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 aren’t copies like generics-they’re highly similar versions of complex biologic drugs, made from living cells. The FDA doesn’t rate them like you’d rate a movie or a restaurant. Instead, they go through one of the most detailed scientific reviews in medicine to prove they’re safe and effective. If you’re trying to understand why some biosimilars are approved and others aren’t, or why your doctor might hesitate to switch you to one, it all comes down to how the FDA evaluates them.

What Makes a Biosimilar Different From a Generic

Generics are simple. They’re chemically identical copies of small-molecule drugs like ibuprofen or metformin. You can synthesize them in a lab using the same ingredients every time. Biosimilars? They’re made from living organisms-bacteria, yeast, or mammalian cells. Even tiny changes in temperature, pH, or cell culture conditions can alter the final product. That’s why a biosimilar isn’t identical to its reference drug-it’s highly similar, with no clinically meaningful differences in safety or effectiveness.

The FDA requires biosimilars to match the reference product in structure, function, and behavior. That means testing for things like protein folding, sugar attachments (glycosylation), and how the drug binds to its target. These aren’t surface-level checks. They’re deep, molecular-level analyses that can take months to complete. A single biosimilar might be tested against 200 to 300 different quality attributes. Generics don’t need any of this. That’s why biosimilars cost more to develop-and why they’re not called generics.

The FDA’s Step-by-Step Approval Process

The FDA doesn’t just look at one piece of data. They build a complete picture using a stepwise approach called the “totality of evidence.” It starts with lab tests, moves to animal studies, then human trials-and only then do they decide if the product is ready for approval.

First comes analytical studies. Scientists use advanced tools like mass spectrometry, capillary electrophoresis, and high-performance liquid chromatography to compare the biosimilar and the reference product molecule by molecule. The goal? To show they’re 95% to 99% similar across critical attributes. If the data shows a gap-even a small one-the application gets put on hold.

If the analytical data looks good, the next step is pharmacokinetic (PK) and pharmacodynamic (PD) studies. These are done in healthy volunteers or patients. They measure how fast the drug enters the bloodstream, how long it stays there, and how it affects the body. These studies usually involve 50 to 100 people and use a crossover design, meaning each participant gets both the biosimilar and the reference drug at different times.

Then there’s immunogenicity. This is huge. Biologics can trigger immune responses. Even a small difference in structure could make the body attack the drug-or worse, attack itself. So developers must track immune reactions over 24 to 52 weeks. The FDA has seen no safety signals from approved biosimilars in nine years of monitoring, but they still require this data for every single product.

For a long time, clinical trials comparing outcomes between the biosimilar and reference drug were mandatory. But in September 2024, the FDA updated its guidance. Now, if analytical data is strong enough-especially for well-understood proteins-those full-scale clinical trials can be skipped. That’s a big shift. It means faster approvals without lowering safety standards.

The Purple Book: The Official FDA Listing

There’s no public “approved drugs” list for biologics like there is for small-molecule drugs. Instead, the FDA maintains the Purple Book. It’s the official database of all licensed biologics, including reference products and their biosimilars. As of October 2025, it lists 387 reference biologics and 43 approved biosimilars.

Each entry includes the approval date, manufacturer, and whether the product is designated as “interchangeable.” That’s a special status. It means the FDA has determined you can switch between the biosimilar and the reference drug without any increased risk. Only 17 of the 43 approved biosimilars have this designation so far.

The Purple Book also shows patent information. Since 2021, reference product sponsors must disclose patent details within 30 days of a biosimilar application being filed. This helps prevent endless legal battles that delay market entry. Still, many biosimilars sit on the shelf for years because of lawsuits. Out of the 43 approved, only 29 have actually reached patients.

Interchangeable vs. Non-Interchangeable: What’s the Difference?

Not all biosimilars are created equal. The FDA has two categories: biosimilar and interchangeable.

A biosimilar is approved based on showing it’s highly similar with no clinically meaningful differences. That’s enough for a doctor to prescribe it, and a pharmacist to dispense it-with permission from the prescriber.

An interchangeable biosimilar goes further. It must prove it can be switched back and forth with the reference product without affecting safety or effectiveness. That requires additional data: multiple switching studies, often in patients with chronic conditions like rheumatoid arthritis or Crohn’s disease. The FDA requires evidence that switching doesn’t increase immune reactions or reduce drug performance.

Why does it matter? In some states, pharmacists can automatically substitute an interchangeable biosimilar without telling the doctor. For non-interchangeable ones, they can’t. That’s a big deal for patients who want cost savings without extra paperwork.

Why Are So Few Biosimilars on the Market?

Even though the FDA has approved 43 biosimilars since 2015, only 29 are actually being sold. The rest are stuck in legal limbo. Patent litigation is the biggest blocker. Reference drug makers often file dozens of patents, creating what’s called a “patent thicket.” Developers spend years fighting in court instead of manufacturing drugs.

Cost is another issue. Developing a biosimilar costs $120 million to $180 million-up to 10 times more than a generic. The analytical phase alone takes 10 to 12 months and requires teams of specialists with expertise in advanced lab techniques. Many small companies can’t afford it.

Payers also play a role. Insurance companies sometimes favor the original brand because of rebates or contracts. Even when biosimilars are cheaper, formularies don’t always list them first. In oncology, biosimilars have taken off-65% to 75% market share within 18 months. But in autoimmune diseases like those treated with adalimumab, adoption is slow. By mid-2025, only 28% of prescriptions were for biosimilars, far below the 50% the FDA expected.

What’s Changing in 2025 and Beyond

The FDA is making moves to speed things up. In June 2025, they introduced a new policy allowing indication extrapolation based on analytical data alone-for certain well-characterized proteins. That means if a biosimilar is approved for one condition, it can be used for others without separate trials, as long as the science supports it.

They’re also building AI tools to review analytical data faster. A pilot program launching in early 2026 will use machine learning to flag inconsistencies in chromatograms or mass spec readings. That could cut review times by months.

And they’re working on guidance for complex biosimilars-like antibody-drug conjugates and gene therapies. Only three applications for these advanced products have been submitted so far. None have been approved. The FDA admits this is a gap. Without clear rules, developers don’t know how to prove similarity for these next-generation drugs.

The goal? By 2030, biosimilars will make up 30% of the biologics market, saving $250 billion in cumulative costs. That’s up from the $150 billion projected in 2018. The science is sound. The regulatory path is clear. The challenge now is getting them into patients’ hands.

Real-World Evidence: Are Biosimilars Safe?

Some patients worry: If it’s not identical, is it safe? The data says yes.

The FDA’s Sentinel Initiative tracks adverse events across millions of patients. As of Q3 2025, biosimilars had 0.8 adverse events per 10,000 patients. The reference products? 0.7. That’s statistically the same. No biosimilar has shown a unique safety risk in nearly a decade of post-market surveillance.

Patient advocacy groups like the Cancer Support Community have praised the FDA’s rigor. Kim Thiboldeaux, their executive director, testified in March 2025 that every approved biosimilar has performed just like its reference drug. No surprises. No hidden risks.

That’s the bottom line. The FDA doesn’t just approve biosimilars because they’re cheaper. They approve them because the science proves they work the same way. And for patients who need life-changing treatments-like those for cancer, rheumatoid arthritis, or diabetes-the option to use a biosimilar could mean the difference between starting treatment… and waiting.