ICH releases guidelines on developing medicines for pregnant population and quality information in CTD

The International Council for Harmonisation (ICH) has recently released two draft guidelines for public consultation. One draft guideline focuses on assessing new drugs for pregnant populations in clinical trials, while the other provides updates to the information requested in the quality section of the Common Technical Document (CTD).

In other recent actions, ICH also released a concept paper that proposes a new addendum for assessing nitrosamine impurities in drug products.

These advances were announced on 21 May following its 13-14 May meeting in Madrid (RELATED: ICH announces new topics, draft guidelines for consultation, Regulatory Focus 21 May 2025).

The ICH E21 guideline aims to establish a globally accepted framework and best practices for including and retaining pregnant and breastfeeding individuals in clinical trials. It addresses principles for collecting a “robust” set of safety, efficacy, and pharmacokinetic data for his population.

According to a concept paper published last May, “there is an increasing acknowledgement of the need to generate data for medicinal products in pregnant and breast-feeding individuals.”

The guidance states that data to assess investigational products during pregnancy and breastfeeding may be drawn from various sources, including pharmacovigilance-generated data, electronic health records, medical claims or health insurance databases, and disease registries.

The guideline states that the decision to include pregnant individuals in a clinical trial should be based on a “weight of evidence” approach and should take into account factors such as the indication and the intended population; nonclinical data; potential benefits of the trial; clinical pharmacology of the investigational product; and the biological “plausibility” of harm arising from exposure during pregnancy.

If clinical or nonclinical data suggests that the investigational product could harm a pregnant individual or the fetus, the sponsor may decide that including this population in clinical trials is inappropriate.

However, in some cases, the benefits of using the product during pregnancy might outweigh the potential risks. This can occur in situations where the target disease affects the health of both the mother and the fetus, such as malaria, or where alternative treatments pose safety concerns during pregnancy, such as methotrexate for systemic lupus erythematosus (SLE). In these cases, including pregnant individuals in these trials may be evaluated on a case-by-case basis.

ICH also released a multidisciplinary M4Q(R2) draft guideline, which harmonizes the format and content of pharmaceutical quality data in the CTD. The guideline covers submissions, variations, and drug master files (DMFs).

According to a concept paper published in November 2021, the M4Q(R1) guideline needs an update since it was adopted in 2002. The guideline is due for revision to “improve registration and lifecycle management efficiency, leverage digital technologies, and accelerate patient and consumer access to pharmaceuticals. “

ICH explained that this revision expands the scope of the M4Q(R1) guidelines by including all pharmaceutical drug substances and products that require marketing authorization.

It also incorporates concepts and data expectations that are better aligned with currently recognized international standards and guidelines.

Additionally, ICH has just published a final concept paper proposing an addendum to the M7 guideline that will focus on risk assessment and control of N-nitrosamine impurities. When adopted, the guidance will be published as M7(R3).

The addendum will include general principles and approaches for establishing acceptable intake limits for nitrosamines and will recommend acceptable intake limits based on the nitrosamine's physicochemical and structural features.

The pharmaceutical industry and regulatory authorities have been addressing safety and quality risks associated with nitrosamines in medications since 2018. This concern arose when N-nitroso-dimethylamine (NDMA) and N-nitroso-diethylamine (NDEA) were detected in some drug products that contained angiotensin II receptor blockers. Since then, many other nitrosamines have been identified in marketed drug products, often at levels that could pose safety and quality risks. These nitrosamines can originate from the drug substance, drug substance intermediates, related compounds, and components of the drug product, frequently occurring during manufacturing and storage.

ICH E21, ICH M4Q(R2); ICH M7 concept paper

ICH releases guidelines on developing medicines for pregnant population and quality information in CTD

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