Special Populations in Bioequivalence: Age and Sex Considerations

When a generic drug hits the shelf, you expect it to work just like the brand-name version. But here’s the thing: most bioequivalence studies that prove this don’t look like the real world. For decades, these tests were done almost entirely on young, healthy men. Why? Because it was easier. But as more drugs are taken by women, older adults, and people with different body types, that approach is no longer good enough. The science has caught up. Regulators are demanding better. And if you’re developing or using generic medications, you need to know why age and sex matter more than ever.

Why Bioequivalence Studies Used to Ignore Women and Older Adults

Bioequivalence studies measure how quickly and how much of a drug enters your bloodstream. The goal is simple: prove that two versions of the same drug - say, a generic and the original - deliver the same amount of active ingredient at the same rate. For years, the go-to subjects were men between 18 and 30. They were seen as the most predictable. Fewer hormonal fluctuations. Less body fat variation. Lower risk of pregnancy. It made statistical analysis cleaner.

But here’s the flaw: most patients aren’t 25-year-old men. Take levothyroxine, a thyroid medication. Nearly two-thirds of users are women. Yet, bioequivalence trials for this drug often included fewer than 25% women. That’s not just a gap - it’s a blind spot. Women metabolize some drugs differently. Their stomachs empty slower. Their liver enzymes work at different speeds. Their body fat percentage is higher. These aren’t minor details. They change how a drug behaves.

The same goes for older adults. As we age, our kidneys and liver slow down. Blood flow changes. Muscle mass drops. A drug that works fine in a 25-year-old might build up to dangerous levels in someone over 65. Yet, until recently, many studies excluded anyone over 50. The assumption was that if a drug worked in a young adult, it would work everywhere. That’s not science. It’s guesswork.

What Regulators Now Require

Regulatory agencies have finally started pushing back. The U.S. Food and Drug Administration (FDA) updated its guidance in May 2023 with clear expectations: if a drug is meant for both men and women, your bioequivalence study must include roughly equal numbers of each. That’s not a suggestion - it’s a requirement unless you can prove otherwise.

The European Medicines Agency (EMA) takes a slightly different approach. Their 2010 guideline says subjects “could belong to either sex” - no hard numbers. But they still expect you to detect formulation differences. That means if your study only includes men and the drug is mostly used by women, you’re taking a risk. The EMA doesn’t demand balance, but they’ll question why you didn’t get it.

Brazil’s ANVISA is the strictest. They require exactly equal male-female splits. Age limits? 18 to 50. No smoking. BMI must be within 15% of normal. Canada? 18 to 55. No smoking. No pregnancy. The rules vary, but the message is the same: don’t assume one size fits all.

For elderly-targeted drugs, the FDA now says: include people 60 and older - or explain why you didn’t. That’s a big shift. You can’t just say “we used young adults because it’s easier.” You have to justify it with data.

The Real Problem: Small Studies and False Signals

Here’s where things get tricky. Many bioequivalence studies still use small groups - 12 to 14 people. That’s the minimum allowed by the EMA. But small samples are dangerous when you’re looking at sex differences.

A 2018 study showed something startling. In a trial with only 14 participants, one group of men showed a 79% difference in drug absorption compared to the reference product - enough to call it “not bioequivalent.” But when the same study was repeated with 36 participants, the result flipped. The difference vanished. Why? In small groups, one or two outliers can skew everything. A man with unusually fast metabolism? A woman with unusually slow absorption? Those anomalies look like real differences. But they’re just noise.

Larger studies - 24 to 36 people - smooth out those spikes. They give you a clearer picture. And when you stratify by sex - meaning you analyze male and female data separately - you can spot real patterns. Not artifacts.

The FDA now recommends this approach: enroll enough people to detect true differences, then split the analysis by sex. If a drug behaves differently in men versus women, you need to know. Not because it’s politically correct - because it’s safer.

Why Women Are Still Underrepresented

Despite the rules, women are still underrepresented. Between 2015 and 2020, only 38% of generic drug studies hit the 40-60% female range. The median? Just 32%. That’s not close to equal.

Why? Recruitment is harder. Women are more likely to have caregiving responsibilities. They’re more likely to be turned away due to pregnancy concerns - even if they’re on birth control. Many clinical trial sites still don’t offer flexible hours or childcare. And let’s be honest: some sponsors still think “men are cheaper and easier.”

But the cost of ignoring this isn’t just regulatory. It’s clinical. Women report more side effects from generic drugs than men. Not because they’re more sensitive - but because the doses were never tested on them. A 2023 University of Toronto study found that 37% of commonly tested drugs are cleared 15-22% faster in men. That means a dose that works for a man might be too low for a woman. Or worse - a dose that’s safe for a man might be toxic for a woman if she metabolizes it slower.

What Sponsors and Researchers Should Do Now

If you’re designing a bioequivalence study, here’s what you need to do:

• Match your population to your target users. If the drug is mostly taken by women over 60, your study should reflect that. Don’t use young men as proxies.
• Enroll at least 24 participants. 36 is better. Small studies don’t cut it anymore, especially if you’re looking at subgroups.
• Split your analysis by sex. Don’t just report overall results. Show the data for men and women separately. Look for differences.
• Include older adults if relevant. If the drug treats osteoporosis, hypertension, or diabetes - conditions common in older people - include participants 60+.
• Document everything. Regulators will ask: Why did you choose this group? Why not include women? Why not include older adults? Have your answers ready.

The Future Is Inclusive - And It’s Already Here

The era of testing drugs only on young men is ending. The FDA’s 2023 draft guidance is the clearest signal yet: diversity isn’t optional. It’s part of the science.

Some companies are already adapting. A 2022 survey found 68% of contract research organizations now actively recruit women. They’re offering evening appointments, transportation help, and better communication. They’re tracking sex-specific pharmacokinetics - not just as a formality, but as a core part of their analysis.

The next step? Sex-specific bioequivalence criteria for drugs with narrow therapeutic windows - like warfarin or digoxin. These drugs have very little room for error. A small difference in absorption can mean a stroke or a heart attack. If women absorb them differently, we need to know - and adjust.

This isn’t about politics. It’s about accuracy. It’s about safety. It’s about making sure that when someone picks up a generic pill, they get the same benefit - no matter their age, gender, or body type.

What This Means for Patients

You don’t need to understand pharmacokinetics to benefit from this change. But you should know this: the generic drug you take was likely tested on people who look more like you than ever before. That’s not a guarantee - but it’s progress.

If you’re a woman, older adult, or someone who’s noticed your medication doesn’t work the same as it did for someone else - your experience matters. Regulators are finally listening. And that’s the real win.