Biosimilar Biological Products: 351(k) Approval and Exclusivity

The FDA approves a biosimilar biological product through an abbreviated pathway, known as Section 351(k), that lets the applicant build on the agency’s earlier finding that a reference biologic is safe and effective. To win approval, the manufacturer must submit analytical, toxicity, and clinical evidence showing its product is highly similar to that reference product and produces no clinically meaningful differences in safety, purity, or potency.¹ More than 90 biosimilars have cleared this pathway, and they typically launch at prices roughly 50 percent below the original.²

What Counts as a Biosimilar

A biological product is a virus, therapeutic serum, toxin, antitoxin, vaccine, blood component, protein, or similar substance used to prevent, treat, or cure disease.³ Biologics are grown inside living cells rather than synthesized from small chemical molecules, and no two independently manufactured batches come out molecularly identical, even from the same facility.

By statute, a biosimilar is a biological product that is “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and shows “no clinically meaningful differences” in safety, purity, or potency.⁴ The active protein must share the same primary amino acid sequence as the original. Small variations in sugar chains or protein folding can exist, but only within ranges that do not affect how the drug works in the body.

This is a weaker match than the identity a generic pill must show. A generic small-molecule drug is chemically identical to the brand. A biosimilar is highly similar, because the living systems that produce it introduce inherent variability. Approved biosimilars now treat conditions ranging from rheumatoid arthritis and psoriasis to cancer, age-related vision loss, osteoporosis, and chemotherapy-induced low white blood cell counts.⁵

The 351(k) Approval Pathway

The Biologics Price Competition and Innovation Act of 2009 created the abbreviated Section 351(k) route. It lets a biosimilar applicant lean on the FDA’s prior determination that the reference product is safe, pure, and potent, rather than reproving that record from scratch as a 351(a) applicant for an original biologic must do.¹ Abbreviated does not mean easy. The applicant still has to generate substantial data of its own to close the gap between its product and the reference.

What the Application Must Show

Under 42 U.S.C. § 262(k)(2), a biosimilar application must contain three categories of evidence:

Analytical studies showing the product is highly similar to the reference product despite minor differences in clinically inactive components.
A toxicity assessment. The statute gives the FDA discretion to let this draw on the analytical or clinical data rather than requiring separate animal studies.
Clinical studies, including immunogenicity testing and pharmacokinetic or pharmacodynamic comparisons, demonstrating safety, purity, and potency for at least one condition of use already approved for the reference product.⁴

Beyond those three pillars, the application has to show the biosimilar uses the same mechanism of action as the reference product (to the extent that mechanism is known), targets conditions already approved for the reference product, and matches its route of administration, dosage form, and strength. The manufacturing facility must meet standards ensuring the product stays safe, pure, and potent over time.⁴

The FDA evaluates the totality of the evidence. No single study decides the outcome, and the agency retains discretion to waive any element it considers unnecessary for a particular product.

What Filing Costs

A biosimilar application triggers a user fee under the Biosimilar User Fee Amendments. For fiscal year 2026, the fee is $1,200,794 for an application that requires clinical data on safety or effectiveness, and $600,397 for one that does not. Small businesses submitting their first biosimilar application, and holding no other approved drug product, may qualify for a waiver.⁶

The Higher Bar for Interchangeability

A plain biosimilar approval is not the same as an interchangeability designation, and the difference matters at the pharmacy counter. To be approved as interchangeable, the manufacturer must show the product can be expected to produce the same clinical result as the reference product in any given patient. For a product administered more than once, the manufacturer must also show that the risk of switching between the biosimilar and the reference product is no greater than the risk of staying on the reference product alone.⁷

The payoff is pharmacy-level substitution. An interchangeable product may be dispensed in place of the reference product without the prescriber authorizing the swap, in the same way a pharmacist can substitute a generic pill for a brand-name one.⁷ Whether that substitution actually happens depends on state pharmacy law. Some states require the pharmacist to notify the prescriber within a few business days; others impose different conditions.⁸

How manufacturers prove the switching standard has shifted. Earlier applicants ran dedicated switching studies that alternated patients between the biosimilar and the reference product across multiple cycles. The FDA has moved toward allowing applicants to meet the standard through an assessment explaining why their existing comparative analytical and clinical data are sufficient without separate switching studies. That change reflects the agency’s growing confidence in the analytical toolkit already required for biosimilarity and cuts the time and cost of pursuing the designation.

When Approval Can Happen: Reference Product Exclusivity

Even a fully prepared 351(k) application cannot move forward on any schedule the applicant chooses. Two statutory clocks tied to the reference product’s original licensure date gate the process.

No biosimilar application can be submitted to the FDA until four years after the reference product was first licensed. And the FDA cannot approve the biosimilar until 12 years after that original licensure date.⁴ The 12-year window can be extended by six months of pediatric exclusivity if the reference product sponsor completes qualifying pediatric studies.⁹ Both clocks run from the licensure date, not from commercial launch, so a reference product that sits on the shelf after approval still burns its own exclusivity.

First Interchangeable Exclusivity

The first biosimilar approved as interchangeable with a given reference product gets its own exclusivity period during which the FDA will not approve a second interchangeable product for the same reference. That period expires on the earliest of:

One year after the first interchangeable product begins commercial marketing.
Eighteen months after a final court decision or dismissal of any patent litigation brought against the first interchangeable applicant.
Forty-two months after approval if patent litigation is still ongoing.
Eighteen months after approval if no patent litigation was brought.¹⁰

Patents on the reference product can also delay approval independently of these FDA exclusivity clocks. Section 262(l) sets up a structured, confidential information exchange between the biosimilar applicant and the reference product sponsor after the FDA accepts the application. The sponsor identifies patents it believes would be infringed, the parties negotiate which to litigate, and the applicant must give the sponsor at least 180 days’ notice before commercially launching, allowing a final opportunity to seek a preliminary injunction.⁴

Naming and How to Verify an Approved Biosimilar

Every biosimilar gets a nonproprietary name built from the core name it shares with the reference product plus a unique four-letter suffix in lowercase, connected by a hyphen. A biosimilar of “epoetin” might be designated “epoetin-abcd.” The suffix carries no meaning; it exists purely to distinguish one manufacturer’s version from another.¹¹ The system applies to all biological products, so originator biologics also carry their own four-letter suffixes.

The FDA recommends that biosimilar labeling include a biosimilarity statement indicating whether the product has been licensed as biosimilar to, or interchangeable with, a specific reference product. The unique suffix also ties each dose to its production facility and lot number, so regulators can trace any adverse event pattern back to a particular manufacturer.

To confirm whether a given biologic has an approved biosimilar, or to check when a reference product’s exclusivity expires, use the Purple Book. It is the FDA’s searchable database listing every licensed biological product, its biosimilar or interchangeable status, its reference product, and the expiration date of any applicable exclusivity.¹²

1
U.S. Food and Drug Administration. Biological Product Innovation and Competition
2
U.S. Department of Health and Human Services. Bringing Lower-Cost Biosimilar Drugs to American Patients
3
Legal Information Institute. 42 USC 262(i)(1)
4
Office of the Law Revision Counsel. 42 USC 262 – Regulation of Biological Products
5
U.S. Food and Drug Administration. Biosimilar Product Information
6
U.S. Food and Drug Administration. Biosimilar User Fee Amendments
7
Office of the Law Revision Counsel. 42 USC 262 – Regulation of Biological Products
8
U.S. Food and Drug Administration. Interchangeable Biological Products
9
U.S. Food and Drug Administration. Background Information – List of Licensed Biological Products with Reference Product Exclusivity
10
Office of the Law Revision Counsel. 42 USC 262 – Regulation of Biological Products
11
Food and Drug Administration. Nonproprietary Naming of Biological Products Guidance for Industry
12
U.S. Food and Drug Administration. Purple Book – Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations