When a patient takes a pill that combines two drugs-say, blood pressure medication and a diuretic-it’s not enough to prove that each drug works on its own. The real question is: does the combination behave the same way in the body as the brand-name version? This is the core challenge of bioequivalence for combination products. Unlike single-drug generics, where you just compare one active ingredient to the original, combination products involve multiple drugs, delivery systems, or even devices. And that changes everything.
Why Bioequivalence Is Harder for Combination Products
Most generic drugs are simple copies. You take a tablet, dissolve it, measure how fast the drug gets into the bloodstream, and compare it to the brand. If the numbers match within 80-125%, it’s approved. But with combination products-like a pill with two active ingredients, a cream with two drugs, or an inhaler that delivers medicine through a mechanical device-things get messy.
Take a fixed-dose combination (FDC), like a pill containing metformin and sitagliptin for diabetes. Each drug has its own solubility, absorption rate, and metabolism path. When you put them together, they can interfere with each other. One might slow down the other’s absorption. Or the excipients (inactive ingredients) in the formulation might change how the drugs dissolve. The FDA now requires generic makers to prove bioequivalence not just to the brand FDC, but also to each individual drug given separately. That means running three-way crossover studies instead of simple two-way ones. These studies need 40-60 healthy volunteers, not the usual 24-36. More people. More time. More cost.
Topical Products: Measuring What You Can’t See
Imagine a cream for eczema that combines calcipotriene and betamethasone. You can’t just swallow it and measure blood levels. The drug has to penetrate the skin’s outer layer-the stratum corneum-to work. But how do you measure that?
The FDA says to use tape-stripping: peel off 15-20 thin layers of skin and analyze how much drug is in each. Sounds simple, right? It’s not. There’s no standard on how thick each strip should be, how much pressure to use, or how to account for differences in skin thickness between people. One lab’s results can vary by 30% from another’s. That’s why some generic developers have run three failed bioequivalence studies in a row for the same product. The science isn’t settled. And until it is, approval is a gamble.
Drug-Device Combos: The User Is Part of the Drug
If you’re using an inhaler, the device isn’t just packaging-it’s part of the medicine. A slightly different mouthpiece, a weaker spring, or a misaligned valve can change how much drug reaches the lungs. The FDA requires that generic inhalers deliver 80-120% of the aerosol particle size and dose uniformity of the brand. But testing this isn’t like measuring a pill. You need specialized equipment to track aerosol particle size distribution, and even then, human behavior matters. Did the patient inhale too fast? Did they hold their breath? Did they clean the device wrong?
According to FDA data, 65% of complete response letters for generic inhalers cite issues with user interface testing. That’s not a drug problem-it’s a design problem. A generic inhaler might contain the exact same chemical, but if it feels different to use, patients won’t get the right dose. And that’s not bioequivalence. That’s therapeutic failure.
The Cost of Failure
Developing a generic version of a single-drug tablet might cost $5 million and take 2 years. A complex combination product? $15-25 million and 3-5 years. And even then, failure rates are high. Modified-release FDCs-like extended-release versions of two drugs-fail 35-40% of the time on first submission. Topical products can cost $5-10 million per clinical study, compared to $1-2 million for standard bioequivalence trials. For small generic companies, that’s a death sentence.
Teva and Viatris have publicly said that bioequivalence issues are the #1 reason their complex product pipelines stall. One company spent 24 extra months trying to get a generic foam for psoriasis approved, failing three times because the drug penetration measurements didn’t match the brand. Each failure meant a new study. Each study meant millions more in costs.
What’s Being Done to Fix This
The FDA knows the system is broken. That’s why they launched the Complex Generic Products Initiative in 2018. Since then, they’ve created 12 product-specific bioequivalence guidances. These aren’t general rules-they’re tailored instructions for specific products. For example, a guidance for a generic HIV combo pill (dolutegravir/lamivudine) now says exactly how to measure both drugs simultaneously, with tighter limits on absorption rates.
One of the biggest breakthroughs is the use of physiologically-based pharmacokinetic (PBPK) modeling. Instead of running human trials, companies simulate how the drugs behave in a virtual human body. Using data on solubility, metabolism, and absorption, they predict bioequivalence. This approach has been accepted in 17 approved generic applications since 2020. It cuts clinical studies by 30-50%, saving millions.
The FDA is also working with NIST to create reference standards for complex products. For inhalers, that means a physical sample with known particle size and dose output-so every lab can calibrate their equipment to the same benchmark. This should cut down on lab-to-lab variability, which has been a major source of failed studies.
The Bigger Picture: Who Gets Left Behind
There are 312 combination products on the FDA’s complex generic list. Topical products lead the pack at 38%, followed by inhalers at 22%. But only 19% of these have approved generics. Why? Because the path is too uncertain, too expensive, and too slow.
Meanwhile, the global market for complex generics hit $112.7 billion in 2023. If bioequivalence hurdles weren’t there, we could see generics for $78 billion in sales by 2028. Instead, patent thickets and regulatory delays are keeping prices high. A single brand-name inhaler can cost $500 a month. A generic? If it ever gets approved, it might be $50. But right now, patients wait. Doctors prescribe what’s available. And healthcare systems pay more.
International differences make it worse. The EMA often demands extra clinical trials that the FDA doesn’t require. That means companies have to run duplicate studies just to sell in Europe. Development costs rise by 15-20%. And for many small firms, that’s the end of the road.
What’s Next
The FDA’s 2024 draft guidance includes 15 new product-specific recommendations, with a focus on respiratory products-where 78% of submissions currently fail bioequivalence testing. They’re also pushing for in vitro-in vivo correlation (IVIVC) for topical products. If a lab test on skin tape strips can reliably predict what happens in a patient’s body, we could cut clinical trials entirely for creams and ointments.
But the real win will come when regulators, manufacturers, and scientists agree on one thing: bioequivalence for combination products can’t be measured with the same tools used for single-drug pills. We need smarter science, better standards, and more flexibility. Otherwise, patients will keep paying more than they should-for drugs that could, and should, be cheaper.
