FDA Listing for Biosimilars: How They Are Evaluated and Approved

The FDA doesn’t rate biosimilars like you’d rate a movie or a restaurant. There’s no star system, no green checkmarks, no consumer reviews. Instead, the FDA uses a strict, science-driven process to decide if a biosimilar is close enough to its reference biologic to be approved for use in patients. This isn’t about convenience or cost alone-it’s about ensuring safety, purity, and effectiveness down to the molecular level.

What Makes a Biosimilar Different From a Generic

People often confuse biosimilars with generics. They’re not the same. Generics are exact copies of small-molecule drugs like aspirin or metformin. You can chemically synthesize them in a lab, and every tablet is identical. Biosimilars, on the other hand, are made from living cells-yeast, bacteria, or mammalian cells. They’re large, complex proteins, like antibodies or hormones. Even tiny changes in how they’re made-temperature, pH, fermentation time-can alter their structure. That’s why a biosimilar isn’t an exact copy. It’s a highly similar version.

The FDA requires biosimilars to be highly similar to the reference product, with no clinically meaningful differences in safety, purity, or potency. That’s the legal standard under Section 351(k) of the Public Health Service Act. It’s not about being identical. It’s about being functionally the same in the body.

The Step-by-Step FDA Approval Process

Getting a biosimilar approved isn’t a shortcut. It’s a marathon with five key steps, each more demanding than the last.

1. Analytical studies: This is where it all starts. Developers use advanced tools like mass spectrometry, capillary electrophoresis, and chromatography to compare the biosimilar and reference product side-by-side. They look at over 200 critical quality attributes-things like molecular weight, glycosylation patterns, folding, and charge variants. The FDA expects 95-99% similarity across these attributes. If the data falls short, the application is rejected before any animal or human testing begins.
2. Animal studies: Toxicity tests are done in relevant animal models, usually mice or monkeys. The FDA can waive this step if analytical data is strong enough, but most sponsors still include it to reduce risk.
3. Pharmacokinetic (PK) and pharmacodynamic (PD) studies: These are human trials, usually in healthy volunteers. Researchers measure how quickly the drug enters the bloodstream (PK) and how it affects the body (PD). A two-way crossover design is standard: patients get the biosimilar, then the reference product, or vice versa, with a washout period in between. At least 50-100 participants are needed to detect small differences.
4. Immunogenicity assessment: This is critical. Biologics can trigger immune responses. The FDA requires monitoring for up to a year to check if the biosimilar causes more antibodies or allergic reactions than the reference product. Data from the FDA’s Sentinel Initiative shows biosimilar adverse event rates are statistically identical to reference products-0.8 per 10,000 patients versus 0.7.
5. Comparative clinical studies: This used to be mandatory for every biosimilar. But in September 2024, the FDA updated its guidance. Now, if analytical and PK/PD data are exceptionally robust, the agency may waive full clinical trials. This change has cut development costs by $50-100 million per product and shortened timelines by 12-18 months, according to Sandoz’s Chief Scientific Officer.

The Purple Book: The Official FDA Listing

Once approved, a biosimilar shows up in the FDA’s Purple Book. This isn’t just a list-it’s the authoritative public record of all approved biologics and their biosimilars. Updated daily since early 2025, it includes: licensure dates, reference products, patent information, exclusivity periods, and interchangeability status.

As of October 2025, the Purple Book lists 387 reference biologics and 43 approved biosimilars. Only 17 of those 43 are designated as interchangeable. That’s a higher bar. An interchangeable biosimilar must prove it can be switched with the reference product without increasing risk or reducing effectiveness. It’s not just about being similar-it’s about being substitutable without a doctor’s intervention. So far, only a few have cleared this hurdle, mostly for insulin and certain infliximab products.

Why the U.S. Process Is Stricter Than Europe’s

The European Medicines Agency (EMA) approved 118 biosimilars by 2025. The FDA approved 43. Why the gap?

The FDA demands more analytical detail. Where the EMA might accept three analytical methods to confirm a protein’s structure, the FDA now requires five to seven orthogonal methods per attribute. The FDA also requires more extensive immunogenicity data and has historically been more cautious about extrapolating indications-using data from one condition to approve use in others.

Dr. Steven Kozlowski, former director of FDA’s Office of Biotechnology Products, said in a 2023 interview: “The FDA’s approach is more comprehensive, and that’s why approval takes longer.” The median time from IND submission to approval in the U.S. is 3.2 years. In Europe, it’s 2.1 years.

Real-World Impact: Who’s Using Biosimilars and Why

Biosimilars have saved patients and payers billions. The U.S. biosimilar market grew from $1.2 billion in 2018 to $12.7 billion in 2024. That’s 18% of the total biologics market.

Oncology leads adoption. Biosimilars for rituximab and trastuzumab now hold 65-75% of the market within 18 months of launch. Patients get the same treatment at 15-30% lower cost. But autoimmune drugs like adalimumab have been slower. By Q2 2025, adalimumab biosimilars had only 28% market share-far below the 50% the FDA projected in 2020. Why? Payers restrict access. Some doctors still prefer the original brand, even though studies show no difference in outcomes.

What’s driving change? Real-world evidence. The FDA’s Sentinel Initiative tracks millions of patient records. No biosimilar has shown a unique safety signal in nine years of monitoring. That’s powerful data.

Challenges and the Road Ahead

The biggest hurdles aren’t scientific-they’re financial and legal. Developing a biosimilar costs $120-180 million, mostly for analytical work. Patent litigation delays average 2.7 years before launch. Of the 43 approved biosimilars, only 29 have actually reached patients.

The FDA’s 2025 roadmap aims to fix this. New guidance for complex molecules like antibody-drug conjugates is coming in late 2026. AI tools for reviewing analytical data will launch in early 2026. And a formal framework for assessing interchangeability of combination products is due by mid-2027.

Still, gaps remain. Gene therapies and cell-based products don’t yet have clear biosimilar pathways. As the FDA noted in its September 2025 Science Board meeting: “The lack of standardized methods for emerging modalities is the biggest regulatory challenge ahead.”

What This Means for Patients and Providers

If you’re a patient, you can trust that every FDA-approved biosimilar has been held to the same safety standard as the original. You’re not getting a second-rate drug. You’re getting a scientifically validated alternative that works the same way.

If you’re a provider, the key is knowing the difference between “biosimilar” and “interchangeable.” Only interchangeable products can be substituted at the pharmacy without a new prescription. Always check the Purple Book for the latest status.

For everyone, the message is simple: biosimilars aren’t a compromise. They’re a smarter way to deliver life-saving treatments at a lower cost-with no sacrifice in safety.