Why Science? | ICH E21 Pregnant and Breastfeeding Individuals in Clinical Trials

The ICH Assembly endorsed the E21 technical document at Steps 2a and 2b in June 2025. Regional consultation followed, and the document remained in the Step 3 phase when checked on 27 October 2026. Its recommendations are therefore a current consensus draft for consultation rather than an implemented Step 4 harmonised guideline.

The human biology in e21 is a step 3 draft comes with an ethical duty to learn carefully. The ICH Assembly endorsed the E21 technical document at Steps 2a and 2b in June 2025. Regional consultation followed, and the document remained in the Step 3 phase when checked on 27 October 2026. Its recommendations are therefore a current consensus draft for consultation rather than an implemented Step 4 harmonised guideline. Keep this boundary visible: E21 remained a Step 3 draft on 27 October 2026.

A strong science note separates observation from interpretation. Map e21 is a step 3 draft across participant, fetus or infant, medicine exposure, disease exposure and decision point. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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When pregnant or breastfeeding people are routinely excluded, product information may lack data on dose, effectiveness, maternal outcomes, fetal outcomes, milk transfer and infant effects. Clinicians must still treat serious conditions. Responsible inclusion asks when direct evidence can reduce that uncertainty with acceptable safeguards.

For exclusion can create its own evidence problem, timing connects exposure to meaning. When pregnant or breastfeeding people are routinely excluded, product information may lack data on dose, effectiveness, maternal outcomes, fetal outcomes, milk transfer and infant effects. Clinicians must still treat serious conditions. Responsible inclusion asks when direct evidence can reduce that uncertainty with acceptable safeguards. Preserve this safeguard: Protection must be proportionate to the actual medicine, disease and participant context.

A strong science note separates observation from interpretation. Ask who is represented in exclusion can create its own evidence problem, who is missing and what consequence follows from that gap. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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The draft encourages sponsors to consider pregnancy and breastfeeding early rather than after pivotal trials are finished. Development plans can identify necessary nonclinical studies, pharmacology information, disease context, formulation issues, monitoring methods and evidence gaps before an eligible participant appears at a study site.

A trustworthy account of early planning changes the whole development programme keeps every person and uncertainty in view. The draft encourages sponsors to consider pregnancy and breastfeeding early rather than after pivotal trials are finished. Development plans can identify necessary nonclinical studies, pharmacology information, disease context, formulation issues, monitoring methods and evidence gaps before an eligible participant appears at a study site. Remember: Maternal, fetal and infant interests overlap but are not interchangeable.

A strong science note separates observation from interpretation. Build the timeline for early planning changes the whole development programme from preconception through treatment, pregnancy, birth, feeding and follow-up. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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Pregnancy can change disease course, treatment need and the consequences of undertreatment. Some conditions threaten the pregnant person, fetus or both; others allow treatment to wait. A sound plan distinguishes background obstetric risk, disease-related risk and treatment-related uncertainty instead of placing every pregnancy into one category.

The human biology in the disease context shapes benefit and risk comes with an ethical duty to learn carefully. Pregnancy can change disease course, treatment need and the consequences of undertreatment. Some conditions threaten the pregnant person, fetus or both; others allow treatment to wait. A sound plan distinguishes background obstetric risk, disease-related risk and treatment-related uncertainty instead of placing every pregnancy into one category. Keep this boundary visible: Observational pregnancy evidence can be affected by selection, timing and incomplete outcome capture.

A strong science note separates observation from interpretation. Separate measured exposure, observed outcome and causal interpretation for the disease context shapes benefit and risk. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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Reproductive and developmental toxicity studies under ICH S5(R3), mechanism information and animal exposure can identify hazards and guide monitoring. Species differences, dose relationships and uncertain human relevance limit direct translation. Nonclinical findings inform the clinical plan but do not automatically prove either safety or harm in people.

For nonclinical evidence is one bridge, not the whole answer, timing connects exposure to meaning. Reproductive and developmental toxicity studies under ICH S5(R3), mechanism information and animal exposure can identify hazards and guide monitoring. Species differences, dose relationships and uncertain human relevance limit direct translation. Nonclinical findings inform the clinical plan but do not automatically prove either safety or harm in people. Preserve this safeguard: E21 remained a Step 3 draft on 27 October 2026.

A strong science note separates observation from interpretation. Map nonclinical evidence is one bridge, not the whole answer across participant, fetus or infant, medicine exposure, disease exposure and decision point. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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A protocol should state whether pregnant or breastfeeding individuals may enrol, continue treatment after pregnancy, or enter a dedicated study. Criteria need scientific reasons tied to the medicine, condition, trial phase and available data. A blanket rule based only on reproductive potential can exclude people without improving the evidence.

A trustworthy account of eligibility criteria should match the actual question keeps every person and uncertainty in view. A protocol should state whether pregnant or breastfeeding individuals may enrol, continue treatment after pregnancy, or enter a dedicated study. Criteria need scientific reasons tied to the medicine, condition, trial phase and available data. A blanket rule based only on reproductive potential can exclude people without improving the evidence. Remember: Protection must be proportionate to the actual medicine, disease and participant context.

A strong science note separates observation from interpretation. Ask who is represented in eligibility criteria should match the actual question, who is missing and what consequence follows from that gap. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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Requirements for contraception and pregnancy testing should follow the medicine’s reproductive risk, pharmacokinetics, treatment duration and trial procedures. The plan should respect autonomy, privacy, feasibility and local practice. Tests and counselling must be described clearly, while incidental or uncertain results need an appropriate response route.

The human biology in contraception and pregnancy testing need proportionate logic comes with an ethical duty to learn carefully. Requirements for contraception and pregnancy testing should follow the medicine’s reproductive risk, pharmacokinetics, treatment duration and trial procedures. The plan should respect autonomy, privacy, feasibility and local practice. Tests and counselling must be described clearly, while incidental or uncertain results need an appropriate response route. Keep this boundary visible: Maternal, fetal and infant interests overlap but are not interchangeable.

A strong science note separates observation from interpretation. Build the timeline for contraception and pregnancy testing need proportionate logic from preconception through treatment, pregnancy, birth, feeding and follow-up. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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When pregnancy occurs, the protocol should define immediate safety review, treatment decisions, unblinding rules, consent for follow-up and data collection. Automatic discontinuation may remove beneficial treatment or make outcomes harder to interpret. Continuing or stopping should be a clinical, participant-centred decision supported by the protocol and emerging evidence.

For pregnancy during a trial should have a planned pathway, timing connects exposure to meaning. When pregnancy occurs, the protocol should define immediate safety review, treatment decisions, unblinding rules, consent for follow-up and data collection. Automatic discontinuation may remove beneficial treatment or make outcomes harder to interpret. Continuing or stopping should be a clinical, participant-centred decision supported by the protocol and emerging evidence. Preserve this safeguard: Observational pregnancy evidence can be affected by selection, timing and incomplete outcome capture.

A strong science note separates observation from interpretation. Separate measured exposure, observed outcome and causal interpretation for pregnancy during a trial should have a planned pathway. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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A medicine taken for the pregnant person can create fetal exposure through the placenta, while untreated disease may also cause fetal harm. Benefit-risk assessment should keep both pathways visible. Dose, gestational timing, duration and organ-development windows matter, so a single exposure label can hide biologically different situations.

A trustworthy account of treatment for maternal benefit may also affect the fetus keeps every person and uncertainty in view. A medicine taken for the pregnant person can create fetal exposure through the placenta, while untreated disease may also cause fetal harm. Benefit-risk assessment should keep both pathways visible. Dose, gestational timing, duration and organ-development windows matter, so a single exposure label can hide biologically different situations. Remember: E21 remained a Step 3 draft on 27 October 2026.

A strong science note separates observation from interpretation. Map treatment for maternal benefit may also affect the fetus across participant, fetus or infant, medicine exposure, disease exposure and decision point. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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Some interventions are used during pregnancy to benefit the fetus as well as, or instead of, the pregnant person. That purpose changes endpoints, consent discussion, monitoring and follow-up. The research plan should describe whose outcome is being improved and how competing maternal and fetal considerations will be handled.

The human biology in a treatment may be intended for fetal benefit comes with an ethical duty to learn carefully. Some interventions are used during pregnancy to benefit the fetus as well as, or instead of, the pregnant person. That purpose changes endpoints, consent discussion, monitoring and follow-up. The research plan should describe whose outcome is being improved and how competing maternal and fetal considerations will be handled. Keep this boundary visible: Protection must be proportionate to the actual medicine, disease and participant context.

A strong science note separates observation from interpretation. Ask who is represented in a treatment may be intended for fetal benefit, who is missing and what consequence follows from that gap. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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Physiological changes can alter plasma volume, protein binding, kidney filtration, hepatic metabolism and absorption. Drug exposure in pregnancy may therefore differ from exposure outside pregnancy. Sampling schedules and models should be practical, sparse where appropriate and connected to a meaningful dose question rather than collecting burdensome measurements without a decision use.

For pregnancy pharmacokinetics may differ, timing connects exposure to meaning. Physiological changes can alter plasma volume, protein binding, kidney filtration, hepatic metabolism and absorption. Drug exposure in pregnancy may therefore differ from exposure outside pregnancy. Sampling schedules and models should be practical, sparse where appropriate and connected to a meaningful dose question rather than collecting burdensome measurements without a decision use. Preserve this safeguard: Maternal, fetal and infant interests overlap but are not interchangeable.

A strong science note separates observation from interpretation. Build the timeline for pregnancy pharmacokinetics may differ from preconception through treatment, pregnancy, birth, feeding and follow-up. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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A breastfeeding study may measure the medicine and relevant metabolites in human milk, maternal plasma and, when justified, infant samples. Paired mother–infant information can help estimate transfer and infant exposure. Timing relative to dose, milk sampling completeness, feeding pattern and infant age are essential for interpretation.

A trustworthy account of lactation studies connect milk concentration to infant exposure keeps every person and uncertainty in view. A breastfeeding study may measure the medicine and relevant metabolites in human milk, maternal plasma and, when justified, infant samples. Paired mother–infant information can help estimate transfer and infant exposure. Timing relative to dose, milk sampling completeness, feeding pattern and infant age are essential for interpretation. Remember: Observational pregnancy evidence can be affected by selection, timing and incomplete outcome capture.

A strong science note separates observation from interpretation. Separate measured exposure, observed outcome and causal interpretation for lactation studies connect milk concentration to infant exposure. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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Finding a substance in milk establishes a route of exposure but not the absorbed infant dose or clinical consequence. Infant gastrointestinal absorption, metabolism, prematurity, health status and cumulative feeding matter. Conversely, a low average concentration can miss peak exposure or a susceptible infant, so uncertainty must remain visible.

The human biology in milk transfer is not the same as infant effect comes with an ethical duty to learn carefully. Finding a substance in milk establishes a route of exposure but not the absorbed infant dose or clinical consequence. Infant gastrointestinal absorption, metabolism, prematurity, health status and cumulative feeding matter. Conversely, a low average concentration can miss peak exposure or a susceptible infant, so uncertainty must remain visible. Keep this boundary visible: E21 remained a Step 3 draft on 27 October 2026.

A strong science note separates observation from interpretation. Map milk transfer is not the same as infant effect across participant, fetus or infant, medicine exposure, disease exposure and decision point. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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Maternal, pregnancy, birth, neonatal and infant outcomes unfold on different timelines. The study should predefine what is collected, for how long and from which sources. Longer follow-up may be important for developmental outcomes, but it also raises attrition, consent, linkage and interpretation challenges that need realistic plans.

For follow-up should fit plausible outcomes, timing connects exposure to meaning. Maternal, pregnancy, birth, neonatal and infant outcomes unfold on different timelines. The study should predefine what is collected, for how long and from which sources. Longer follow-up may be important for developmental outcomes, but it also raises attrition, consent, linkage and interpretation challenges that need realistic plans. Preserve this safeguard: Protection must be proportionate to the actual medicine, disease and participant context.

A strong science note separates observation from interpretation. Ask who is represented in follow-up should fit plausible outcomes, who is missing and what consequence follows from that gap. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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Useful analysis may connect the pregnant participant, pregnancy, fetus or infant and relevant clinical events. Identifiers and dates must support linkage while privacy and access are controlled. The record should distinguish one pregnancy with multiple offspring and avoid double-counting events reported by several clinicians or systems.

A trustworthy account of safety reporting needs linked records without losing privacy keeps every person and uncertainty in view. Useful analysis may connect the pregnant participant, pregnancy, fetus or infant and relevant clinical events. Identifiers and dates must support linkage while privacy and access are controlled. The record should distinguish one pregnancy with multiple offspring and avoid double-counting events reported by several clinicians or systems. Remember: Maternal, fetal and infant interests overlap but are not interchangeable.

A strong science note separates observation from interpretation. Build the timeline for safety reporting needs linked records without losing privacy from preconception through treatment, pregnancy, birth, feeding and follow-up. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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Pregnancy registries, health records, claims and pharmacovigilance reports can add evidence after approval, especially for uncommon outcomes. Their usefulness depends on exposed and comparison groups, timing, outcome validation, confounding, missing early losses and selection into the data source. Large datasets do not remove these design problems.

The human biology in postmarketing and real-world data can extend the picture comes with an ethical duty to learn carefully. Pregnancy registries, health records, claims and pharmacovigilance reports can add evidence after approval, especially for uncommon outcomes. Their usefulness depends on exposed and comparison groups, timing, outcome validation, confounding, missing early losses and selection into the data source. Large datasets do not remove these design problems. Keep this boundary visible: Observational pregnancy evidence can be affected by selection, timing and incomplete outcome capture.

A strong science note separates observation from interpretation. Separate measured exposure, observed outcome and causal interpretation for postmarketing and real-world data can extend the picture. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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The receipt records the ICH draft status, disease and treatment context, inclusion rationale, nonclinical bridge, reproductive-risk information, eligibility, contraception and testing plan, pregnancy pathway, lactation design, mother–infant linkage, endpoints, follow-up, safety review, real-world sources, consent, privacy, findings and remaining uncertainty.

For a complete e21 receipt preserves decisions and uncertainty, timing connects exposure to meaning. The receipt records the ICH draft status, disease and treatment context, inclusion rationale, nonclinical bridge, reproductive-risk information, eligibility, contraception and testing plan, pregnancy pathway, lactation design, mother–infant linkage, endpoints, follow-up, safety review, real-world sources, consent, privacy, findings and remaining uncertainty. Preserve this safeguard: E21 remained a Step 3 draft on 27 October 2026.

A strong science note separates observation from interpretation. Map a complete e21 receipt preserves decisions and uncertainty across participant, fetus or infant, medicine exposure, disease exposure and decision point. Record the source, version or date, population or device context, method, result and one uncertainty. If the official record does not show a field, write “not shown” instead of filling the gap from memory.

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