ICH E21: What Pregnant and Breastfeeding Patients and Clinicians Can Reasonably Expect

Overview

Regulators and experts are increasingly arguing that pregnant and breastfeeding people should be considered for inclusion in clinical research rather than automatically excluded. Recent draft guidance and international work on the ICH E21 concept mark a policy shift toward a “principle of inclusion,” but the change is gradual and conditional. This article summarizes what the draft guidance and related evidence mean in practice for patients and clinicians, and it highlights realistic timelines and remaining limits.

What the regulatory documents say — and do not promise

The U.S. Food and Drug Administration has posted the ICH E21 draft as its preferred approach to include or retain pregnant and breastfeeding people in clinical trials; the document emphasizes early planning, benefit–risk assessments, safety monitoring and updating product information when data permit ^[1]. The ICH Step‑2 materials stress the same “principle of inclusion” across pre‑ and postmarketing trials and recommend proactive strategies such as early PK/PD planning, targeted sampling, and ethics/consent approaches that reduce participant burden ^[2]. The European Medicines Agency has opened parallel public consultation, reflecting international momentum ^[3].

Important limitations

• The ICH E21 text was at Step‑2/public consultation in mid‑2025; local regulatory adoption and formal implementation will vary by jurisdiction and can take years ^[2].
• The guidance asks sponsors to “consider” inclusion and to plan early; it is not an immediate mandate to run large randomized pregnancy trials for most products ^[1][2][3].

Why policy change matters — and what the evidence still shows

Multiple expert reports and label reviews document the practical need for better data. A 2024 National Academies report called out legal, ethical and structural barriers that drive exclusion and estimated that only a small fraction of approved medicines had human pregnancy data to guide prescribing between 2010 and 2019 ^[4]. A separate cross‑sectional review of product labeling (2010–2019) found human pregnancy data in about 10–11% of new therapeutics’ labels, with continued reliance on animal data and observational sources ^[6]. These findings underpin the push for policy change but also show how far data gaps persist.

Near‑term tools that will matter to clinicians and patients

Even if trial inclusion increases over time, several complementary strategies will determine how quickly evidence improves for pregnant and breastfeeding people:

• Targeted early PK/PD sampling and opportunistic approaches during standard care can generate human data more quickly than waiting for dedicated trials, a strategy recommended in the ICH materials ^[2].
• Physiologically based pharmacokinetic (PBPK) modeling can help predict pregnancy‑related changes and guide monitoring, but models require human data for validation and cannot fully replace prospective PK/PD studies ^[8][9].
• Postmarketing surveillance and real‑world evidence platforms (for example, FDA’s Sentinel work on pregnancy) will remain essential to detect rare or delayed outcomes not captured in trials, though these systems have limits for long‑term infant follow‑up and very rare congenital outcomes ^[9].

Policy and liability barriers — progress, but not an immediate fix

Implementation work from federal bodies shows incremental progress: past recommendations (for example, removing “pregnant women” as a default “vulnerable population” in some regulations) and PRGLAC follow‑up actions aim to lower procedural hurdles and expand registries and funding ^[5]. The National Academies report also highlighted perceived liability risks as a driver of exclusion and offered recommendations to reduce those barriers; changing practice will therefore require legal, institutional and cultural shifts in addition to new guidance ^[4].

Practical takeaways for patients and clinicians

• Expect incremental improvements rather than immediate, wholesale changes. The ICH E21 draft signals an intent to change norms, but national adoption and visible increases in trial enrollment will take years ^[2][3].
• Where trial data remain absent, clinicians and patients will continue to rely on registries, observational studies, and validated modeling to inform shared decision‑making; ask whether a pregnancy exposure registry or targeted PK study exists for a given drug ^[6][8][9].
• Regulators’ emphasis on early planning means sponsors should justify exclusions in protocols; clinicians and patient advocates can use this expectation when discussing trial access and design with study teams or institutional review boards ^[1][2][5].

What remains uncertain

Key uncertainties include the pace of national implementation of E21 principles, how consistently sponsors will apply inclusion planning across therapeutic areas, and how well postmarket systems will capture long‑term infant outcomes. Quantitative estimates of how quickly human pregnancy data will increase are not available; published label reviews cover products through 2019 and do not fully capture more recent postmarket work ^[6]. PBPK and RWE strengthen evidence but do not eliminate the need for prospective human data ^[8][9].

Bottom line

ICH E21 and related regulatory activity represent an important shift from reflexive exclusion toward planned inclusion. For patients and clinicians, this should translate into more deliberate trial planning, expanded registries, and better use of modeling and real‑world data over the coming years — but not an immediate flood of randomized pregnancy trials or instant labeling fixes. Clear, realistic expectations and continued investment in registries, targeted PK studies, and postmarket surveillance will determine whether this policy momentum becomes measurable improvements in care.