Age and Sex in Bioequivalence Studies: What Regulators Really Require

When a generic drug hits the shelf, you assume it works just like the brand-name version. But here’s the thing: bioequivalence studies-the clinical trials that prove this-are often done on a very narrow group of people. For decades, these studies mostly used young, healthy men. Why? Because it was easier. But that’s changing. And if you’re taking a medication every day-whether you’re a 65-year-old woman with hypothyroidism or a 28-year-old man on antidepressants-you need to know how much that study design actually reflects your body.

Why Bioequivalence Studies Used to Be All About Young Men

Back in the 1980s and 90s, bioequivalence studies were designed like clockwork: 12 to 24 healthy male volunteers, aged 18 to 35, with a BMI between 18 and 25. They didn’t smoke. They didn’t drink. They were physically fit. And they were almost always men.

The logic was simple: since each person takes both the generic and brand-name drug in a crossover design, their own body becomes the control. If the drug levels in their blood look the same across both versions, the products are considered equivalent. It was efficient. It was cheap. And it was deeply flawed.

The problem? Men and women don’t process drugs the same way. Women tend to have higher body fat percentages, lower muscle mass, different liver enzyme activity, and hormonal fluctuations that affect how quickly drugs are absorbed, distributed, and cleared. Age changes this even more. Older adults often have slower kidney function, reduced liver metabolism, and changes in stomach acidity-all of which can alter how a drug behaves in the body.

Yet, for years, regulators accepted data from these homogenous groups as representative of everyone. That meant a drug proven safe and effective in young men might behave differently in a 70-year-old woman with reduced kidney function. And no one was checking.

What the FDA, EMA, and ANVISA Actually Require Today

Regulators didn’t ignore the issue forever. By the 2010s, evidence piled up that sex and age mattered. The U.S. Food and Drug Administration (FDA) updated its guidance in 2013, then again in May 2023. Now, if a drug is meant for both men and women, the FDA says you must include similar proportions of each sex in your bioequivalence study. That means roughly 50-50. Not 80-20. Not 70-30. Close to equal.

The European Medicines Agency (EMA) took a softer tone. Their 2010 guideline says subjects “could belong to either sex”-but doesn’t require balance. That’s a big difference. It leaves room for sponsors to enroll mostly men and still get approval. But even the EMA now expects sponsors to justify why they didn’t include both sexes if the drug is used by both.

Brazil’s ANVISA is stricter. They require exact 50-50 male-female splits, and participants must be between 18 and 50 years old. No exceptions. No older adults. No smokers. No one with a BMI outside ±15% of normal. It’s a tight box.

Age is another layer. The FDA now says: if your drug is meant for older adults-say, for osteoporosis or high blood pressure-you need to include people 60 and older. Or, you have to explain why you didn’t. That’s new. Before, you could test only in 25-year-olds and assume it worked the same in 75-year-olds. Now, that’s not enough.

Why Balance Matters More Than You Think

Here’s where it gets real. In 2017, a small bioequivalence study on a common blood pressure drug showed something strange. In men, the generic version delivered only 79% of the brand’s exposure. That looked like a failure. But in women? It delivered 95%. The study concluded the products were equivalent overall. But that average masked a dangerous truth: the drug might be under-dosing men.

Turns out, it was a statistical fluke. The study had only 14 people. A few outliers skewed the data. A follow-up with 36 participants showed no real difference between the two versions. But the lesson stuck: small studies, especially those with unbalanced groups, can give false signals.

Larger, balanced studies are better at spotting real differences. They also catch what’s called a “sex-by-formulation interaction”-where the generic and brand behave differently in men versus women. That’s not just a statistical curiosity. It’s a safety issue. If a drug is absorbed slower in women, it might not work as well. If it’s cleared faster in men, it might cause side effects.

Take levothyroxine, a thyroid hormone used by millions. Nearly two-thirds of users are women. Yet, bioequivalence studies for this drug often enroll fewer than 25% women. That’s not just outdated-it’s risky. Women may need different dosing. Their absorption can change with menstrual cycles, pregnancy, or menopause. If the generic was only tested on men, you’re guessing how it works for most of your patients.

The Real Cost of Not Including Women and Older Adults

Sponsors don’t want to do this because it’s harder-and more expensive. Recruiting women, especially those who are not young or healthy, takes longer. Sites report recruitment times increase by 40% when you aim for gender balance. Women are less likely to participate in clinical trials due to family responsibilities, safety concerns, or lack of flexible scheduling.

And it’s not just about enrollment. Once you have a balanced group, you need to analyze the data by sex. That means more statistical power, more subgroup analysis, more documentation. It adds weeks to the timeline and thousands to the budget.

But the cost of not doing it is higher. In 2021, the FDA analyzed 1,200 generic drug applications and found only 38% achieved 40-60% female participation. The median? Just 32%. That’s not representative. That’s negligence dressed up as efficiency.

And it’s not just women. Older adults are routinely excluded. But 60% of all prescription drugs are taken by people over 65. If your study only tests people under 50, you’re not proving bioequivalence for the people who need it most.

What’s Changing-and What’s Still Broken

The FDA’s 2023 draft guidance is the biggest shift in decades. For the first time, they’re not just suggesting balance-they’re requiring it. If you’re testing a drug for both sexes, you must include similar numbers of men and women. No more hiding behind “it’s not necessary.”

The EMA is reviewing its 2010 guideline. Updates are expected in 2024. ANVISA is already enforcing balance. Canada’s Health Canada accepts 18-55 year olds, with no explicit sex requirement-but they’re watching. Globally, the pressure is building.

But gaps remain. There’s still no standardized way to analyze sex-by-formulation interactions. No agreed-upon threshold for what counts as a “significant” difference between men and women. And while the FDA requires inclusion of older adults, they don’t say how many. One 65-year-old in a study of 36? That’s not enough.

Also missing: studies for children, pregnant women, or people with chronic diseases. The FDA allows healthy volunteers with stable conditions like hypertension or diabetes-but only if the drug doesn’t interfere with the study. That’s a loophole. Most people taking these drugs have other health issues. We still don’t know how generics behave in those real-world populations.

What You Should Know as a Patient

You don’t need to understand statistical models to protect yourself. Here’s what you can do:

• If you’re a woman taking a daily medication-especially one for thyroid, depression, or heart conditions-ask your pharmacist: “Was this generic tested in women?”
• If you’re over 60 and your medication was recently switched to a generic, pay attention to side effects or changes in effectiveness. It’s not “all in your head.”
• Report any unexpected changes to your doctor. That data matters. It helps regulators spot problems.
• Support advocacy groups pushing for more inclusive clinical trials. Change doesn’t happen without pressure.

The system is slowly getting better. But progress is uneven. The science is clear: bodies aren’t one-size-fits-all. Bioequivalence studies need to reflect that.

How Industry Is Adapting

Some companies are ahead of the curve. In 2022, a survey of contract research organizations (CROs) found 68% now have proactive strategies to recruit women: flexible hours, childcare support, targeted advertising, even partnerships with women’s health clinics.

But only 29% track sex-specific pharmacokinetic data routinely. That’s a red flag. If you’re not measuring how the drug behaves differently in men and women, you’re not really studying bioequivalence-you’re just hoping it works.

The most successful sponsors now design studies with sex and age as variables from day one. They stratify randomization. They pre-specify subgroup analyses. They include older adults in the primary cohort-not as an afterthought.

It’s more work. But it’s also smarter. And it’s becoming the new standard.

The Future of Bioequivalence

The next big step? Sex-specific bioequivalence criteria for narrow therapeutic index drugs-medications like warfarin, lithium, or levothyroxine, where small changes in blood levels can cause serious harm.

A 2021 report from the National Academies of Sciences recommended exactly that. And a 2023 University of Toronto study found that 37% of commonly tested drugs are cleared 15-22% faster in men than women. That’s not noise. That’s biology.

The FDA’s 2023-2027 strategic plan names “enhancing representation of diverse populations” as a top priority. That’s not marketing speak. It’s a mandate.

Bioequivalence isn’t just about matching drug levels. It’s about matching real people. And until studies reflect the actual users of these drugs, we’re not truly ensuring safety or effectiveness. We’re just pretending.