draft guidance, Guidance for Industry: Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act, to clarify certain provisions for the 12-year exclusivity period for biological reference products and the resulting licensing and application procedures for biosimilars. The draft guidance is intended to assist sponsors who are developing biological products, sponsors of biologics license applications (BLAs), and other interested parties in providing information that will help the FDA determine the date of first licensure for a reference product.
Under Section 351(k)(7)(C) of the Public Health Service Act (PHS Act), as added by the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), licensure of an application for a biosimilar or interchangeable product may not be made effective by the FDA until 12 years after the reference product referred to in the 351(k) application was first licensed. In addition, a 351(k) application may not be submitted to the FDA for review until four years after the date of first licensure of the reference product. This period of time in which a 351(k) application may not be licensed (or submitted for review) is known as the reference product exclusivity period. Thus, a decision on the date of first licensure of a reference product submitted under 351(a) is, in effect, a decision on eligibility for reference product exclusivity and specifies the date on which such exclusivity begins to run.
The draft guidance specifies that the date of first licensure generally will be the initial date the particular product at issue was licensed in the United States with certain exceptions. The date of first licensure does not include licensure for the following: a supplement for the biological product that is the reference product; a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.
The draft guidance specifies that a sponsor may submit information to assist the FDA in determining the date of first licensure for a biological product to determine whether the product is eligible for its own period of exclusivity or is subject to an exclusion described in 351(k)(7)(C). This information should
describe the structural similarities and differences between its proposed product and any previously licensed biological product that was the subject of a 351(a) application filed by the same sponsor or manufacturer (or its licensor, predecessor in interest, or other related entity). For protein products, described structural differences should include, as appropriate, any differences in amino acid sequence, glycosylation patterns, tertiary structures, post-translational events (including any chemical modifications of the molecular structure such as pegylation), and infidelity of translation or transcription, among others.
In determining whether a biological product includes a modification to the structure of a previously licensed biological product, the FDA also will consider the principal structural molecular features of both products and whether the modified product affects the same molecular target (i.e., receptors, enzymes, ion channels, structural or membrane transport proteins, nucleic acids, and pathogens) as the previously licensed product. If a sponsor employs a cell line modified from that used to manufacture the previously licensed product (for example, one employing a modified gene construct) to manufacture a new product, modification of the structure will not simply be presumed. Instead, a sponsor must first demonstrate that the product has been structurally modified and that the change has resulted in a change in safety, purity, or potency. If the sponsor cannot adequately characterize the biological product, the FDA recommends that the sponsor consult FDA for additional guidance.
In the draft guidance, the FDA said it is reviewing options for making information publicly available regarding reference product exclusivity and dates of first licensure. Once a method is determined, plans to communicate this information will be provided on the FDA’s website.