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At the Spring Academic Conference of the Korean Society of Pharmacoepidemiology and Risk Management (KoPERM), held on May 29, Hyungok Jeon, Deputy Director of the Global Harmonization Center (GHC) at the Ministry of Food and Drug Safety (MFDS), presented on "Korea's ICH Activities and Guideline Status," sharing the latest developments in ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guideline development and their domestic implementation progress. Of particular note, ICH M14 — the guideline for the use of RWD in non-interventional safety studies — and E2D(R1) — the updated standard for post-marketing safety data management — were highlighted as key agenda items. This signals that pharmaceutical companies responsible for post-marketing safety management must establish a regulatory-acceptable framework when using RWD to address post-marketing safety issues, monitor potential safety signals, and conduct additional pharmacovigilance activities under RMP.

 

Background: A Shifting Regulatory Landscape

In the global regulatory environment, evidence generation using Real-World Data (RWD) has already become a cornerstone of post-marketing safety evaluation. ICH is actively working to systematize the principles under which RWD-based non-interventional safety studies can be accepted by regulatory authorities — and ICH M14 is at the center of that effort.

According to the presentation at this conference, MFDS is currently participating in 16 Expert Working Groups. The following are the key guidelines with direct relevance to post-marketing safety and Real-World Evidence (RWE):

Code	Guideline	Key Focus	Current Stage
ICH M14	Guideline on the Use of RWD in Non-Interventional Safety Studies (Planning, Design, Analysis, and Reporting)	Establishes regulatory acceptance criteria for the full lifecycle of RWD-based post-marketing safety studies; includes fit-for-use data requirements, research-question-driven design, bias control, and transparency/reproducibility standards	Step 5 (Final Adoption)
ICH E2D(R1)	Post-Marketing Safety Data Management: Definitions and Standards for Expedited Reporting (ICSR)	Modernizes ICSR definitions and reporting standards; strengthens electronic submission requirements and global regulatory harmonization; reflects alignment with RMP-based monitoring	Step 3 (Domestic Implementation Underway)
ICH E23	Considerations for the Use of RWE in Efficacy Evaluation of Medicines	Establishes methodological principles for using RWD in regulatory decision-making on drug efficacy; defines criteria for RWE acceptance in efficacy assessment	Pre-Step 1 (Under Discussion)

What ICH M14 Requires of Pharmaceutical Companies

ICH M14 is not simply a reporting guideline. It sets the standard for the entire research design framework that RWD-based non-interventional safety studies must follow in order to be accepted by regulatory authorities. The guideline centers on four core principles:

① Research-Question-Driven Design

Studies must begin with a clearly defined research question — specifically, what safety uncertainty is this study intended to resolve — rather than starting from the data source. Study population, exposure and outcome variables, comparators, and follow-up period must all be designed around that central question.

② Fit-for-Use Data Validation

The completeness, accuracy, timeliness, and traceability of data must be iteratively assessed against the research question. Where a single data source is insufficient, data linkage or primary data collection should be considered.

③ Bias Control and Confounding Management

Selection bias, information bias, and residual confounding must be identified in advance, and an analysis plan including sensitivity analyses must be pre-specified and documented. Regulatory authorities evaluate not only analytical results but also the adequacy of the bias control strategy itself.

④ Transparency and Reproducibility

Study protocols, Statistical Analysis Plans (SAPs), analysis code, and data derivation processes must be documented and pre-registered. Regulatory acceptability hinges not on the direction of the findings, but on the transparency of the process that led to them.

Domestic Implementation Timeline: Key Dates for Pharmaceutical Companies

Based on the domestic ICH guideline implementation plan disclosed at this conference, ICH M14 has already reached Step 5 (final adoption), and MFDS implementation is expected to accelerate. The key timeline for pharmaceutical companies is as follows:

Timeframe	Guideline	Practical Implications
Through 2026	ICH M14 - Domestic Implementation	Review of RMP-based non-interventional safety study protocols; re-definition of research questions; SOP updates required
2026(Underway)	E2D(R1) - ICSR Management and Reporting Standards Revision	Impacts PV operations broadly: adverse event reporting systems, electronic submission requirements, reporting timelines; early internal review recommended
TBD	E23 — Use of RWD in Efficacy Evaluation	Begin developing proactive response strategies for RWE designs intended for regulatory approval and reimbursement purposes

SeltaSquare Insight: Now Is the Time to Build the Framework

The adoption of ICH M14 signals that regulatory expectations for RWD-based post-marketing safety research have risen significantly and explicitly.

"Is your post-marketing safety management program systematically prepared to meet regulatory requirements?"

The question is no longer simply whether data can be collected. Regulators will now examine what research question is being asked, what study design is being used, and how findings are validated and reported.

The key challenges facing pharmaceutical companies today include:

• Are research questions for RMP-based additional pharmacovigilance activities clearly defined?
• Has the fit-for-use status of your data sources been assessed to a level that regulators would find convincing?
• Are protocols, SAPs, and bias control plans documented prior to study initiation?
• Is analysis code and data handling retained in a reproducible format?
• Are RMP-based safety study results consistently aligned with PSUR/PBRER submissions and other regulatory filings?

With SeltaSquare — From Research Question Design to Regulatory Submission