Welcome to Alston & Bird’s introduction to biological products regulation. In this five-part intro-level series, we provide answers to a number of questions drug developers may have about the regulation and regulatory pathway for their products.
The series includes:
- Is the Product a Biological Product?
- What Is the Regulatory Pathway for Biological Products?
- Unlocking Reference Product Exclusivity: What Sponsors Need to Know
- Preparing for the FDA’s Pre-License Inspection
Section 351(k) of the Public Health Service Act (PHSA) establishes an abbreviated licensure pathway for biological products that are demonstrated to be biosimilar to, or interchangeable with, an FDA-licensed reference product. Recent Food and Drug Administration (FDA) guidance signals a significant shift toward reducing development burdens for biosimilars and interchangeable biosimilars while maintaining scientific rigor.
Under the PHSA, a product is considered biosimilar if it meets two key prongs:
- Highly Similar. The product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components under Section 351(i)(2)(A) of the PHSA.
- No Clinically Meaningful Differences. There are no clinically meaningful differences in safety, purity, and potency under Section 351(i)(2)(B) of the PHSA.
Historically, sponsors relied on extensive clinical trials to satisfy these requirements. However, the FDA's recent draft guidance on comparative efficacy studies (CES) indicates a move away from Phase 3–like trials. Instead, sponsors can now demonstrate biosimilarity through a combination of advanced analytical assessments and comparative pharmacokinetic or pharmacodynamic (PK/PD) data.
To meet the interchangeability standard, a biosimilar must satisfy two additional requirements under Section 351(k)(4) of the PHSA:
- In Any Given Patient Standard. The product must produce the same clinical result as the reference product in any given patient.
- Switching Standard. For products administered more than once, the risk of alternating or switching between the biosimilar and reference product must not be greater than continuing to use the reference product.
There is no requirement to conduct clinical studies for every indication to support interchangeability. For the “in any given patient” standard under Section 351(k)(4)(A)(ii) of the PHSA, sponsors do not need to perform clinical studies across all proposed indications. Instead, a sponsor may select one indication for study and then extrapolate the data to other indications, provided there is a robust scientific justification. The FDA generally accepts extrapolation based on factors such as mechanism of action, pharmacologic pathways, and analytical characterization.
For the “switching” standard under Section 351(k)(4)(B) of the PHSA, the FDA's June 2024 draft guidance reflects updated thinking on when a switching study may be necessary. The guidance signals a shift away from requiring switching studies in most cases. Instead, sponsors may rely on comparative analytical assessments, combined with clinical data generated as part of the biosimilarity demonstration, to meet the switching standard. Although clinical studies are not broadly required to establish interchangeability, the statutory distinction between biosimilarity and interchangeability remains in place. Sponsors should therefore continue to prepare robust scientific justifications for extrapolation when seeking an interchangeability designation.
Section 351(k)(6) of the PHSA grants exclusivity to the first licensed interchangeable biosimilar, blocking approval of subsequent interchangeable biosimilars for defined periods depending on litigation outcomes. The FDA does not currently have a guidance document on how to interpret or implement the statutory provision governing the first interchangeable exclusivity (FIE). Instead, in novel or first-impression scenarios, the FDA has interpreted FIE on a case-by-case basis through internal memoranda. The determination of FIE is published in the Purple Book. Because whether a product qualifies for FIE informs critical business decisions, sponsors should closely monitor precedential FIE determinations to guide their product development and exclusivity strategies.
Many consider biosimilars to be the biologic equivalent of generics, but because they fall under a different statutory framework, there are notable differences. For example, generic drugs must have the same labeling as the reference listed drug (RLD), except for certain differences allowed under 21 C.F.R. § 314.94(a)(8). In contrast, biosimilars are not subject to the same labeling requirement and have additional flexibility allowing labeling differences.
Another key distinction from generics is in product presentation. The FDA has allowed presentation differences for interchangeable biosimilars—a departure from its past approach to generics. In January 2025, the FDA approved for the first time an interchangeable biosimilar in an autoinjector presentation while the reference product was available only in a vial or prefilled syringe format. This approval signals that interchangeability determinations can be made even when presentations differ, something the FDA has not yet permitted for generics. This precedent provides new flexibility and opportunities for biosimilar development.
The FDA’s recent policy shift significantly reduces the development burden for biosimilars and interchangeable biologics, creating new opportunities for sponsors to streamline development and differentiate products. Our team will continue to monitor FDA updates and provide timely insights to help sponsors navigate this evolving regulatory landscape.
If you have any questions, or would like additional information, please contact one of the attorneys on our FDA: Drug & Device team.
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