FDA Listing for Biosimilars: How They Are Evaluated and Approved

When you hear the word "biosimilar," you might think it’s just another name for a generic drug. But that’s not true. Biosimilars are not generics. They’re not even close. Generics are exact chemical copies of small-molecule drugs, like aspirin or metformin. Biosimilars are copies of complex biological drugs-medicines made from living cells, like antibodies, hormones, or proteins. These drugs treat serious conditions: cancer, rheumatoid arthritis, Crohn’s disease, and more. Because they’re made from living systems, no two batches are exactly alike. That’s why the FDA doesn’t just approve them like it does generics. It runs a deep, multi-layered scientific review to prove they’re as safe and effective as the original.

How the FDA Approves Biosimilars

The FDA doesn’t "rate" biosimilars like it rates generic drugs with an AB rating. Instead, it evaluates them for biosimilarity. That means the biosimilar must be "highly similar" to the reference product-with no clinically meaningful differences in safety, purity, or potency. The process starts long before any human trials. It begins in a lab with advanced instruments that analyze the molecule down to its atomic structure.

Manufacturers must show that their biosimilar matches the reference product across 200 to 300 critical quality attributes. These include things like molecular weight, amino acid sequence, glycosylation patterns, and protein folding. The FDA requires 95% to 99% similarity for most of these attributes. That’s not a suggestion-it’s a hard requirement. If even one key feature falls outside that range, the application gets rejected.

Once analytical data proves high similarity, the next step is usually animal studies to check for toxicity. Then, human studies follow: pharmacokinetic (PK) and pharmacodynamic (PD) trials in healthy volunteers or patients. These are typically small-50 to 100 people-and use a crossover design where participants get both the biosimilar and the reference product at different times. The goal isn’t to prove the biosimilar works better, but to prove it works the same.

Immunogenicity is another major hurdle. Biologics can trigger immune responses. Even a tiny difference in structure might cause the body to attack the drug, reducing its effectiveness or causing side effects. So manufacturers must monitor immune reactions over 24 to 52 weeks. The FDA’s Sentinel Initiative has tracked over 10 million patient-years of biosimilar use since 2015. So far, there’s no evidence that approved biosimilars cause more immune reactions than the originals.

The Purple Book: The Official FDA Listing

If you want to know which biosimilars are approved in the U.S., you go to the Purple Book. It’s the FDA’s official database of all licensed biologics-both reference products and their biosimilars. Unlike the Orange Book for generics, the Purple Book includes patent information, exclusivity periods, and licensure dates. It was updated in 2021 to require reference product sponsors to share patent details with biosimilar developers within 30 days of disclosure.

As of October 2025, the Purple Book lists 387 reference biologics and 43 approved biosimilars. Only 17 of those are designated as "interchangeable." That’s a higher standard. An interchangeable biosimilar must show that switching between it and the reference product won’t increase safety risks or reduce effectiveness. So far, only products like adalimumab and insulin biosimilars have reached this level. Most are still labeled as "biosimilar"-meaning they can be prescribed, but a pharmacist can’t substitute them without the doctor’s approval.

Biosimilars vs Generics: The Key Difference

Here’s the simplest way to understand the difference:

• Generics: Chemically identical to the brand-name drug. Made from simple molecules. The FDA only needs to prove bioequivalence-same absorption, same blood levels.
• Biosimilars: Nearly identical, but not exact. Made from living cells. The FDA must prove biosimilarity through thousands of tests, animal studies, and human trials.

Think of it like this: a generic is a photocopy of a handwritten note. A biosimilar is a hand-drawn replica of a painting. You can’t just match the colors-you have to match the brushstrokes, the texture, the layering. That’s why biosimilars cost more to develop than generics. A typical generic might cost $1 million to bring to market. A biosimilar? $120 million to $180 million.

Why the Process Takes So Long

It’s not just science-it’s also legal. Many biosimilars get delayed by patent lawsuits. Even after the FDA approves a biosimilar, the original drug maker can sue to block it. Between 2015 and 2025, the FDA approved 43 biosimilars. But only 29 actually reached the market. The average delay between approval and launch? 11.3 months. That’s because drug companies often hold dozens of patents on a single biologic, creating what’s called a "patent thicket."

Manufacturing is another bottleneck. Biosimilars require specialized facilities, trained scientists, and advanced tools like mass spectrometers and capillary electrophoresis machines. A single analytical study can take 10 to 12 months. One company told the FDA that developing a biosimilar requires 200 to 300 person-years of scientific work. That’s the equivalent of five full teams working for five years.

What’s Changing in 2025

The FDA has made big changes to speed things up. In September 2024, it updated its guidance to allow manufacturers to skip comparative clinical trials if analytical data is strong enough. That’s a major shift. Before, every biosimilar needed a full clinical trial. Now, for well-characterized proteins like monoclonal antibodies, companies can rely on advanced analytics alone. This could cut development time by 12 to 18 months and save $50 million to $100 million per product.

In June 2025, the FDA introduced a new rule: biosimilars can now get approval for all indications of the reference product based only on analytical data-no extra clinical studies needed. This is called "extrapolation." For example, if a biosimilar is approved for rheumatoid arthritis, and the original drug is also approved for psoriasis and Crohn’s, the biosimilar can be approved for all three without testing it in patients with psoriasis or Crohn’s.

The Purple Book is now a live, searchable database with daily updates. And the FDA is testing AI tools to analyze analytical data faster. These changes are already working. In 2024, the U.S. biosimilar market hit $12.7 billion-up from $1.2 billion in 2018. Analysts predict it will hit $250 billion in savings by 2030.

Who Benefits?

Patient groups like the Cancer Support Community have praised the FDA’s strict standards. They say the rigorous review has kept patients safe. Real-world data from the FDA’s Sentinel system shows adverse event rates for biosimilars are statistically the same as for the original drugs-about 0.8 per 10,000 patients, compared to 0.7 for the reference products.

But cost savings aren’t automatic. Even though biosimilars are cheaper to make, many insurers and pharmacy benefit managers still favor the original brand. In autoimmune diseases like rheumatoid arthritis, adalimumab biosimilars launched in 2023 only captured 28% of the market by mid-2025. In cancer, though, biosimilars for rituximab and trastuzumab have taken over 65% to 75% of the market within 18 months. Why? Oncologists are more comfortable switching. They see the data. They trust the science.

What’s Next?

The next frontier is complex biosimilars-things like antibody-drug conjugates and fusion proteins. So far, only three applications for these have been submitted. None have been approved. The FDA says it’s working on new guidance for these products, expected by Q3 2026.

Another challenge: gene therapies. These are the next generation of biologics. But there’s no clear way to measure biosimilarity for them yet. The FDA admits this is the biggest regulatory gap. Without standardized methods, biosimilars for gene therapies can’t be approved.

For now, the U.S. system is slower than Europe’s. The EMA has approved 118 biosimilars. The FDA has approved 43. But the FDA’s standards are stricter. And that matters. When a patient gets a biosimilar, they need to know it’s not just similar-it’s safe. And the FDA’s process ensures that.