FDA Revises Guidance on Switching Studies for Biosimilar Interchangeability | Venable LLP
On June 20, 2024, the FDA issued a draft guidance, “Considerations for Demonstrating Interchangeability with a Reference Product: Update” that revises the need for switching studies to demonstrate a biosimilar is interchangeable. The initial guidance on interchangeability was published in 2019, before the FDA had received and reviewed any applications for interchangeable biosimilars. The update is based on the FDA’s experience gained in approving 13 interchangeable biosimilars and current scientific thinking and analytical assessment techniques.
In order to obtain an interchangeability designation, which allows pharmacists to automatically substitute the drug product without prescriber intervention (subject to state law), the applicant must show that the biological product “can be expected to produce the same clinical result as the reference product in any given patient”, 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” (PHS Act §§ 351(k)(4)(A)(ii) and (k)(4)(B)). Under the initial guidance, switching studies were generally recommended to demonstrate interchangeability.
According to the FDA, since the publication of the initial Interchangeability Guidance, “experience has shown that for the products approved as biosimilars to date, the risk in terms of safety or diminished efficacy is insignificant following single or multiple switches between a reference product and a biosimilar product.” This has caused an evolution in the FDA’s thinking about the need for switching studies to demonstrate interchangeability.
Under the updated draft guidance, instead of conducting a switching study “Applicants may choose to provide an assessment of why the comparative analytical and clinical data provided in the application or supplement support a showing that the switching standard set forth in section 351(k)(4)(B) of the PHS Act has been met. Any such assessment should include any other information the applicant considers relevant to support a showing that the risk, in terms of safety and diminished efficacy, from alternating or switching between the reference product and the proposed interchangeable product is not greater than the risk of using the reference product without such alternation or switch.” Applicants that already have a pending aBLA for a proposed biosimilar can submit an amendment with an assessment for interchangeability review.
The FDA noted that nine of the 13 interchangeable biosimilars approved to date were approved without switching studies. Therefore, despite switching studies previously being viewed as a requirement, and significant hurdle, to obtaining an interchangeability designation, it appears that has not been the case, and the updated guidance’s revised approach follows consistent FDA flexibility regarding interchangeables. The recent trend by the FDA has been toward approving more biosimilars as interchangeable, with five of the eight biosimilar approvals in 2024 being for interchangeable biosimilars. The Biden White House has also sought to remove the distinction between biosimilars and interchangeables, including in its FY 2025 Department of Health and Human Services Budget a provision that eliminates the separate designations (previously reported Biden FY25 HHS Budget Eliminates the Separate Interchangeability Designation for Biosimilars).
While there has been concern that having separate biosimilar and interchangeable designations has caused confusion and hindered uptake of biosimilars, so far the data has not supported that. Instead, biosimilar uptake is affected by many factors, including the indications for which the drugs are prescribed. For example, according to Samsung Bioepis’s Q4 2024 Biosimilar Market Report, oncology, ophthalmology, and pegfilgrastim biosimilars have reached an average market share of 75% three years post launch, where immunology, filgrastim, epoetin alfa, and insulin glargine biosimilars have only averaged a 23% market share after three years. This is despite the fact that oncology drugs such as trastuzumab, bevacizumab, and rituximab do not have any FDA-approved interchangeables, and immunology drugs (such as adalimumab) and insulin glargine have numerous FDA-approved interchangeables.
Payer preferences also have had a significant effect on biosimilar uptake regardless of interchangeability status. For example, the Humira® (adalimumab) biosimilar Hyrimoz® (adalimumab-adaz), saw prescription growth of 36% in the first week after CVS Caremark removed Humira® from its formulary. At that time, Hyrimoz® had not yet received an interchangeability designation. By contrast, Cyltezo® (adalimumab-adbm), the first Humira® interchangeable, has achieved less than 1% market share despite receiving an interchangeability designation.
Comments on the draft guidance will be accepted until August 20, 2024.
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The author would like to thank April Breyer Menon for her contributions to this article.
