ICH M14 Guideline: General Principles on Planning, Designing, Analysing, and Reporting of Non-interventional Studies That Utilise Real-World Data for Safety Assessment of Medicines

Setting a Global Standard for Real-World Evidence

The International Council for Harmonisation (ICH) has finalized M14, the first global guideline that details how to plan, design, analyze, and report non-interventional studies using real-world data (RWD) for post-marketing safety assessment.

Over the last 10-15 years, regulatory agencies have issued their own guidances on designing and conducting non-interventional studies using RWD to inform regulatory decision-making. Given that sponsors often develop drugs, vaccines, and other products for use in multiple countries, differences among agency-specific guidances make it difficult to efficiently generate real-world evidence (RWE) that will meet multiple regulatory needs. 

Regulators and industry alike have long called for harmonized guidance to enable efficient RWE generation that meets expectations for regulatory decision-making on a global scale. The adoption of M14 last month marks a significant step toward global alignment on RWE standards. M14 establishes a single, consensus-based guideline for using RWD to address post-marketing safety questions, developed through collaboration among more than 20 global authorities and organizations, including the FDA, EMA, PMDA, Health Canada, ANVISA, and WHO.

Based on principled epidemiology and best practices

M14 emphasizes that credible RWE isn’t achieved through a checklist but through a stepwise, iterative process, a focus on transparency, and seeking regulatory input:

• Start with the question, not the dataset. Define the safety question first, then identify the study design and data that are fit for addressing the question.
• Conduct feasibility in two phases. Begin with a preliminary screen of potential data sources based on initial study design. Next, perform a detailed feasibility assessment based on a draft protocol to confirm that sufficient patient count and exposure, outcome, and covariate variables can be validly operationalized in the selected RWD source. These recommendations follow the SPIFD process co-authored by Aetion scientists.
• Practice transparency. Develop a detailed protocol and statistical analysis plan with documented rationale underlying the design features. Use available tools, such as ISPE/ISPOR’s HARmonized Protocol Template to Enhance Reproducibility (HARPER) Initiative and visualizations to ensure clear communication. Publicly register the protocol prior to implementation and post study results.
• Engage regulators early. Seek early regulatory input to assure alignment on the key study design elements and initial feasibility findings. Early engagement can help avoid “surprise” feedback from regulators after great effort has already been made to develop the full protocol.

In short, M14 emphasizes a “show your work” approach to generating robust and trustworthy RWE of product safety for regulatory decision-making.

From guidance to application

M14 delivers what industry researchers have long requested: harmonized, practical guidance for generating RWE that can be trusted for regulatory decision-making. It’s a milestone in global alignment that sets clear standards for using RWD to address post-marketing safety questions. Though centered on using RWD to address safety questions, M14 guidance principles are generally applicable across real-world studies.

At Aetion, a Datavant Company, we share the same commitment to generating credible RWE for improving public health. The principles in M14 are the same principles that have guided our science and platform from the start, so that every study we conduct produces interpretable, trustworthy, and reproducible results.

Learn more about how Aetion helps sponsors and researchers generate RWE for regulatory decision-making.