By Amanda Murphy, Jeffrey Jacobstein, and Yicong Du
On May 09, 2019, the U.S. FDA issued final guidance titled “Considerations in Demonstrating Interchangeability with a Reference Product.” It is intended to assist sponsors in demonstrating that a proposed therapeutic protein product is interchangeable with a reference product for the purposes of submitting a marketing application or supplement under section 351(k) of the Public Health Service Act (PHS Act) (42 U.S.C. 262[k]).
The FDA will find interchangeability if there is sufficient information to show that the biological product “is biosimilar to the reference product” (351[k][A][i]), that it “can be expected to produce the same clinical result as the reference product in any given patient” (351[k][A][ii]), and that “for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch” (351[k][B]).
The guidance indicates that the FDA intends to consider the totality of the evidence on a case-by-case basis. A product’s degree of complexity, clinical experience, risk assessments, and post-marketing data are all factors that may impact the type and amount of information needed to support a demonstration of interchangeability.
Information necessary to meet the section 351(k)(4)(A) standard may include: (1) identification and analysis of critical quality attributes, (2) analysis of the mechanism of action in each condition of use, (3) analysis of any differences in pharmacokinetics and biodistribution in different patient populations, (4) analysis of any differences in the immunogenicity risk in different patient populations, (5) analysis of any differences in toxicities in each condition of use and in each patient population, and (6) information on other factors that affect safety and efficacy.
For the 351(k)(4)(B) requirement, the FDA expects sponsors to conduct switching studies for products dosed more than once, which evaluate changes in treatment that result in two or more alternating exposures (switch intervals) to the proposed interchangeable product and to the reference product. Sample size, number, and duration of switches, as well as timing of sampling are all considerations in the study design. It is possible to use a non-U.S.-licensed comparator in a switching study, as long as the sponsor justifies the relevance of the data obtained in such study. Once the proposed product meets the requirements for licensure as an interchangeable product for one condition of use, the sponsor may seek licensure for additional conditions of use for which the reference product is licensed.
Finally, given the complexity of biologic products and the distinct features contributing to the interchangeability assessment for different products, sponsors should seek early discussions and continue to work closely with the FDA at every stage of the process to ensure an effective and efficient process for demonstrating the interchangeability of a chosen biologic product.
Bio: Amanda Murphy and Jeffrey Jacobstein are partners at the law firm Finnegan, Henderson, Farabow, Garrett & Dunner. Yicong Du is a summer associate at the firm