ICH E21 "Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials"

US FDA has just endorsed the draft guideline of ICH E21 "Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials". E21 Training Material can also be found at ich.org. 

The ICH E21 guideline aims to provide recommendations for the appropriate inclusion and retention of pregnant and breastfeeding individuals in clinical trials. This is crucial because historically, these populations have been largely excluded, leading to a significant lack of data on the safety and efficacy of medicinal products during pregnancy and lactation.

For clinical trialists, the guideline emphasizes:

• Proactive Planning: Sponsors should consider strategies to generate data on medicinal product use in pregnancy and breastfeeding from early stages of development, including nonclinical studies through post-approval.

• Risk-Benefit Evaluation: A thorough assessment of potential risks and benefits for both the pregnant or breastfeeding individual and the fetus/breastfed infant is essential.

• Ethical Considerations and Informed Consent: The guideline stresses the importance of obtaining truly informed consent, ensuring clear communication of potential risks and benefits, and avoiding any undue influence or coercion. Efforts should be made to reduce the burden of study procedures on these participants.

• Study Design and Implementation: It provides practical guidance for designing clinical trial protocols, including considerations for data collection, safety monitoring, and follow-up for both mother and child. This also includes pharmacokinetic (PK) and dosing considerations, as physiological changes during pregnancy can impact drug pharmacokinetics.

• Addressing Unmet Medical Need: The inclusion of pregnant and breastfeeding individuals is particularly important for conditions where there is a high unmet medical need for treatment in pregnancy or while breastfeeding, though the guideline's scope is not limited to these scenarios.

• Data Generation: The overarching objective is to facilitate the generation of robust clinical data that allows for evidence-based decision-making on the safe and effective use of medicinal products by these individuals and their healthcare providers.

The ICH E21 guideline is a significant step towards improving the evidence base for prescribing medications during pregnancy and lactation, ultimately aiming for better patient outcomes for these underserved populations.

Just several weeks ago, I wrote a blog post on this same topic "Managing Pregnancies in Clinical Trials: Regulatory Guidance and Best Practices", which offered a comprehensive overview of the historical exclusion of pregnant women from clinical trials, the reasons behind this, and the evolving regulatory landscape advocating for their inclusion. The article emphasized a balanced approach, highlighting FDA's shift towards diversity in trials and the ethical imperative to gather data on drug use in pregnancy to ensure evidence-based care. It delved into practical aspects like informed consent, pre-screening procedures, managing pregnancies discovered during trials (including stopping drug, unblinding, and re-consenting), and the importance of detailed data collection and specialized safety monitoring. The blog post also strongly argued for the ethical benefits of inclusion, asserting that systematic exclusion leads to greater harm by forcing healthcare providers and patients to make decisions without adequate evidence. 

The newly endorsed ICH E21 guideline directly aligns with various FDA guidance described in the blog post and significantly reinforces the "balanced approach" and the ethical arguments. 

• ICH E21 provides a more harmonized, international standard for how this inclusion should be achieved proactively throughout drug development. 
• ICH E21 offers detailed recommendations on study design, ethical considerations, pharmacokinetic and dosing adjustments, safety monitoring, and data collection specifics for pregnant and breastfeeding individuals, directly addressing the "when and how" question you pose at the end of your article. 
• ICH E21 reiterates the need for IRBs with maternal-fetal expertise, suggesting consultation with specialists for study design and safety monitoring. 
• ICH E21 highlights the critical importance of robust informed consent and ongoing safety monitoring for both the mother and the child. 
• ICH E21 essentially provides the detailed, internationally agreed-upon framework, moving the industry further towards systematic and responsible inclusion rather than historical exclusion.