Biosimilar Interchangeability: Why Switching Studies May No Longer Be Required

A June 2024 FDA draft guidance proposes that a biosimilar may earn the "interchangeable" designation without a dedicated switching study, letting sponsors argue interchangeability from comparative analytical and pharmacokinetic data instead. If finalized, it would loosen an expectation set in 2019, on the strength of better protein characterization and several years of real-world switching safety data. The label still means the same thing it always did: a substitution status, not a verdict that the product is clinically better than a plain biosimilar.

Key points#

• A biosimilar and an interchangeable biosimilar meet the same core scientific bar for similarity to the reference product.
• Interchangeable is an extra, substitution-focused designation that lets a pharmacist swap the product without calling the prescriber, subject to state law.
• The 2024 draft would let sponsors justify interchangeability from analytical and pharmacokinetic evidence rather than a default switching trial.
• Insulin glargine was the first interchangeable biosimilar in the United States, which makes diabetes care a useful lens for the change.
• This is a draft. Dropping a study type is not the same as dropping the evidence standard.

Two designations people keep merging#

The confusion starts with treating "biosimilar" and "interchangeable" as a single idea. They are not.

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. That is the whole bar for biosimilarity, and it is a high one.

Interchangeability is a second designation stacked on top. 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. For a product given more than once, there is an added condition: the risk of alternating or switching between the two must be no greater than staying on the reference product throughout.

The reason the distinction exists is entirely practical, and it lives at the pharmacy counter. An interchangeable product can be substituted for its reference biologic by a pharmacist without contacting the prescriber, in the same way a generic small-molecule drug is swapped, subject to state pharmacy law. As the FDA stresses in its consumer explainer, interchangeability is a regulatory and legal status about who may authorize a substitution. It is not a statement that the product works better than an ordinary biosimilar.

Why switching studies became the default#

To grant that substitution authority, the 2019 final guidance leaned on dedicated switching studies. These are trials that alternate patients between the reference product and the proposed interchangeable, then compare pharmacokinetics, immunogenicity, safety, and effectiveness against a group kept on the reference product the entire time.

The worry being tested was narrow and specific. Repeated switching between two closely related biologics might, in theory, provoke a different immune response or shift drug levels in a way that steady use of either product alone would not. A switching study is built to hunt for exactly that signal.

There was a good reason for caution: the agency wrote the 2019 guidance before it had reviewed a single interchangeable application. It was setting expectations in advance of any experience. Several years of actual submissions then changed what the evidence could support.

What shifted the agency's thinking#

The 2024 proposal rests on two lines of evidence.

The analytical case#

Modern laboratory methods can characterize a highly purified therapeutic protein in fine structural detail and model how it behaves in the body, using batteries of orthogonal physicochemical and in vitro assays. When two products are shown to match that closely at the molecular and functional level, the agency's reasoning is that a residual, switching-specific hazard becomes hard to credit. A focused analytical and pharmacokinetic assessment can then carry the argument that a separate switching trial was meant to make.

The real-world case#

The second line is empirical. Across the reviews and published literature the FDA drew on, single or multiple switches between a reference biologic and its biosimilar were not linked to meaningful differences in effectiveness or safety, immunogenicity included. The agency also looked at its own track record. By the time the draft appeared, more than a dozen products had been designated interchangeable, and most had reached that status without a dedicated switching study, because the comparative data package was already judged sufficient.

Legal analysts at Goodwin read the update as letting a sponsor supply an assessment of why existing comparative analytical and clinical data already satisfy the statutory switching standard, rather than run a switching trial by reflex. The Federal Register notice is explicit that this is a draft revision of the 2019 guidance, open for public comment.

Insulin makes the stakes concrete#

Diabetes care is a clean example of why any of this matters, and it is close to research important questions about how chronic-disease therapies reach the people who depend on them.

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. Insulin is dosed daily, self-administered, and dispensed in enormous volumes, so pharmacy-level substitution is where the interchangeable label turns into real effects on access and cost for people living with diabetes. Insulin is also, as proteins go, comparatively well characterized, which is part of why it became an early proving ground for the analytical argument the 2024 draft now generalizes.

It is worth being precise about what substitution does and does not decide. An interchangeable insulin can be swapped at the pharmacy under applicable state law, but the molecule and its clinical behavior are what the similarity and interchangeability assessments already established. The designation governs who may authorize the switch, not whether the two products are expected to act alike.

How to read this without over-reading it#

Three guardrails will keep your reading of it honest.

First, this is a draft proposal. The direction is clear and has drawn supportive comment, but the operative document is guidance under revision, not law, and guidance describes the FDA's current thinking rather than binding rules.

Second, removing a routine switching-study expectation is not the same as removing evidence. The weight shifts onto rigorous comparative analytical and pharmacokinetic characterization, which for a complex biologic is demanding on its own terms.

Third, interchangeability remains a separate label sitting on top of biosimilarity. Dropping one study type does not collapse that distinction or soften the same-clinical-result standard written into the statute.

The fair takeaway, whether you prescribe the drug or take it, is that protein science has matured to a point where the agency believes a switching-specific risk can often be evaluated in the laboratory rather than reproduced in a trial. That is a claim about when the evidence is sufficient, assessed product by product, not a blanket reassurance about the medicine in your hand.