A sponsor designs a multi-site clinical trial intended for regulatory submission in Switzerland, the EU, and the United States. The protocol includes pregnant participants. The regulatory requirements across the three jurisdictions sound similar: benefit-risk assessment, ethics committee review, informed consent, safety monitoring, liability coverage. They are not similar in the ways that matter. The points of divergence create risks that a single-jurisdiction analysis cannot identify and that the assumption of harmonization may obscure until the divergence produces a consequence the sponsor did not anticipate.
1. The Illusion of Convergence
All three jurisdictions are ICH members. All three are moving toward inclusion of pregnant participants in clinical trials. All three are expected to adopt ICH E21 once it is finalized, which is anticipated in Q1 2028.1ICH, ‘E21 Guideline on Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials’ (Draft, Step 2, endorsed 14 May 2025). Finalization anticipated Q1 2028. The convergence narrative is appealing: a single international guideline producing a harmonized approach across the three regulatory systems this series examines. The narrative is also incomplete. Beneath the shared policy direction, the three regulatory systems diverge on questions that determine whether a protocol can actually enroll pregnant participants: what ethics committees require, how liability is allocated, whether insurance is available, what constitutes adequate consent, and what happens when an adverse event occurs. These are not peripheral implementation details. For many sponsors, they are the factors that decide whether a protocol can move from scientific justification to actual enrollment.
A sponsor who designs a single global protocol on the assumption that ICH E21 harmonization will resolve cross-border complexity may discover (at the ethics committee stage, the insurance procurement stage, or the adverse event stage) that the guideline leaves open the jurisdictional differences that matter most. The underlying evidence gap is shared across jurisdictions: one analysis estimates that, when a drug’s safety in pregnancy is unknown at the time of regulatory approval, an average of 27 years passes before sufficient evidence emerges to rate that safety with confidence.2MP Adam, JE Polifka and JM Friedman (2011) 157C Am J Med Genet C 175, cited in G Guglielmi (2026) 650 Nature 286: 27-year evidence-latency estimate. The regulatory mechanisms for closing it are not shared.
2. Similar Words, Different Machinery
The Swiss Humanforschungsgesetz (HFG) establishes additional conditions for research involving pregnant women under Art. 26 HFG, implemented through the Verordnung über klinische Versuche mit Ausnahme klinischer Versuche mit Medizinprodukten (KlinV).3Art. 26 HFG (SR 810.30); Art. 19 KlinV (SR 810.305), as amended 7 June 2024, in force since 1 November 2024. The EU Clinical Trials Regulation (CTR) sets pregnancy-specific conditions in Art. 33 CTR, supplementing the general conditions of Art. 28 CTR.4Regulation (EU) No 536/2014 [2014] OJ L158/1 (CTR), Art. 33, supplementing Art. 28. The US framework operates through 45 CFR 46, Subpart B, providing additional protections for pregnant women, human fetuses, and neonates.545 CFR 46, Subpart B (Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research). All three frameworks sound protective. The word “protective” performs different work in each.
Swiss law works through cantonal ethics committees, and neither the HFG nor the KlinV defines the expertise a committee needs to review a pregnancy trial, an ambiguity covered in the article on Swiss trials with pregnant participants. EU law works through a Part I and Part II assessment in CTIS, in which the reporting Member State coordinates the scientific assessment but each concerned Member State carries out the ethical assessment independently, and this produces the variation described in the article on EU trials with pregnant participants. US law works through IRBs, each independent within its own institution, that apply the “minimal risk” threshold with no working definition for fetal exposure, inside a dual FDA and HHS structure in which guidance recommends compliance with provisions that would not otherwise apply; the article on FDA-regulated trials with pregnant participants takes that structure apart.
Because the review bodies differ, a protocol approved under one framework may meet objections under another even where the science and the risk profile are the same: each body brings its own expectations to the same regulatory concept. A benefit-risk assessment that satisfies a Swiss cantonal ethics committee may not satisfy an Italian Part II assessment, which may not satisfy a US IRB applying Subpart B’s prospect-of-direct-benefit analysis. A sponsor is unlikely to resolve this through protocol design alone. The resolution depends on engagement with each jurisdiction’s decision-makers, whose criteria are not publicly harmonized and may not be internally consistent.
3. One Protocol, Three Consent Standards
The informed consent requirements for pregnant participants diverge across jurisdictions in ways that a global consent form template may not accommodate. Swiss law introduced electronic consent for clinical trials through Art. 7c KlinV, effective since 1 November 2024, a procedural modernization that no other jurisdiction has implemented in the same form for pregnancy trials.6Art. 7c KlinV (n 3) (electronic consent), in force since 1 November 2024. Art. 29 CTR governs informed consent generally; Art. 33 CTR’s pregnancy-specific conditions apply alongside but do not themselves modify the consent regime. Implementation is subject to Member State-level institutional expectations that may add requirements beyond the regulation’s text. The US framework introduces the Subpart B requirement for biological father consent in specified circumstances, a provision that has no equivalent in either Swiss or EU law and that interacts with evolving reproductive rights jurisprudence across US states in ways the regulation does not address.745 CFR § 46.204(e); for detail, see the article on FDA-regulated trials with pregnant participants.
Beyond the formal requirements, the underlying conception of the pregnant participant’s autonomy (balanced against fetal interests, partner consent requirements, and institutional oversight expectations) differs across jurisdictions in ways that affect protocol design, site selection, and the legal defensibility of the consent obtained. A consent document that satisfies Swiss requirements may omit provisions the US framework expects. A consent document that satisfies Subpart B’s father-consent provision may include elements that have no legal basis under EU or Swiss law and whose inclusion could create confusion about the participant’s rights in those jurisdictions. Whether a consent obtained under one jurisdiction’s standards satisfies another’s requirements is a question the regulatory frameworks do not coordinate; a sponsor operating across all three would typically need to resolve it through document design, site-level adaptation, and legal analysis that the consent form itself is unlikely to contain.
4. Liability and Insurance: The Unharmonized Risk
On liability, the three jurisdictions differ in a way ICH E21 cannot resolve. In Switzerland, liability follows the HFG regime, with mandatory insurance and a burden-of-proof debate that remains pending before the BAG (Federal Office of Public Health).8Art. 19–20 HFG; BAG, ‘Evaluation of Liability Regulation in the Swiss Human Research Act’ (asim, University Hospital Basel, 2015; updated 2018). See the section on liability and insurance in the article on Swiss trials with pregnant participants. In the EU, Art. 76 CTR leaves compensation to twenty-seven national regimes that approach causation, burden of proof, and damage calculation differently.9Art. 76 CTR (n 4); see the section on liability across the Member States in the article on EU trials with pregnant participants. The United States has no federal compensation scheme; liability there runs through state tort law, jury determination, and the learned intermediary doctrine. The Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) recommended in 2018 reducing liability barriers, with the Vaccine Injury Compensation Program invoked as a model; that recommendation remains unimplemented.10PRGLAC, ‘Report to the Secretary of Health and Human Services’ (September 2018), Recommendation 7; see the section on compensation in the article on FDA-regulated trials with pregnant participants.
A clinical trial agreement governing a multi-jurisdictional pregnancy trial would typically need to allocate risks whose magnitude depends on which jurisdiction’s law applies to a particular claim, a determination that may itself be contested. Insurance cover would have to account for actuarial uncertainty that differs by jurisdiction: an insurer comfortable with Swiss liability law may balk at the US litigation environment, and an insurer willing to cover EU trials may require exclusions for particular Member States whose liability regimes carry a higher risk of claims. The contractual allocation cannot override the applicable mandatory liability regime; it can only attempt to distribute the financial consequences of a regime the parties cannot control. The interaction between the clinical trial agreement’s governing law clause and the mandatory application of local liability regimes (the overriding mandatory provisions, or lois de police, that apply irrespective of the law the parties choose) creates a tension that standard choice-of-law provisions may not resolve, particularly where an adverse fetal or neonatal outcome gives rise to claims in multiple jurisdictions simultaneously.
5. Three Frameworks, One Adverse Event
When an adverse event occurs in a pregnancy trial running across all three jurisdictions, the reporting obligations diverge in timeline, format, institutional recipient, and the definition of what constitutes a reportable event. Swiss safety reporting under the KlinV requires notification to Swissmedic. EU reporting of suspected unexpected serious adverse reactions (SUSARs) proceeds via EudraVigilance under Art. 42 CTR, with annual safety reporting under Art. 43 CTR and Member State cooperation in safety assessment governed by Implementing Regulation (EU) 2022/20.11Art. 42–43 CTR (n 4); Commission Implementing Regulation (EU) 2022/20 of 7 January 2022 [2022] OJ L5/14. US Investigational New Drug (IND) safety reporting operates under 21 CFR 312.32, with a narrative report, Form FDA 3500A (MedWatch) or an electronic submission as the permitted formats. Each framework must be satisfied independently, and the determination of whether a particular fetal outcome constitutes a reportable event may yield different answers under each framework’s criteria.
The Maternal and Fetal Adverse Event Terminology, published in 2022 by Spencer and colleagues with Anna David as senior author, offers a voluntary common standard for defining and grading adverse events in pregnancy trials, separately for the pregnant woman and the fetus.12RN Spencer and others, ‘Development of standard definitions and grading for Maternal and Fetal Adverse Event Terminology’ (2022) 42(1) Prenatal Diagnosis 15. Its adoption, however, does not guarantee compliance with any jurisdiction’s specific reporting requirements. A sponsor using these definitions as its primary framework would still need to map them onto each jurisdiction’s regulatory expectations, a mapping exercise that produces different results depending on the jurisdiction. Whether a particular adverse in-utero finding constitutes a SUSAR under the CTR, whether it triggers an IND safety report under 21 CFR 312.32, and whether it requires notification to Swissmedic under the KlinV are three separate determinations, each governed by its own criteria, timelines, and institutional expectations. The coordination burden falls largely on the sponsor.
6. ICH E21: The Harmonization That Leaves the Hard Questions Open
ICH E21 is expected to harmonize the scientific and methodological framework: development strategy, nonclinical data requirements, study design principles, informed consent approaches, safety monitoring expectations, and labeling considerations. These are significant contributions. E21 covers both pregnant and breastfeeding individuals; this article deals only with pregnancy. The guideline establishes a shared vocabulary and a common set of expectations that did not exist before its drafting.13ICH (n 1). EMA characterized ICH E21 as a “change in paradigm” in its 4 June 2025 news announcement.
ICH E21 will not harmonize liability regimes, insurance requirements, ethics committee composition and expertise standards, compensation mechanisms, IRB or ethics committee interpretive approaches to “minimal risk” or “direct benefit,” and the institutional relationships that determine whether a protocol proceeds from approval to enrollment. The gap between harmonized aspiration and unharmonized mechanism is where legal, regulatory, and commercial complexity concentrates, and where the assumption that ICH E21 resolves the cross-border challenge may prove most costly.
The three jurisdictions will also implement E21 on different timelines. Swissmedic has committed to adopting ICH E21 but has not specified a transposition timeline. The EMA’s Committee for Medicinal Products for Human Use (CHMP) adopted the draft at Step 2b on 22 May 2025, but Member State-level integration depends on national institutional processes the EMA cannot direct. The FDA published its notice of availability for the draft in the Federal Register on 21 July 2025, but HHS has not initiated the Subpart B reform that would align the underlying regulations with the guideline’s expectations.14FDA, ‘E21 Inclusion of Pregnant and Breastfeeding Women in Clinical Trials’ 90 Fed Reg 34279 (21 July 2025), Docket FDA-2025-D-1797. A sponsor submitting a trial in 2028 or 2029 may encounter jurisdictions at different stages of E21 integration: one that has fully adopted the guideline’s expectations, another that has acknowledged but not implemented them, and a third where the existing regulatory text and the incoming guideline point in different directions without resolution.
7. The Coordination That Protocols Cannot Achieve
A sponsor pursuing a multi-jurisdictional pregnancy trial would typically need to coordinate regulatory submissions, ethics committee engagement, insurance procurement, clinical trial agreements, consent frameworks, and safety reporting across three systems that share a direction but not a mechanism. That coordination involves judgments about risk tolerance, institutional relationships, and commercial priorities that no regulatory framework addresses, because each framework addresses only its own jurisdiction, and the interaction between jurisdictions is the sponsor’s problem to solve.
The clinical trial agreement for a multi-jurisdictional pregnancy trial would need to accomplish what the regulatory frameworks do not: allocate liability across regimes that differ fundamentally in their approach to research-related injury, establish insurance coverage across markets that cannot price the risk, coordinate consent requirements that reflect different conceptions of participant autonomy, and address safety reporting obligations that may require different determinations about the same clinical event. Whether a particular agreement structure can achieve this depends on the trial’s specific design, the participating institutions’ risk appetite, the available insurance products, and the governing law’s interaction with the mandatory provisions of each participating jurisdiction, none of which standard templates accommodate.
The regulatory direction is clear and, from a public health perspective, welcome. The mechanism is not clear. It remains jurisdiction-specific, incompletely defined, and unresolved on the questions sponsors face when deciding whether to include pregnant participants. The evidence gap is shared. The path to closing it is not.