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M14 – General Principles on Plan, Design, Analysis, and Reporting of Non-Interventional Studies That Utilize Real-World Data for Safety Assessment of Medicines
Guideline number: M14
Status: Implementation (Step 5)
Adopted (Step 4): 4 September 2025
This topic was endorsed by the ICH Assembly in June 2021.
The ICH M14 Guideline reached Step 4 of the ICH process on 4 September 2025.
The M14 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 (see ICH E8);
- Provides recommendations with the intent to harmonise expectations for the design, planning, analysis, and reporting of non-interventional safety studies to facilitate regulatory review.
The ICH Harmonised Guideline was finalised under Step 4 in July 1997. This document covers the preclinical safety testing requirements for biotechnological products. It addresses the use of animal models of disease, determination of when genotoxicity assays and carcinogenicity studies should be performed, and the impact of antibody formation on duration of toxicology studies.
An addendum was proposed to provide clarification on S6 and an update of the following topics discussed in the original ICH S6 Guideline: species selection, study design, immunogenicity, reproductive and developmental toxicity and assessment of carcinogenic potential. The Harmonised addendum provides further complementary guidance to the S6 Guideline and helps to define the current recommendations and reduce the likelihood that substantial differences will exist among regions.
The addendum reached Step 4 of the harmonisation process in June 2011 and was integrated as part II in the core Guideline that was then renamed S6(R1).
Q+A
Q+A Status: Implementation (Step 5)
