Breaking Down FDA’s E21 Draft Guidance: Including Pregnant and Breastfeeding Women in Clinical Trials with Regina Atim

What It Covers

Pharmacist and maternal health expert Regina Atim examines FDA's July 2025 E21 draft guidance, which establishes a framework for proactively including pregnant and breastfeeding women in clinical trials, addressing decades of exclusion rooted in the thalidomide and DES disasters of the mid-twentieth century.

Key Questions Answered

• •Historical exclusion drivers: Two catastrophic drug events — thalidomide (1957–1961), prescribed for morning sickness and causing birth defects, and DES (1940s–1970s), linked to vaginal cancers and reproductive abnormalities in offspring — established the 1964 Helsinki Declaration protections that defaulted sponsors and IRBs toward excluding pregnant women from all subsequent clinical research.
• •Pregnancy ADME changes: Drug absorption, distribution, metabolism, and excretion differ significantly from non-pregnant adults, vary by trimester, and may not normalize until six to twelve months postpartum. Without pregnancy-specific data, clinicians extrapolate adult doses, risking either dangerous accumulation or underdosing — the latter carrying consequences like spina bifida from untreated fever.
• •E21 early engagement strategy: Sponsors should initiate Type C or INTERACT meetings with FDA before IND submission to agree on inclusion triggers, pharmacokinetic parameters, required specialists such as maternal-fetal medicine, IRB safety criteria, lactation strategy, and post-marketing commitments — converting regulatory compliance into a collaborative, derisking partnership rather than a reactive submission process.
• •Real-world evidence gap: Systematic collection of real-world data from pregnant patients taking existing drugs would resolve many current safety debates. The ongoing acetaminophen controversy — despite seventy years of use and its 1960s adoption in pregnancy — exists precisely because structured observational data was never collected, leaving only empirical clinical experience rather than documented evidence.
• •Sponsor competitive advantage: Including pregnant and breastfeeding women early in clinical development enables early signal detection, more informative labeling with trimester-specific dosing, and smoother FDA review cycles. Sponsors who proactively disclose safety signals avoid regulatory restrictions that apply when agencies determine a sponsor "should have known" — making inclusion a risk management strategy, not just an ethical obligation.