When a generic drug hits the market, it’s supposed to work just like the brand-name version. That’s the whole point of bioequivalence testing. But here’s the problem: for decades, these tests were done almost entirely on young, healthy men. Even when the drug was meant for women, older adults, or both, the studies didn’t reflect who actually took it. That’s changing-slowly, but decisively.
Why Bioequivalence Matters
Bioequivalence (BE) studies measure how quickly and how much of a drug enters your bloodstream. If two versions of the same drug-say, a generic and the original-deliver the same amount at the same rate, they’re considered bioequivalent. That means you can swap one for the other without worrying about effectiveness or safety.
But here’s the catch: your body doesn’t process drugs the same way as someone else’s. Age, sex, weight, liver function, even hormones can change how a drug behaves in your system. If a study only tests one group, you’re making assumptions about everyone else. And those assumptions can be dangerous.
The Old Way: Young Men Only
For years, regulators and sponsors stuck with young, healthy male volunteers. Why? It was simple. Men have less hormonal variation than women. Their bodies are more predictable. Recruitment was easier. Costs were lower. And statistically, it was easier to detect small differences between formulations in a homogeneous group.
But that logic ignored reality. Women metabolize drugs differently. Older adults absorb them slower. And yet, most BE studies didn’t reflect that. Take levothyroxine, a drug used by millions of women over 50. Studies for this drug often included fewer than 25% women-even though nearly two-thirds of users are female. That’s not just outdated. It’s risky.
Regulators Are Catching Up
The U.S. Food and Drug Administration (FDA) didn’t formally address this until 2013. Even then, it was a gentle nudge. But in May 2023, the FDA released a draft guidance that changed everything. If a drug is meant for both men and women, the study must include similar numbers of each. No more excuses. No more "it’s too hard" or "we don’t have enough women." If you’re testing a drug for heart disease, diabetes, or depression-conditions that affect both sexes equally-you need both sexes in your trial.
The European Medicines Agency (EMA) took a softer approach. Their 2010 guideline says subjects "could belong to either sex," but doesn’t require balance. Still, they’re reviewing it now. Brazil’s ANVISA already requires equal male-female distribution. Canada accepts ages 18 to 55. The U.S. allows adults 18 and older, but insists on including people over 60 if the drug targets them.
These aren’t just suggestions. They’re becoming requirements. And sponsors who ignore them risk delays, rejections, or even being forced to run new studies after approval.
Age Isn’t Just a Number
Older adults aren’t just older versions of young people. Their kidneys work slower. Their liver enzymes change. Body fat increases. Muscle mass drops. All of this affects how drugs are absorbed, distributed, and cleared.
For drugs meant for seniors-like blood thinners, antihypertensives, or dementia medications-testing only on 25-year-olds makes no sense. The FDA now requires sponsors to include subjects aged 60 and older, unless they can prove it’s unnecessary. That means if you’re developing a new version of a drug used by 70-year-olds, you need 70-year-olds in your study.
But here’s the challenge: older adults often have other health conditions. They take multiple medications. That makes them harder to study. The EMA and ANVISA still require healthy volunteers. The FDA is more flexible-if the drug doesn’t interfere with testing, you can include people with stable chronic conditions. That’s a big step forward.
Sex Differences Are Real-And Measurable
It’s not just about fairness. It’s about science.
A 2023 University of Toronto study found that 37% of commonly tested drugs are cleared 15-22% faster in men than in women. That’s not a small difference. That’s enough to make a drug ineffective-or toxic-if dosed the same way.
One study in 2017 looked at a common heart medication. In men, the generic version showed only 79% of the brand’s exposure. In women, it was 95%. At first glance, it looked like the drug wasn’t bioequivalent. But when they ran a larger study with 36 participants, the numbers balanced out. The initial result was a statistical fluke-caused by too few women in the group.
Small studies are dangerous. With only 12 people, one outlier can skew everything. But when you include enough men and women, those outliers cancel out. That’s why regulators now push for 24-36 participants, not the bare minimum of 12.
Why It’s Hard to Get It Right
Even with clear guidelines, companies still struggle.
Recruiting women for clinical trials is harder. Many are caregivers, have jobs, or worry about pregnancy risks. Sites report recruitment takes 40% longer when targeting balanced sex ratios. That means more money, more time, more logistics.
And then there’s the data. Most sponsors still don’t track sex-specific pharmacokinetics. They run the study, get an average result, and call it good. But if men and women respond differently, you’re missing critical information. The FDA now requires sponsors to analyze data by sex-especially if the drug is used by both. That means reporting separate AUC and Cmax values for each group. It’s extra work. But it’s necessary.
Another problem? Justifications. If you want to run a study with only men or only women, you now have to explain why. Not "it’s easier," but "here’s the pharmacokinetic data showing no difference in metabolism between sexes." That’s a high bar. And most sponsors aren’t ready for it.
What’s Changing in Practice
Change is happening. Not fast enough, but it’s happening.
In 2022, 68% of contract research organizations (CROs) started actively recruiting women. They’re offering flexible hours, childcare support, and better communication. Some are even partnering with women’s health clinics.
But only 29% of them routinely analyze results by sex. That’s a gap. You can recruit women, but if you don’t look at their data separately, you’re still missing the point.
And the numbers? Between 2015 and 2020, only 38% of generic drug studies reached 40-60% female participation. The median? Just 32%. That’s nowhere near where it should be.
What This Means for You
If you’re a patient: know that the generic you’re taking may not have been tested on people like you. Ask your pharmacist or doctor. If you’re on a drug that’s mainly used by women or older adults, and you notice side effects or reduced effectiveness, it might not be you-it might be the study design.
If you’re in pharma: stop treating bioequivalence as a checkbox. Start treating it as a science. Include the right people. Analyze the data by sex and age. Don’t wait for regulators to force you. Do it because it’s the right thing to do-and because the next audit will demand it.
If you’re a regulator: keep pushing. The data is clear. Representation isn’t optional. It’s essential for safety and efficacy.
The Future Is Inclusive
The next big step? Sex-specific bioequivalence criteria for narrow therapeutic index drugs-like warfarin, lithium, or levothyroxine. These drugs have very little room for error. A 10% difference in absorption can mean hospitalization.
The National Academies of Sciences recommended in 2021 that regulators develop separate bioequivalence ranges for men and women for these drugs. The FDA’s 2023-2027 plan says it’s a priority. That means soon, a generic drug might need to prove equivalence separately for men and women-not just an average.
This isn’t about politics. It’s about biology. And biology doesn’t care about convenience. It only cares about what works.
The era of testing drugs on young men and assuming it works for everyone is over. The science says so. The regulators say so. And the patients deserve better.
Why were bioequivalence studies historically done only on young men?
Early bioequivalence studies used young, healthy men because their physiology was seen as more predictable and less variable than women’s, especially due to hormonal fluctuations. Recruitment was easier, costs were lower, and statistical power was simpler to achieve in a homogeneous group. This practice persisted despite growing evidence that sex and age significantly affect drug metabolism, leading to potential safety and efficacy gaps in real-world use.
What are the current FDA requirements for sex representation in bioequivalence studies?
As of the May 2023 draft guidance, the FDA requires that if a drug is intended for use by both sexes, bioequivalence studies must include similar proportions of males and females-roughly a 50:50 split. If the drug is meant for only one sex, only that sex should be enrolled. Sponsors must provide scientific justification if they deviate from this standard. Female participants must also use contraception or abstain from sex during the study.
Do age requirements differ between regulatory agencies?
Yes. The FDA requires subjects to be 18 or older and encourages inclusion of those aged 60+ for drugs targeting older adults. ANVISA (Brazil) limits participants to ages 18-50. Health Canada allows 18-55. The EMA requires 18+, with no upper limit, but emphasizes healthy volunteers. The key difference is that the FDA now expects inclusion of elderly populations when relevant, while others maintain stricter age caps.
How do sex differences affect drug absorption and metabolism?
Sex differences can impact enzyme activity, body composition, hormone levels, and kidney/liver function. For example, women often have higher body fat and lower muscle mass, which affects how drugs are distributed. Some liver enzymes, like CYP3A4, work differently between sexes. A 2023 study found that 37% of commonly tested drugs are cleared 15-22% faster in men, meaning women may experience higher drug levels at the same dose.
What happens if a bioequivalence study doesn’t include enough women or older adults?
Regulators may reject the application or request additional studies. The FDA now requires justification for non-representative populations, and sponsors who ignore this risk delays, increased costs, or even withdrawal of approval. Real-world data shows that underrepresentation leads to unexpected side effects or reduced effectiveness in underrepresented groups-putting patients at risk.
Is it enough to just recruit more women, or do we need to analyze data by sex?
Recruiting more women is necessary but not sufficient. You must analyze pharmacokinetic data separately by sex. Otherwise, you’re masking differences. For example, a drug might appear bioequivalent overall, but fail in women due to higher variability. The FDA now explicitly requires subgroup analysis by sex, especially for drugs used by both genders, to ensure safety across populations.
What’s the minimum number of participants needed for a reliable bioequivalence study?
Regulatory minimums are 12 evaluable subjects per sequence under EMA guidelines. But in practice, most studies enroll 24-36 participants. Smaller studies (n=12-14) are prone to false positives or negatives due to outliers. Larger studies (n≥36) provide better statistical power to detect true differences and account for sex- or age-related variability.
