Guidance Breakdown: Inclusion of Pregnant and Breastfeeding Women in Clinical Trials (E21 Draft)
A new draft has sponsors expected to plan pregnancy and lactation data collection from the start—not as an afterthought.
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The ICH just released a draft version of its long-anticipated guideline E21, Inclusion of Pregnant and Breastfeeding Women in Clinical Trials. Once finalized, this guidance will represent the FDA’s current thinking (along with other ICH regulatory agencies) on how and when to collect clinical data in these historically overlooked populations.
The central theme is straightforward: if a product is likely to be used by pregnant or lactating women post-approval, data collection shouldn’t wait until that day arrives. Instead, sponsors should proactively plan studies across all stages of development—before and after marketing—to make sure drug labeling reflects safe, evidence-based use in these populations.
The guidance also provides a framework for transitioning from mandatory contraception requirements to planned inclusion as evidence accumulates, with specific considerations for unintended pregnancies that occur during trials with contraception requirements.
Comments are open on the draft until October 21, 2025, on docket number FDA-2025-D-1797.
We’ve distilled the key points below.
Why this guidance now?
Pregnant and breastfeeding women have routinely been excluded from clinical trials, often removed the moment pregnancy is detected. The result? Sparse or nonexistent labeling information—forcing patients and providers to make high-stakes treatment decisions with little or no human data to go on.
The consequences are well documented. Women may be denied beneficial treatment or receive subtherapeutic doses. Some stop breastfeeding unnecessarily. Others are prescribed therapies with unknown fetal or infant risks.
These gaps are precisely what E21 aims to address by shifting the default from exclusion to informed inclusion.
Who’s covered—and what’s expected?
E21 applies to investigational products where women of childbearing potential are among the anticipated user population, with particular importance for conditions with high unmet medical need during pregnancy or breastfeeding.
That includes small molecules, biologics, vaccines, and gene or cell therapies. If a product may be used by someone who is pregnant or breastfeeding, the guidance encourages sponsors to consider collecting data—either through direct enrollment or structured follow-up.
Importantly, this includes both premarket and postmarketing phases. Inclusion isn’t limited to formal clinical trials. Pregnancy exposure registries, real-world evidence, and structured safety monitoring all count toward building an evidence base.
For pregnant women in clinical trials
One of the guidance’s clearest messages is that pregnancy data shouldn’t be an afterthought. Sponsors should plan for inclusion as early as possible, especially when treatment during pregnancy is likely or unavoidable.
In some cases, early pregnancy enrollment may be urgent. This includes life-threatening maternal or fetal conditions, unmet medical need, or public health emergencies. The guidance points out that deferring pregnancy studies is no longer sufficient without a strong scientific or ethical rationale.
Before enrollment, sponsors are expected to build a “weight-of-evidence” case that supports the benefit-risk balance.
That weight-of-evidence framework should include:
Nonclinical reproductive tox data
Pharmacology and PK/PD data
Gestational timing of drug exposure
Product novelty
And any known or predicted risks
This requires "an integrated assessment" and "systematic expansion of data collection across relevant sources and patient populations, guided by data-driven decisions to safeguard study participants.
From a design standpoint, E21 encourages interventional trials but leaves room for observational designs. Sample sizes should anticipate possible withdrawals. Even small studies can generate valuable pharmacokinetic (PK) data, especially across trimesters, where drug metabolism and distribution may vary.
Sponsors are encouraged to consider physiologically based pharmacokinetic (PBPK) modeling when appropriate.
For breastfeeding women in clinical trials
Lactation inclusion is also addressed head-on. Sponsors should plan how to gather data on drug exposure through breast milk, infant systemic absorption, and potential clinical effects—both beneficial and harmful.
E21 establishes a systematic three-step approach for breastfeeding data collection.
First, sponsors should determine the concentration of investigational product in breastmilk relative to maternal therapeutic blood levels.
Second, they should use breastmilk concentration data to estimate the daily infant dose and relative infant dose.