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Safety Management at the Intersection of Regulation, Practice, and Technology

The 2025 KoNECT–MOHW–MFDS International Conference once again served as a key platform for in-depth discussion across clinical trials and pharmacovigilance (PV). Day 1 was dedicated to “Safety Management”, focusing on how clinical trial safety systems are evolving in response to global regulatory harmonization and technological advancement.

Across four sessions—ranging from RSI development, DSUR strategy, benefit-risk assessment, to lifecycle safety management—the overarching message was clear: Clinical safety is no longer a compliance-driven reporting function, but a strategic, data-driven safety management system across the product lifecycle.

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Session 1

Topic: Developing Reference Safety Information (RSI) for Clinical Trials

Speaker: Nicholas Costello (MSD)

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1. Session Background

This session focused on the evolving impact of recent updates in ICH E6(R3) and the EU Clinical Trial Regulation (EU CTR) on clinical trial safety management.

Key discussions centered on the definition and development process of Reference Safety Information (RSI), associated regulatory expectations, and the critical linkage between RSI and the Adverse Drug Reaction (ADR) section within the Investigator’s Brochure (IB).

2. Key Presentation Highlights

1) Definition and regulatory basis of RSI

RSI is a cumulative document that lists expected adverse drug reactions (ADRs) associated with an investigational medicinal product and serves as a key reference standard for clinical safety reporting.

ICH E6(R3) formally introduces and defines RSI, clarifying its role within the clinical trial framework. RSI is used as a reference for SUSAR determination and serves as a benchmark document for ensuring consistency in DSUR safety profile evaluations.

2) Role of EU CTR Q&A guidance

The EU CTR Q&A (v7.1) provides the most detailed regulatory guidance on RSI to date. It recommends that RSI be: Clearly presented as a dedicated section within the Investigator’s Brochure (IB), Structured in a tabular format, Coded using MedDRA PT level and organized by SOC, Accompanied by frequency data at an aggregated level.

3) Key content requirements

RSI content requirements include: Serious or life-threatening SARs must be explicitly identified, Hypothetical risks and class effects should be excluded, Recurrent SARs should be included when occurring more than once.

Aggregated datasets should consider multiple dimensions, including: Study phase, Indication, Dose, Concomitant medications, Inclusion of healthy volunteer studies.

4) Operational considerations

From an operational perspective: RSI consistency should be ensured across development programs, Indication-specific RSI segmentation is recommended (e.g., oncology vs immunology), Pediatric studies require independent RSI development, as adult data cannot be extrapolated, RSI should be regularly updated in alignment with DSUR reporting cycles.

The IB ADR section should cover a broader safety scope than RSI, including: Non-serious ADRs, Dose-related differences, Subgroup-specific variations.

3. Key Implications and Challenges

1) Regulatory harmonization

RSI is positioned as a core document spanning ICH guidelines, EU CTR requirements, and DSUR frameworks, serving as a central reference point for global safety reporting consistency.

Rather than a supplementary appendix, RSI is increasingly viewed as a structural anchor for regulatory alignment across jurisdictions.

2) Operational challenges

While early-stage development may require only a declaration of “no observed SARs,” increasing complexity arises as development progresses.

Key challenges include: Data aggregation across studies and phases, Alignment of RSI update cycles with DSUR timelines, Regulatory interpretation of SAR inclusion criteria, Decisions on indication- or age-specific RSI segmentation.

These areas often require early and continuous engagement with regulatory authorities.

3) Industry implementation direction

Pharmaceutical companies and CROs are encouraged to proactively establish RSI development and maintenance systems aligned with global regulatory expectations. In particular, integrating RSI lifecycle management with DSUR and IB updates under a unified governance framework is considered essential for operational efficiency and compliance readiness.

4. Conclusion

This session emphasized that RSI should not be viewed as a simple adverse event listing, but as a central pillar of clinical trial safety management and regulatory consistency. Going forward, harmonized interpretation and implementation of RSI requirements across regulatory authorities and industry stakeholders will be essential to improving the quality, consistency, and reliability of clinical safety reporting globally.

 

Session 2

Topic: Developing Reference Safety Information (RSI) for Clinical Trials

Speaker: Katerina Rok Song (International Vaccine Institute, IVI)

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1. Session Background

This session addressed benefit–risk (B/R) assessment and risk management strategies across the entire clinical trial lifecycle. Drawing on vaccine development experience, it covered the full spectrum from early-stage B/R definition, through in-trial risk monitoring, to management of unexpected safety issues.

A central message of the session was that benefit–risk assessment is not a one-time evaluative step, but a continuously evolving “living process” throughout clinical development.

 

2. Key Presentation Highlights

1) Timing and approach to Benefit–Risk assessment

Benefit–risk assessment should begin as early as the pre–Clinical Development Plan (CDP) stage, and be continuously updated as development progresses.

This includes distinguishing between: Anticipated risks identified early in development, Emerging risks observed during clinical trials.

Even in vaccines with well-established preventive efficacy, potential variability in specific high-risk subpopulations should be considered from the outset.

 

2) Integration into clinical trial design

Benefit–risk considerations should be embedded from the Target Product Profile (TPP) stage, and systematically reflected in protocol design, including: Eligibility criteria, Sample size determination, Selection of safety endpoints alongside efficacy endpoints, Adjustment of observation periods based on adverse event characteristics. In addition, exclusion of high-risk populations and proactive safety optimization should be incorporated where appropriate.

 

3) Safety measures for critical risks

Clinical protocols should include structured safeguards such as: Exclusion criteria for high-risk populations, Strengthened informed consent and re-consent processes, Ongoing oversight by Data and Safety Monitoring Boards (DSMB) and internal Safety Monitoring Committees (SMC), Clearly defined emergency unblinding procedures for rapid response to unexpected safety events.

 

4) Routine safety evaluation and immediate hazard response

PV teams are expected to implement structured and frequent safety monitoring activities, including: Regular safety review meetings (e.g., biweekly safety reviews), Periodic DSMB assessments, Continuous evaluation of safety signals. For immediate hazards, a 24/7 response infrastructure is essential, along with clearly defined escalation pathways and decision-making governance.

 

5) Case example: vaccine trial in pregnant populations

A vaccine clinical trial in pregnant populations illustrated key operational challenges. Despite high disease burden and unmet medical need, the study was delayed due to early safety signals. Following extensive discussions with regulatory authorities and international organizations, the trial was eventually resumed.

This case highlighted the importance of: Continuous benefit–risk reassessment, Adaptive safety decision-making, International regulatory collaboration in sensitive populations.

 

3. Key Implications and Challenges

1) Importance of early integration

Benefit–risk assessment must be consistently integrated across non-clinical, clinical, and protocol development stages, with early decisions shaping downstream clinical strategy.

 

2) Risk-informed clinical design

Risk considerations should directly inform trial design elements such as: Eligibility criteria, Safety monitoring frequency, Sample size planning, Endpoint selection.

The goal is to proactively minimize preventable safety risks rather than react to them post hoc.

 

3) Establishing rapid response systems

Given the unpredictability of immediate safety hazards, organizations must predefine: Emergency response scenarios, Escalation pathways, Decision-making authorities. to ensure rapid and coordinated action when needed.

 

4) Lessons from real-world case experience

The pregnant population vaccine trial demonstrated that benefit–risk evaluation is not static but must be continuously refined through regulatory dialogue and real-world evidence. It also underscored the need for early adoption of structured benefit–risk frameworks in sensitive population studies.

 

4. Conclusion

This session reinforced that benefit–risk assessment is a continuous, lifecycle-spanning core process in clinical development, rather than a preliminary review step. The effectiveness of clinical safety management increasingly depends on: Early and continuous integration of risk considerations, Robust safety governance structures, Proactive planning for critical risk scenarios, Rapid response capabilities for unforeseen safety events.

Overall, the session reflected a broader paradigm shift in clinical safety management—from reactive safety oversight toward predictive, strategy-driven risk governance across the entire clinical lifecycle.

 

Session 3

Topic: Lifecycle Safety Strategy: Signal Detection and Risk Escalation from Clinical Trials to Market

Speaker: Minkyung Shin (SELTA SQUARE Inc.)

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1. Session Background

This session emphasized the importance of managing pharmacovigilance (PV) as a continuous, lifecycle-spanning process, extending from clinical development through post-marketing surveillance. A key message was that signal detection and risk escalation must be systematically designed and operationalized already during the clinical phase, as this is essential for both patient safety and regulatory compliance. 

 

2. Key Presentation Highlights

1) Importance of clinical-stage pharmacovigilance

Pharmacovigilance should not be limited to post-marketing activities but must begin during clinical trials.

Although clinical datasets are inherently incomplete, this limitation can be addressed through: Integrated safety data reviews, Pre-definition of Adverse Events of Special Interest (AESIs). Safety insights generated during clinical development form the foundation for future risk management strategies.

 

2) Core role of clinical PV

A central component of clinical PV is early signal detection. To support this, the establishment of a Safety Monitoring Team (SMT) is essential. SMTs function as cross-functional hubs responsible for ongoing safety oversight. In parallel, an Aggregate Safety Assessment Plan (ASAP) enables a structured approach to managing fragmented clinical data, ensuring a consistent and integrated view of safety across the product lifecycle.

 

3) Data sources and analytical approaches

Safety evaluation relies on both structured and unstructured data sources, including: Structured data: adverse events (AE), serious adverse events (SAE), ECG results, vital signs, Unstructured data: narrative reports, free-text entries in eCRFs, External data sources: class effects from related compounds, literature data, and regulatory safety communications. 

 

4) Value of the Safety Monitoring Team (SMT)

SMTs integrate clinical, statistical, and regulatory perspectives to enable holistic safety evaluation of both structured and unstructured data. They serve as a decision-making hub for risk escalation, enabling: Rapid identification of safety signals, Early protocol modifications, Input generation for Risk Management Plans (RMPs), While SMTs are typically composed of PV experts and medical leads, they differ from DSMBs in that they do not hold independent advisory authority.

 

5) Aggregate Safety Assessment Plan (ASAP)

ASAP provides a structured framework for consistent safety data integration across clinical development and post-marketing stages. Key objectives include: Standardization of safety data (e.g., MedDRA terminology harmonization), Safety pooling across studies with similar indications or mechanisms, Exposure-adjusted analyses to minimize bias. ASAP is increasingly referenced in regulatory submissions (e.g., PBRER) and is becoming a focus area in regulatory inspections.

 

6) Signal detection and risk escalation process

Safety signals in clinical development are typically identified through: AE pattern analysis, Laboratory trend evaluation, Narrative data review. A structured escalation framework is required to ensure appropriate response. 

▲ Risk Escalation key steps

Key triggers for risk escalation include: Threshold exceedance, Sudden increases in event frequency, Occurrence of serious cases.

 

7) Global and technological trends

Major regulatory authorities, including the FDA, are increasingly adopting AI-based real-time signal detection systems in regulatory review and PV monitoring.

Similarly, Korea is advancing toward AI-enabled safety systems. Overall, PV is shifting from a reactive model to a proactive safety paradigm leveraging real-world data (RWD) and real-world evidence (RWE).

 

3. Key Implications and Challenges

1) Strengthening clinical–post-marketing continuity

Clinical and post-marketing safety should no longer be viewed as separate domains but as a single integrated lifecycle safety system.

 

2) Organizational readiness

Early implementation of structured systems such as SMT and ASAP is essential, as they form the foundation for more efficient post-marketing safety management.

 

3) Data standardization

Consistency in data structure and terminology (e.g., narrative data and MedDRA coding) is critical to improving the accuracy and reliability of signal detection.

 

4) Adoption of global trends

AI-driven analytics and RWE-based proactive safety management are rapidly becoming baseline expectations among regulators and industry stakeholders.

 

4. Conclusion

This session reinforced that lifecycle pharmacovigilance beginning at the clinical stage is fundamental to ensuring patient safety and regulatory trust.

The discussion highlighted that without early implementation of structured signal detection and risk escalation processes, it becomes significantly more difficult to maintain reliable safety management in the post-marketing phase.

Accordingly, both industry and regulators are increasingly expected to adopt integrated frameworks such as ASAP, SMT, standardized data systems, and AI-enabled safety analytics, marking a clear shift toward proactive, data-driven pharmacovigilance.

 

Session 4

Topic: Development Safety Update Reports (DSUR): Role, Strategic Applications, and Key Considerations

Speaker: Soyeon Hwang (C&R Research Inc.)

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1. Session Background

The final session focused on the role and strategic use of the Development Safety Update Report (DSUR) in clinical development.