Biosimilar versus interchangeable biosimilar

Every interchangeable biosimilar is a biosimilar, but a biosimilar is not interchangeable until the FDA says so. The Biologics Price Competition and Innovation Act of 2009 (BPCIA) created both categories in PHS Act section 351(k). Biosimilarity (351(i)(2)) means highly similar to the reference product notwithstanding minor differences in clinically inactive components, with no clinically meaningful differences in safety, purity and potency. Interchangeability (351(i)(3)) adds the FDA biosimilar interchangeability requirements of 351(k)(4) and the legal consequence of pharmacy-level substitution.

The practical point for sponsors is that biosimilar interchangeability is a US-specific commercial lever, not a quality grade. The EU, Japan and Taiwan approve biosimilars without a comparable designation.

The statutory criteria (PHS Act section 351(k)(4))

Section 351(k)(4) sets two FDA criteria for biosimilar interchangeability, and both must be met with data in the 351(k) application. The statute reads, in substance:

1. 351(k)(4)(A): the product is biosimilar to the reference product and "can be expected to produce the same clinical result as the reference product in any given patient."
2. 351(k)(4)(B): for a product 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."

Criterion (A) is a population-to-individual shift. Biosimilarity is shown on populations; biosimilar interchangeability asks whether the result holds for any given patient, which FDA interprets through the totality of evidence, the immunogenicity profile and clinical experience. Criterion (B) applies only to products given more than once, which covers nearly all chronic biologics and oncology antibodies, and historically drove switching studies.

Two things the FDA criteria do not require are worth stating. They do not require a higher degree of analytical similarity than the biosimilar standard. And they do not require interchangeability to be requested with biosimilarity; an applicant may file a supplement later.

Switching studies: the 2019 guidance and the later draft update

The FDA biosimilar interchangeability requirements for 351(k)(4)(B) have moved from expecting a dedicated switching study to proposing that, in most cases, none is needed. The May 2019 final guidance, Considerations in Demonstrating Interchangeability With a Reference Product, described the expected design. A June 2024 draft update states that FDA's experience with approved biosimilars shows the risk of switching to be insignificant, and that an applicant may instead submit an assessment of why its comparative analytical and clinical data support the switching standard.

The 2019 design logic is still instructive. Three or more switches exposed patients to the biosimilar after the reference and the reference after the biosimilar, ending on the biosimilar so PK could be measured on the test product. PK was chosen over efficacy because it is the most sensitive measure of an exposure change caused by immunogenicity. Sponsors should assume the assessment route is available but keep the 2019 design in reserve for products with immunogenicity-driven PK variability.

Presentation and device considerations

Because an interchangeable biosimilar may be substituted without the prescriber's knowledge, the FDA expects its presentation to be usable by a patient trained on the reference product. The May 2019 final guidance makes three points about presentation and device:

• Match the licensed presentations: a sponsor should not seek licensure for a presentation for which the reference product is not licensed, for example an autoinjector where the reference is licensed only in a vial and a prefilled syringe.
• Compatibility with the formulation: data showing that the presentation is compatible with the drug product, including extractables and leachables, performance and stability.
• Device constituent part: data on the use and performance of the device constituent part, so that the FDA can assess it as part of the combination product.

For a vial-presented oncology antibody administered by healthcare professionals, device considerations are limited to container, closure and reconstitution steps. For subcutaneous self-administered products, the device data package can be as demanding as the clinical package, and the biosimilar interchangeability decision may cover one presentation and not another.

First-interchangeable exclusivity

The first applicant to obtain biosimilar interchangeability for a reference product earns a period during which the FDA may not find a second product interchangeable with the same reference. Section 351(k)(6) sets it as the earliest of:

• one year after the first commercial marketing of the first interchangeable product;
• 18 months after a final court decision on all patents in suit, or dismissal of the litigation;
• 42 months after approval of the first interchangeable product if patent litigation is still ongoing; or
• 18 months after approval if the applicant was not sued.

The exclusivity blocks later biosimilar interchangeability determinations, not later biosimilar approvals, so a second biosimilar can still be licensed and marketed; it simply cannot be substituted at the pharmacy until the period ends. The FDA's Purple Book database records which licensed biosimilars hold an interchangeability determination; the first was granted in 2021 to an insulin glargine product.

Pharmacy substitution and state law

An FDA interchangeability determination permits substitution; whether and how a pharmacist may actually substitute is governed by state law. Nearly every US state has enacted legislation on substitution of interchangeable biologics, and the statutes share a common structure:

• FDA determination required: only products the FDA has determined interchangeable may be substituted.
• Prescriber communication: the pharmacist must communicate the product dispensed to the prescriber within a defined period, often through an electronic record system.
• Prescriber override: "dispense as written" or equivalent blocks substitution.
• Patient notification and record-keeping: the patient is informed and the pharmacy retains a dispensing record for a set period.

For sponsors, state law determines whether interchangeability converts to volume. Payer formularies and purchasing contracts also drive uptake independently of substitution rights, which is why many biosimilars compete without pursuing biosimilar interchangeability at all.

How the EU approaches interchangeability differently

The EU has no biosimilar interchangeability designation and does not need one, because the EMA and the Heads of Medicines Agencies consider every EU-approved biosimilar interchangeable with its reference product and with other biosimilars of the same reference. The joint EMA/HMA statement of September 2022 formalized that position at EU level. Interchangeability in the EU sense means a prescriber may exchange one product for another with the same expected clinical effect; it does not itself authorize pharmacy substitution.

Pharmacy-level substitution, where a pharmacist dispenses a different product without consulting the prescriber, remains a national competence; some Member States permit it for certain classes, others prohibit it or leave it to tendering practice. The EMA states that interchangeability decisions rely on national competent authorities and are outside the remit of EMA and the CHMP.

The consequence for a global program is asymmetric. An EU-authorized product can be interchanged across the EU on the strength of its biosimilar approval, while the same product in the US needs a separate 351(k)(4) determination before pharmacy substitution. Sponsors should treat the FDA biosimilar interchangeability requirements as a US-specific workstream with its own data, device and timing decisions.