ICH -E21 (USFDA) Guidance: Including Pregnant and Breastfeeding Women in Clinical Trials

Sharan Murugan
Jul 27
3 min read

In May 2025, the FDA, as part of the International Council for Harmonisation (ICH), endorsed and released for consultation the draft E21 guidance:"Inclusion of Pregnant and Breastfeeding Women in Clinical Trials". This guidance represents a significant step towards improving evidence-based treatment for pregnant and breastfeeding women, who have traditionally been excluded from clinical research.

Background:

Many pregnant or breastfeeding women have medical conditions needing ongoing or new treatments. Yet historically, clinical trials have largely excluded them — either from the start or by withdrawing them if pregnancy occurs. As a result:

Clinicians often have to prescribe drugs without robust data on safety or efficacy in these populations.
Dosing decisions may be based on data from non-pregnant women, ignoring physiological changes during pregnancy or postpartum.
Women may avoid needed treatments or stop breastfeeding prematurely out of concern for unknown drug effects.

The objective is to generate robust clinical data to support evidence-based decisions for the use of medicinal products by pregnant and breastfeeding women and their healthcare providers. The scope covers pre- and postmarketing clinical trials of investigational products, both for general indications and those specific to pregnancy or breastfeeding.

Ethical considerations

Including these populations is ethically supported by the Declaration of Helsinki and ICH principles like those in E6(R3) and E8(R1).Key points:

The risks and benefits must be carefully weighed.
Pregnant or breastfeeding women should not be included without safeguards (e.g., risk mitigation, informed consent).
Institutional Review Boards (IRBs) or Ethics Committees with expertise in these populations should review trial protocols.

Including pregnant women: practical strategies

The guidance offers detailed recommendations, such as:

Develop a data-driven plan early, informed by nonclinical data, PK/PD considerations, and known disease risks.
Include pregnant women in trials once there is sufficient safety data and a favorable benefit-risk profile.
Plan for special assessments, like fetal exposure, pregnancy outcomes, and longer infant follow-up.
Consider whether to remove mandatory contraception requirements in some trials to allow natural inclusion of pregnant participants.
When unexpected pregnancies occur in trials with contraception requirements, evaluate whether the woman can remain in the trial after re-consent.

Including breastfeeding women: practical strategies

The E21 draft guidance encourages:

Early planning for lactation studies to measure investigational product in breast milk.
Understanding infant exposure and potential effects.
Including breastfeeding women in clinical trials when there is low risk or potential benefit to the child.
Designing protocols to minimize burden (e.g., aligning visits with routine care, providing lactation support).
Collecting PK data at different stages of lactation and monitoring infant outcomes.

Study design and data collection

Sponsors are advised to:

Plan sample sizes and endpoints thoughtfully, knowing recruitment may be challenging.
Use pharmacokinetic modeling (e.g., PBPK) to guide dose adjustments.
Collect real-world evidence (RWE) and use postmarketing data, including pregnancy registries.
Include patient input and consult with relevant experts (e.g., obstetricians, neonatologists).

Informed consent and participant support

Special considerations include:

Explaining potential risks and benefits to the woman and fetus/infant.
Allowing flexible study procedures to reduce burden (e.g., home visits, remote monitoring).
Seeking consent for long-term infant follow-up.
Ensuring women who become pregnant during a trial are re-consented appropriately.

Labeling considerations

The guidance also lists data that might be used in labeling, including:

Recommended dosage adjustments during pregnancy or breastfeeding.
Information on fetal exposure, effects on lactation, and potential infant outcomes.
Specific monitoring recommendations for these populations.

For more details, refer to the official documents: