Complex Generic Drugs: Why Some Products Are Harder to Approve

Not all generic drugs are created equal. While you might think a generic version of a brand-name medicine is just a cheaper copy, that’s not true for every drug. Some generics-called complex generic drugs-are incredibly hard to get approved, even when the patent on the original drug has expired. These aren’t simple pills you can swap out. They’re liposomal injections, inhalers, long-acting injectables, or peptide-based therapies. And getting them through the FDA? It’s like trying to rebuild a jet engine with spare parts while blindfolded.

What Makes a Generic Drug "Complex"?

A complex generic drug isn’t just a molecule in a capsule. It’s a system. The active ingredient might be a large protein, a polymer, or a fat-coated particle that releases medicine slowly over weeks. The delivery method could be an inhaler with a precise spray pattern, or an injection that needs to stay stable in your body for months. Even tiny changes in how it’s made can change how it works.

The FDA defines these as products with:

• Complex active ingredients (like peptides or liposomes)
• Complex formulations (think nanoparticles or gels that don’t dissolve easily)
• Complex delivery systems (inhalers, patches, implantable devices)
• Drug-device combinations (like auto-injectors or nebulizers)

These aren’t just hard to make-they’re hard to prove are the same as the brand-name version. For a regular pill, you can dissolve it, measure the active ingredient, and call it a day. But with a liposomal injection? You need to check particle size, how the drug leaks out over time, how it’s absorbed in the body, and whether it triggers an immune response. That’s not one test. That’s a dozen, each more complicated than the last.

The Approval Process Isn’t Built for This

The standard way to get a generic drug approved is through an Abbreviated New Drug Application, or ANDA. It’s called "abbreviated" because you don’t have to run full clinical trials. You just prove your version is bioequivalent-meaning it acts the same way in the body as the brand-name drug.

But bioequivalence doesn’t work the same way for complex drugs. Take bupivacaine liposome injectable, a long-acting painkiller. The brand version releases the drug slowly over 72 hours. A generic version might release it over 60 hours. Is that close enough? Maybe. But how do you prove it? You can’t just measure blood levels at one point. You need to track how the drug moves through tissue, how it’s absorbed, how long it lasts. The FDA had to invent a whole new way to test this before approving the first generic version in 2019.

That’s the problem. The rules were written for aspirin, not for fat-coated nanoparticles that linger in your muscles for days.

Why So Few Get Approved

Since 2015, only about 15 complex generic drugs have been approved by the FDA. Meanwhile, over 1,000 regular generics got the green light in the same period. Why such a gap?

• Science is hard: Characterizing a liposome or a peptide requires expensive tools like cryo-electron microscopes and advanced chromatography. Not every generic company has these.
• Testing is expensive: A single complex generic can cost $20 million to $50 million to develop. For a regular pill? Maybe $2 million.
• Time is long: Development takes 5 to 7 years. Regular generics? 2 to 3 years.
• Regulatory uncertainty: If the FDA hasn’t published a specific guidance for your drug, you’re guessing what they want. One company spent three years developing a generic inhaler, only to be told the device’s nozzle shape was too different from the brand version-even though patients couldn’t tell the difference.

And here’s the kicker: even if you get it right, the FDA might still say no. There’s no guarantee. That’s why many companies just give up and stick to easy generics.

Regulatory Hurdles Are Getting Worse, Not Better

The FDA tried to fix this with GDUFA II in 2017. They created a special track for complex generics and promised faster reviews. They also launched the Pre-ANDA Meeting Program, where companies can sit down with FDA scientists before submitting an application. By 2023, over 1,200 of these meetings had been held.

They also published over 160 Product-Specific Guidelines (PSGs) in 2019 alone-detailed roadmaps telling companies exactly what data they need. But here’s the problem: not every complex drug has a PSG. And when they don’t? Companies are flying blind.

One expert put it bluntly: "FDA’s expectations are unclear and appear to be continuously evolving." That means a company might spend millions building a drug, only to have the FDA suddenly demand a new test they didn’t know was needed.

International rules make it worse. In China, you need a local agent and often must run clinical trials there. In Brazil, labs and clinical sites must be certified under strict international standards. So even if you solve the science, you still have to navigate a maze of foreign regulations.

Who’s Really Affected?

The biggest losers here aren’t the drug companies. They’re the patients.

Many complex drugs treat chronic conditions: chronic pain, COPD, cancer, autoimmune diseases. These aren’t optional medications. They’re life-changing. But because generics are so hard to get approved, patients are stuck paying hundreds or even thousands of dollars a month for brand-name versions-even when the patent expired years ago.

The Commonwealth Fund found that most new generics approved today aren’t the first generic. They’re the fourth, fifth, or sixth version of a drug that’s already cheap. That doesn’t lower prices much. What patients need are the first generics of complex drugs-and those are the ones that rarely come to market.

What’s Changing? Slowly.

There’s hope. The FDA is investing in better science. They’re using machine learning to predict how a drug will behave in the body. They’re adopting quality-by-design methods, where manufacturers build in quality from the start instead of testing for it at the end. These approaches could cut approval times by 35% or more.

In 2023, the FDA promised to review most new generic applications within 10 months. They hired 128 new staff for the generic drug program. They’re pushing for more PSGs. And they’re working with manufacturers to design better bioequivalence studies.

But progress is slow. The bupivacaine liposome approval in 2019 was a milestone-but it took over a decade of back-and-forth. That’s not a model. That’s an exception.

What’s Next?

By 2028, complex generics could make up 25% of the $250 billion global generic drug market. That’s because over $75 billion in branded complex drugs will lose patent protection by then. If the system doesn’t adapt, patients will keep paying high prices while drugmakers sit on billions in potential savings.

The solution isn’t just more money or more staff. It’s smarter rules. Clearer guidance. And a willingness to accept that a drug doesn’t have to be identical to work the same way.

Right now, the FDA is trying to catch up. But until the system learns how to evaluate complex drugs on their own terms-not by the standards of aspirin-we’ll keep seeing the same pattern: breakthrough science, long delays, and patients waiting.