ICH M14 guideline on planning and reporting real-world data safety studies enters implementation phase 

The International Council for Harmonisation (ICH) has adopted its M14 guideline, General Principles on Planning, Designing, Analysing, and Reporting of Non-interventional Studies That Utilise Real-World Data for Safety Assessment of Medicines, providing harmonized recommendations for the generation of real-world evidence (RWE) in post-marketing safety submissions. 

With this adoption, the M14 Guideline has reached Step 4 of the ICH process as of September 4, 2025 and entered Step 5, the implementation phase. This marks the point at which the guideline moves from development to regulatory use across ICH regions, creating a consistent international approach to planning, designing, analyzing, and reporting non-interventional pharmacoepidemiological studies. 

This milestone follows the ICH Assembly’s endorsement of the topic in June 2021 and its release for public consultation at Step 2 in May 2024, which generated approximately 1600 stakeholder comments. 

Objectives and scope 

The M14 Guideline harmonizes expectations across ICH regions for the design, planning, analysis, and reporting of non-interventional pharmacoepidemiological safety studies. According to ICH, the guideline: 

“Provides recommendations for generating real-world evidence (RWE) from real-world data (RWD) for regulatory submissions on post-marketing safety, acknowledging regional differences in RWD definitions and allowing supplementary data, including primary data collection where appropriate.” 

Pharmacoepidemiology is defined 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.” The guidance is aimed at regulators, sponsors, researchers, and public health organizations that rely on non-interventional studies to understand medicine safety in routine clinical practice. 

Recommendations for study design and conduct 

The guideline sets out a stepwise approach that begins with a clearly defined study rationale and research question, followed by the identification of the “study population, exposure, comparator(s), outcome, and covariates.” It recommends determining minimum data requirements, assessing the representativeness of the data source, and addressing potential sources of bias and confounding. 

ICH notes that: 

“RWD sources alone may be insufficient to answer the research question of interest,”  

meaning that additional data may be required. To address this, the guideline includes recommendations for when and how to combine secondary RWD with primary data collection in non-interventional studies. 

Examples of suitable data sources include electronic health records (EHRs), administrative claims data, patient registries, and patient-generated health data. For studies using multiple data sources or federated data networks, researchers 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 further underscores the importance of involving a multidisciplinary study team, including epidemiologists and biostatisticians, to ensure methodological rigor. It provides detailed guidance on protocol development, data curation, statistical analysis, and transparent reporting. It also highlights that adverse events, product quality complaints, and other safety findings identified during a study may need to be reported to regulatory authorities in accordance with the ICH E2D guideline on post-approval safety data management. 

Regional considerations and next steps 

While M14 establishes a harmonized framework, some differences remain between regions due to variations in privacy requirements, adverse event reporting, and data accessibility. The final version incorporates advanced methodological concepts to support diverse study designs and address potential challenges in study execution. 

With Step 4 adoption now complete, ICH recommends that regulators across all ICH regions implement the M14 Guideline to ensure a consistent approach to post-marketing safety evidence.