On June 20, FDA issued a draft guidance proposing to remove switching studies from the interchangeable biosimilar approval process.
The draft guidance eliminates the longstanding recommendation that biosimilar developers provide clinical data showing interchangeability with reference drug products, citing experience and improvements in analytical and modeling technology.
Interchangeable Versus Standard Biosimilars
Established in 2009 by the Biologics Price Competition and Innovation Act, FDA approves biosimilars as either standard or interchangeable, interchangeable biosimilars able to be substituted or “interchanged” for the reference product without approval from the healthcare provider.
In 2019, FDA published its first Guidance on interchangeability. Under the initial guidance, biosimilar applicants can gain interchangeable status by conducting an additional set of clinical trials. These switching studies must demonstrate that switching a patient back and forth multiple times between the biosimilar and its reference product produces no change in safety or efficacy.
Reasoning Behind Interchangeability Guidance Revision
Over the past 14 years, FDA has approved 13 interchangeable biosimilars, gaining insight into any variability seen across such switching studies.
“Since the publication of the 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. Accordingly, FDA’s scientific approach to when a switching study or studies may be needed to support a demonstration of interchangeability has evolved,” FDA stated.
Switching studies are generally recommended to demonstrate interchangeability, however FDA approved 9 out of the 13 interchangeable biosimilars without switching study data. These nine approvals bypassed the switching study requirement due to either an insulin biosimilar waiver, off-label medical benefit, or intravitreal administration.
Additionally, analytical techniques have improved, allowing developers to predict the immunogenicity of potential products and design products with greater precision.
The U.S. is currently the only country that applies separate designations for standard and interchangeable biosimilars. Recently, legislators and regulators have been urging eliminating switching studies to help improve biosimilar adoption and healthcare costs.
For example, according to the Department of Health and Human Services FY2025 Budget in Brief, “The statutory distinction between biosimilars and interchangeable biosimilars has led to confusion and misunderstanding, including among patients and healthcare providers, about the safety and effectiveness of biosimilars and about whether interchangeable biosimilars are safer or more effective than other biosimilars.”
The FY2025 Budget includes a proposal that “would amend section 351 of the Public Health Service Act to no longer include a separate statutory standard for a determination of interchangeability and to deem all approved biosimilars to be interchangeable with their respective reference products.”
Data Assessment Replaces Clinical Switching Studies
FDA’s new Draft Guidance, Considerations for Demonstrating Interchangeability with a Reference Product: Update, proposes that, instead of clinical switching studies, applicants can opt to include an assessment with their application.
This assessment would explain how the clinical and comparative analytical data in the application or supplement show that the safety and diminished efficacy risks of switching the reference product and proposed product are not higher than the risks posed by using the reference product alone.
For pending biosimilar applications, applicants can submit an amendment that includes the interchangeability assessment.
Is Interchangeable Biosimilar Designation Beneficial?
The ability to submit an interchangeability assessment rather than interchangeability clinical studies will likely be most useful for biologic products that can be characterized most easily by available analytical and model technology. Switching studies will likely be required for more complex biologics. In this regard, the new guidance mirrors FDA’s practices with respect to approvals of interchangeable biosimilars.
Nevertheless, providing the option to submit an interchangeable assessment rather than switching studies begs the question of whether any distinction is necessary. Some patients and healthcare providers argue that the confusion caused by the separate designations hinders biosimilar use. Analysts claim that the separate designations have had no effect at all, that many standard biosimilars achieve a significantly higher market share than drugs with interchangeable status, and vice versa. The proposed availability of an alternative path to an interchangeable biosimilar represents the next step in the evolution of the biosimilars market that results from advancements in analytical science and regulatory experience.
FDA is taking comments on the revised Guidance through September 20, 2024 - docket number FDA-2017-D-0154.