ICH adopts M14 guideline on observational studies

The International Council on Harmonisation (ICH) announced on Friday the adoption of its M14 guideline, which aims to harmonize the planning, design, and reporting of pharmacoepidemiologic studies that use real-world data (RWD) to evaluate the safety of marketed drugs and vaccines. The guideline also provides high-level best practices for conducting these studies.

The guideline reached Step 4 of the ICH process in September 2025 and is now ready for regulatory implementation.

The guidance states that “generation of robust evidence to be used for regulatory purposes depends on the reliability and relevance of the data and the application of sound methods to analyse such data. The use of noninterventional studies for regulatory decision-making has increased globally, and multiple guidelines and best practice documents have been developed by regulators and professional societies.”

The ICH Assembly initially approved the topic in June 2021, and the guideline was subsequently issued as Step 2 in May 2024 for public consultation. (RELATED: ICH adopts M12 guideline on drug interaction studies, releases draft M14 guidance on RWD, Regulatory Focus 28 May 2024)

The guideline defines pharmacoepidemiology as a “scientific discipline that uses epidemiological methods to evaluate the use, benefits, and risk of medicines, medical technologies, and other interventions in human populations.” It aims to assist regulatory agencies and sponsors of non-interventional studies, including researchers, public health organizations, and scientific journals when using and assessing data.

The guideline notes that a drug’s safety profile is based on an evolving body of information gathered throughout its lifecycle, from preclinical studies through post-market data. This information is also complemented by additional information, such as non-interventional safety studies and spontaneous adverse event reporting.

The guideline outlines a conceptual framework for generating adequate evidence using fit-for-purpose RWD to address drug safety questions. It recommends initial study designs and addresses protocol development, including the type of data sources to use. It also addresses potential biases and confounding factors.

Moreover, the guideline addresses data management and curation, data analysis, and data reporting. It also covers the submission of data for dissemination and the communication of study materials, including considerations for special populations.

The guideline states that the design, conduct, and interpretation of non-interventional safety studies should include an experienced, multidisciplinary study team of experts in epidemiology and biostatistics. Furthermore, it adds that the protocol should describe and discuss the data sources used and how they are fit for use to address the research question of interest.

Examples of data source types that can be used in these studies, according to the guideline, include data derived from Electronic Health Records (EHRs), administrative claims data, patient registries, and patient-generated data. It also states that “for studies that use data from multiple data sources or study sites (e.g., Federated Data Networks [FDNs], meta-analysis, data pooling, or data linkage), the researcher(s) should describe the rationale and procedures for how data from different sources can be obtained and integrated with acceptable quality, given the potential for heterogeneity in population characteristics, clinical practices, and coding across data sources.”

The guideline states that adverse events, adverse drug reactions, and product quality complaints identified during the study may require reporting to the regulatory authority, as specified under the ICH E2D guideline on “Post Approval Safety Data Management.” It further notes that adverse event reporting requirements may vary by sponsor or applicant, investigator, or by region, due to differences in regulatory reporting requirements.

According to a presentation of the guidelines, not all elements of the guidelines could be harmonized due to regional differences in patient privacy requirements, adverse event reporting, study reporting and record retention, and data accessibility. As noted in the presentation summary, the guideline was revised to include advanced methodology concepts to address a wider range of potential challenges in study design and execution.

There was significant interest when the Step 2 draft was issued, with approximately 1,600 comments submitted, according to ICH.

Pharmaceutical industry stakeholders from both sides of the Atlantic generally supported the ICH M14 guidance but also suggested areas for improvement, such as adding more examples of how the principles will work in practice, addressing the use of artificial intelligence and machine learning (AI/ML), and expanding the scope of the guideline to include combination products. (RELATED: Industry stakeholders call for changes to ICH M14 RWD guideline, Regulatory Focus 14 October 2024)

ICH M14 guideline; Presentation

ICH adopts M14 guideline on observational studies

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