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The FDA Group’s Nick Capman sat down with Regina Atim, PharmD—a pharmacist and maternal/perinatal health advocate who works with biopharma on inspection readiness, human factors, and post-market studies—for a deep dive into FDA/ICH’s E21 draft guidance on including pregnant and breastfeeding women in clinical trials.
With recent controversy over the safety of acetaminophen (Tylenol) use in pregnancy highlighting just how limited the data really is, this episode is especially timely.
Regina explains why exclusion became the default, how physiologic changes in pregnancy break our dosing assumptions, and how E21 provides a practical, ethical roadmap for building the evidence base clinicians and patients urgently need.
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Regina’s key takeaways and recommendations
If you’re short on time, here are standout insights from this episode—paired with the specific E21 elements and Regina’s experience.
How we got here (and why it’s changing). Default exclusion stems from historical tragedies (e.g., thalidomide, DES) and the ethics framework of the Declaration of Helsinki, which led sponsors/IRBs to over-protect by excluding pregnant people rather than designing safer inclusion.
Pregnancy changes ADME—and dosing. Absorption, distribution, metabolism, and elimination shift by trimester; normalization can take 6–12 months postpartum. Doses may need to increase if clearance rises or decrease if accumulation occurs—assumptions from non-pregnant adults rarely hold.
Extrapolation isn’t enough. In practice, clinicians often extrapolate from adult dosing or compound in-house for pediatrics and maternal patients. It’s an approach Regina calls error-prone when physiologic changes aren’t characterized.
Don’t swap in the “wrong” alternatives. Avoid knee-jerk substitutions (e.g., certain NSAIDs) that may carry pregnancy risks. Involve physicians and pharmacists who understand drug metabolism and maternal safety trade-offs.
When participants become pregnant in a trial, don’t auto-withdraw. E21 supports risk-based continuation and monitoring (rather than immediate discontinuation) and early planning for if/when to include breastfeeding women—after exposure characteristics are understood.
Plan lactation evidence in steps. E21 lays out a sequence:
(1) determine drug concentration in breast milk,
(2) estimate daily infant dose/relative infant dose,
(3) collect infant exposure/safety/benefit data—using maternal-only milk studies first, then mother-infant (paired) studies when justified.
Use modeling and nonclinical data. E21 encourages PBPK modeling, PPND/juvenile tox, and other assays to anticipate milk transfer and infant exposure, then confirm with targeted clinical pharmacology and lactation studies.
Design for breastfeeding inclusion. Once milk transfer/infant absorption are characterized (or potential infant benefit outweighs risk), trials may enroll breastfeeding women with protocols that minimize infant risk, allow breastfeeding when exposure is not clinically meaningful, and keep participant burden manageable.
Engage FDA early—define triggers. Regina recommends INTERACT/Type C meetings to agree on inclusion triggers, maternal-fetal expertise, and PK parameters up front, so inclusion can proceed safely and predictably.
Measure success pragmatically. Track the number of drugs with pregnancy/breastfeeding data or indications and the migration of long-used products (e.g., acetaminophen) from “empirically used” toward concrete, prospectively collected evidence via the E21 framework.
What E21 actually says (and how to use it)
Here’s a quick distillation (but please read it cover to cover):
Evidence-generation strategy for breastfeeding: Plan early: quantify breast-milk concentrations, estimate infant dose/relative infant dose, and collect infant exposure/safety/benefit data to inform treatment and labeling. E21 highlights maternal-only milk studies (pump-and-discard) as prerequisites for later mother-infant studies.
Maternal-only milk studies (no infant exposure): Short clinical pharmacology studies in breastfeeding patients—or, when necessary, healthy volunteers—who interrupt or stop breastfeeding until the drug clears. These data model likely infant exposure and inform whether/when to progress.
Mother-infant (paired) studies (with infant exposure): When justified by nonclinical/milk data (and modeling), assess milk and infant plasma to evaluate short-/long-term implications; opportunistic designs are acceptable when mothers continue clinically indicated therapy.
Inclusion of breastfeeding women in efficacy trials: Permissible when infant exposure is not clinically meaningful—or when potential infant benefit outweighs risk—with designs that minimize infant risk and explicitly plan data collection burden.
Early planning matters: E21 urges sponsors to anticipate if/when to include breastfeeding women, consider physicochemical properties and entry mechanisms into milk, and close knowledge gaps as early as possible in development.
Practical steps Regina wants teams to take now
Stand up a pregnancy & lactation plan at inception. Don’t wait for Phase 3—map trimester-specific PK/PD questions, postpartum normalization windows, and the lactation evidence sequence (milk concentration → relative infant dose → infant exposure/safety).
Pre-agree with FDA on inclusion triggers. Use Type C/INTERACT to codify when to continue participants who become pregnant and when to enroll breastfeeding women (after exposure is characterized), and to specify maternal-fetal expertise on your governance team.
Design trials that fit real life. Build recruitment/retention through OB networks and ensure visit schedules and milk-sampling plans don’t over-burden participants—E21 explicitly calls for manageable burden.
Leverage modeling & nonclinical to move faster. Combine PBPK with PPND/juvenile tox and pediatric data (if available) to justify earlier breastfeeding inclusion and to size post-partum studies efficiently.
Tighten clinical decision-support now. Until more data exists, ensure clinicians consult both physicians and pharmacists to avoid unsafe substitutions (e.g., certain NSAIDs) and to tailor dosing to maternal pharmacology.
One thing to bring back to your team
Create a one-page E21 “Inclusion Playbook” for your program:
Continuation criteria if a participant becomes pregnant (risk-based, with MFM oversight).
Breastfeeding evidence plan staged per E21: milk concentration → relative infant dose → paired mother-infant safety.
FDA engagement plan (INTERACT/Type C): inclusion triggers, PK parameters, governance team.
Participant burden check: sampling schedule, pump-and-discard windows, postpartum timing.
Regina Atim, PharmD is a pharmacist and maternal/perinatal health advocate whose career spans clinical practice, regulatory, and industry leadership. She advises biopharma on regulatory strategy—including inspection readiness, human factors engineering, and post-market studies—and founded a maternal-health company developing technology to detect pregnancy-acquired cardiovascular disease to reduce morbidity and mortality.
Connect with her on LinkedIn here.
Read E21 (draft) here and use it as your template for safe, ethical, scientifically sound inclusion of pregnant and breastfeeding women in development programs.
Is your organization ready for E21?
The FDA Group can help you design, resource, and execute compliant inclusion strategies for pregnant and breastfeeding women in clinical trials. Sponsors are now expected to move from automatic exclusion to thoughtful, risk-based inclusion of pregnant and breastfeeding women.
This shift will require:
New protocol designs that anticipate when and how to include these populations.
Pharmacokinetic and pharmacodynamic modeling across trimesters and postpartum.
Breast milk concentration and infant exposure studies staged in alignment with regulatory expectations.
Governance teams that include maternal–fetal medicine experts.
FDA engagement (INTERACT, Type C) to define inclusion triggers and risk controls early.
Operational adjustments to ensure participant recruitment, retention, and safety monitoring without undue burden.
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