Biosimilar Interchangeability: Why Switching Studies May No Longer Be Required

The FDA has proposed dropping routine switching studies for interchangeable biosimilars, letting sponsors instead justify interchangeability from comparative analytical and pharmacokinetic data. The June 2024 draft guidance reflects sharper protein characterization and accumulated switching-safety evidence. Interchangeable remains a regulatory substitution label, not a mark of clinical superiority over an ordinary biosimilar.

What "interchangeable" actually means

Two distinct ideas often get blurred. A biosimilar is a biologic shown to be highly similar to an already approved reference product, with no clinically meaningful differences in safety, purity, and potency. Interchangeability is a separate, additional designation. Under the Public Health Service Act, an interchangeable product must be expected to produce the same clinical result as the reference product in any given patient, and, for a product administered more than once, the risk of alternating or switching between the two must be no greater than staying on the reference product alone.

The practical consequence sits at the pharmacy counter. An interchangeable product can be substituted for its reference biologic by a pharmacist without contacting the prescriber, subject to state pharmacy law. That is why the FDA historically asked for more. As the agency lays out in its consumer-facing explainer, interchangeability is a regulatory and legal status tied to substitution authority, not a statement that the product is clinically better than a plain biosimilar. A biosimilar and an interchangeable biosimilar are held to the same core scientific bar for similarity.

Why switching studies were the old default

The 2019 final guidance leaned toward dedicated switching studies: trials that alternate patients between the reference product and the proposed interchangeable, then compare pharmacokinetics, immunogenicity, safety, and efficacy against patients kept on the reference product. The concern being tested was specific. Repeated switching might, in theory, provoke a different immune response or subtly alter exposure in a way that continuous use would not. Switching studies were designed to look for exactly that signal.

The FDA wrote that guidance before it had reviewed a single interchangeable application. Several years of real submissions changed the evidence picture.

What changed the agency's thinking

Two lines of evidence underpin the 2024 proposal. The first is analytical. Modern methods can structurally characterize highly purified therapeutic proteins and model their in vivo functional behavior with considerable sensitivity, using orthogonal physicochemical and in vitro assays. When two products are shown to be that close at the molecular and functional level, the agency's position is that a residual, switching-specific risk becomes correspondingly implausible, and a targeted analytical and pharmacokinetic assessment can carry the argument.

The second line is empirical. In the reviews and literature the FDA drew on, single or multiple switches between a reference biologic and its biosimilar were not associated with meaningful differences in efficacy or safety, including immunogenicity. The agency also pointed to its own approval record. By the time of the draft, more than a dozen interchangeable biosimilars had been designated, and most of them had reached that status without a dedicated switching study, the agency instead finding the comparative data package sufficient. As legal analysts at Goodwin summarized, the update would let a sponsor provide an assessment of why the existing comparative analytical and clinical data satisfy the statutory switching standard, rather than run a separate switching trial by default. The Federal Register notice frames this explicitly as a draft update to the 2019 guidance, open for public comment.

Why insulin is the sharp example

Insulin makes the stakes concrete. The first interchangeable biosimilar approved in the United States was an insulin glargine product, cleared in 2021 as interchangeable with its reference long-acting insulin. Because insulin is dosed daily, self-administered, and dispensed in high volumes, pharmacy-level substitution is where interchangeability translates into real access and cost effects for people with diabetes. Insulin is also comparatively well characterized as proteins go, which is part of why it became an early proving ground for the analytical argument now generalized in the draft.

Being precise about substitution matters here. An interchangeable insulin can be swapped at the pharmacy under applicable state law, but the underlying molecule and its clinical performance are what the similarity and interchangeability assessments already established. The designation governs who can authorize the switch, not whether the two products are expected to behave alike.

What to watch, and what not to over-read

A few cautions follow. First, this remains a draft proposal. The direction of travel is clear and has drawn supportive comment, but the operative document is guidance under revision, not settled law, and guidance describes the FDA's current thinking rather than binding requirements. Second, dropping a routine expectation for switching studies is not the same as removing evidence. The burden shifts toward rigorous comparative analytical and pharmacokinetic characterization, which for a complex biologic is demanding in its own right. Third, interchangeability is still a distinct label layered on top of biosimilarity, and eliminating a study type does not collapse that distinction or change the same-clinical-result standard written into the statute.

For a clinician or a patient, the reasonable read is that the science of protein characterization has matured to the point where the agency believes a switching-specific risk can often be assessed analytically rather than reproduced in a trial. That is a statement about evidence sufficiency, evaluated case by case, not a blanket assurance about any individual product.

This article is educational and is not medical advice; decisions about any specific therapy belong with a qualified prescriber who knows the individual case.