Periodic Safety Update Report (PSUR): The Complete Pharmacovigilance Compliance Guide

A periodic safety update report (PSUR) is a mandatory pharmacovigilance document that pharmaceutical companies must submit to regulatory authorities to provide a comprehensive assessment of a drug's benefit-risk profile during the post-marketing phase. These reports ensure continuous monitoring of product safety throughout a medication's lifecycle.

For drug safety professionals, PSUR reporting represents one of the most critical ongoing compliance requirements after market authorization. Missing submission deadlines or providing incomplete safety data can trigger regulatory enforcement actions, marketing authorization suspensions, or significant financial penalties.

The challenge? PSUR preparation requires coordinating global safety data, analyzing thousands of adverse event reports, conducting literature searches across multiple databases, and synthesizing complex risk-benefit assessments into a standardized regulatory format - all within strict regulatory timelines.

In this guide, you'll learn:

• What a periodic safety update report is and when it's required under ICH guidelines
• Key differences between PSUR and PBRER (Periodic Benefit-Risk Evaluation Report) formats
• PSUR submission timelines, frequency requirements, and data lock points across FDA, EMA, and other regulatory authorities
• Essential components of PSUR reporting including safety data analysis, signal detection, and risk management updates
• Best practices for efficient PSUR preparation, quality review, and regulatory submission

What Is a Periodic Safety Update Report (PSUR)?

A periodic safety update report is a comprehensive pharmacovigilance document submitted to regulatory authorities at defined intervals following a drug's marketing authorization. The PSUR provides an integrated analysis of all available safety data, including adverse event reports, clinical trial results, literature findings, and non-clinical studies, to assess whether the product's benefit-risk balance remains favorable.

Key characteristics of periodic safety update reports:

• Mandatory submission requirement for all authorized medicinal products with specified frequency (annual, biannual, or based on international birth date)
• Global data aggregation encompassing worldwide safety information from all sources (spontaneous reports, clinical trials, literature, post-authorization studies)
• Standardized format following ICH E2C(R2) guidelines with defined sections covering exposure data, clinical safety findings, signal evaluation, and benefit-risk analysis
• Regulatory assessment tool allowing health authorities to monitor ongoing product safety and determine if regulatory action is needed

PSUR vs PBRER: Understanding the Regulatory Evolution

The pharmacovigilance landscape underwent significant harmonization with the introduction of the Periodic Benefit-Risk Evaluation Report (PBRER) format, which evolved from traditional PSUR requirements.

Format Comparison: PSUR vs PBRER

Regional Terminology Variations

Different regulatory authorities use distinct terminology for essentially equivalent periodic safety reports:

Why the Shift from PSUR to PBRER?

The evolution from traditional PSUR to PBRER format reflects a fundamental change in pharmacovigilance philosophy:

Traditional PSUR limitations:

• Focused primarily on adverse event compilation without integrated benefit analysis
• Inconsistent structure across regions led to duplicate reporting with regional variations
• Limited emphasis on signal detection and evaluation
• Benefit assessment often treated as afterthought in separate section

PBRER improvements:

• Integrated benefit-risk assessment woven throughout the entire document
• Systematic signal evaluation with transparent methodology
• Standardized structure accepted across ICH regions (reducing duplication)
• Enhanced focus on what the data means for prescribers and patients, not just what happened
• Required inclusion of cumulative summary tabulations and interval data comparisons

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Key Insight: While many regions still use the term "PSUR" in regulations and practice, the content requirements have evolved to align with ICH E2C(R2) PBRER format. Most modern "PSURs" are actually PBRERs in structure and content.

PSUR Reporting Timeline and Frequency Requirements

Periodic safety update reports must be submitted according to defined schedules determined by the International Birth Date (IBD), regulatory authority requirements, and product lifecycle stage.

International Birth Date (IBD) Concept

The International Birth Date is the date of the first marketing authorization for a medicinal product granted to any company in any country worldwide. The IBD serves as the anchor point for calculating PSUR submission dates globally.

IBD determination:

• Based on first approval anywhere in the world (not company-specific or region-specific)
• Remains constant regardless of subsequent approvals in other regions
• Used to calculate data lock points for all periodic safety reports
• Typically corresponds to the first ICH region approval date

Standard PSUR Submission Frequencies

Regional Variations in Submission Requirements

European Union (EMA):

• Follows IBD-based frequency unless otherwise specified in marketing authorization
• Union reference dates (EU-RD) may apply for certain product groups
• Single assessment through Pharmacovigilance Risk Assessment Committee (PRAC)
• Can request modified frequency based on risk management plan

United States (FDA):

• Historically required company-specific timelines based on US approval date
• Now accepts IBD-based PBRERs for many products
• Some products subject to REMS (Risk Evaluation and Mitigation Strategy) may have different reporting frequencies
• New Drugs (NDAs) and Biologics (BLAs) may have specific postmarketing requirements

Japan (PMDA):

• Reexamination period for new drugs (typically first 8 years) requires frequent reporting
• After reexamination, transitions to less frequent periodic reporting
• Local approval date often used rather than IBD

Health Canada:

• Accepts IBD-based PBRER submissions
• May specify alternative frequencies in Notice of Compliance (NOC)
• Risk management plan commitments may modify standard timelines

PSUR Submission Deadlines

After the data lock point (DLP), companies have a specified period to prepare and submit the report:

Data Lock Point Calculation Examples

Example 1: Product with IBD of March 15, 2023

Example 2: Product with IBD of January 1, 2020

Currently in year 5 post-IBD (as of January 2026), the product would be on a 3-year reporting cycle:

• Most recent DLP: January 1, 2025 (submission due March 11, 2025)
• Next DLP: January 1, 2028 (submission due March 11, 2028)

Essential Components of PSUR/PBRER Structure

The ICH E2C(R2) guideline defines a standardized 19-section structure for PBRERs. Understanding each component is critical for complete and compliant reporting.

PBRER Core Sections (ICH E2C R2)

Critical PSUR Data Requirements

Section 5: Estimated Exposure - Calculation Methods

Exposure estimation is essential for understanding the denominator when assessing adverse event rates. Common methods include:

Section 16: Signal Detection Requirements

Signal evaluation must address:

• Methodology for signal detection (statistical methods, data mining, literature monitoring)
• New signals identified during reporting period
• Status of ongoing signal evaluations from previous reports
• Closed signals with rationale for closure
• Prioritization criteria for signal investigation

Section 19: Integrated Benefit-Risk Analysis - Core Questions

The final section must address:

1. Has the benefit-risk balance changed during this reporting period?
2. What are the implications for the product's marketing authorization?
3. Are regulatory actions warranted (label updates, restrictions, additional studies)?
4. What benefit-risk information should be communicated to prescribers and patients?

PSUR Preparation: Best Practices and Common Challenges

Efficient PSUR preparation requires systematic data collection, cross-functional coordination, and rigorous quality control to meet regulatory timelines.

PSUR Preparation Timeline

Common PSUR Preparation Challenges

PSUR Quality Control Checklist

Before submission, verify:

Completeness:

• [ ] All 19 ICH E2C(R2) sections present and complete
• [ ] Summary tabulations include both cumulative and interval data
• [ ] Literature search covers full reporting period with documented methodology
• [ ] All ongoing signals from previous PSUR have status updates
• [ ] Exposure estimates provided with calculation methodology explained

Accuracy:

• [ ] Data lock point and reporting period dates correct and consistent throughout
• [ ] Adverse event numbers reconcile between narrative and tabulations
• [ ] MedDRA coding version specified and consistent
• [ ] References to previous PSURs accurate (section 13)
• [ ] Marketing authorization dates verified against official sources

Consistency:

• [ ] Company Core Safety Information (CCSI) referenced is current version
• [ ] Signal conclusions align with risk management plan updates
• [ ] Benefit-risk conclusion consistent with data presented in sections 7-18
• [ ] Regulatory actions reported match actual label changes and restrictions

Compliance:

• [ ] Submission within 70 days of data lock point
• [ ] Electronic format meets regional gateway requirements (EMA Gateway, FDA ESG)
• [ ] Document version control and approval signatures documented
• [ ] Cross-references to risk management plan, REMS, or safety specifications included

PSUR Submission Procedures by Region

Regulatory authorities have specific submission requirements, formats, and procedures for periodic safety update reports.

European Union PSUR Submission

Submission Route:

• Electronic submission through EMA PSUR Repository (single assessment procedure)
• Centrally authorized products (CAPs) submit to EMA
• Nationally/mutually recognized products may submit through national procedures or opt for single assessment

Technical Requirements:

Single Assessment Procedure:

• Pharmacovigilance Risk Assessment Committee (PRAC) conducts centralized review
• Rapporteur appointed to lead assessment
• Conclusion applies across EU member states
• Timeline: 60-day assessment period for routine PSURs

United States (FDA) PSUR/PBRER Submission

Submission Route:

• Electronic Submissions Gateway (ESG) using eCTD format
• Submit under original NDA/BLA application number
• Module 1.8.2 for periodic safety reports

Technical Requirements:

FDA-Specific Considerations:

• FDA does not mandate IBD-based reporting for all products but accepts harmonized IBD-based PBRERs
• Products with REMS may have specific reporting requirements beyond standard PBRER
• Post-marketing requirement (PMR) safety studies should be cross-referenced
• FDA typically does not issue formal assessment reports for routine periodic safety reports

Other Major Markets

Japan (PMDA):

• Uses Pharmaceuticals and Medical Devices Agency (PMDA) electronic submission system
• Japanese language required (translation from English PBRER common)
• Reexamination period products require detailed interval safety reports
• Format follows ICH E2C(R2) with local adaptations

Health Canada:

• Electronic submission through Health Canada's Electronic Submission Platform
• Accepts ICH-format PBRERs
• Must submit within 70 days of DLP
• Cross-reference to Risk Management Plan if applicable

Australia (TGA):

• Electronic Business Services (EBS) portal submission
• Accepts ICH PBRER format
• May be submitted as part of multi-region submission strategy

Signal Detection and Management in PSUR Context

Signal detection represents a core component of PSUR preparation, requiring systematic evaluation of safety data to identify new risks or changes to known risks.

What Constitutes a Signal?

ICH E2E definition: "Information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action."

Signal Detection Methods for PSUR

Signal Prioritization Framework

Not all signals warrant equal attention. Prioritization considers:

Seriousness:

• Does the signal involve death, hospitalization, disability, or other serious outcomes?
• What is the medical significance of the event?

Frequency:

• How many cases have been reported?
• What is the reporting rate relative to exposure?

Strength of Evidence:

• Is there a temporal relationship (drug preceded event)?
• Is there biological plausibility?
• Are there positive rechallenge or dechallenge cases?
• Do multiple independent data sources support the signal?

Public Health Impact:

• What is the estimated population exposure?
• Are vulnerable populations (pediatrics, elderly) affected?
• Is the indication for serious or life-threatening condition (where benefit may outweigh risk)?

Signal Evaluation Process

Common Signal Categories in PSUR

New Signals:

• Previously unrecognized adverse reactions not in current labeling
• New populations at risk (e.g., drug-drug interaction identified)
• New aspect of labeled reaction (e.g., longer time to onset than previously known)

Ongoing Signals:

• Signals under evaluation from previous PSUR that remain open
• May be awaiting additional data (e.g., completion of post-authorization safety study)
• Status update required in each PSUR until closed

Closed Signals:

• Signals evaluated and determined not to represent true risk
• Signals confirmed and addressed through labeling update
• Must provide rationale for closure

Integration with Risk Management Plans and REMS

Periodic safety update reports do not exist in isolation but are integrated with broader pharmacovigilance systems including Risk Management Plans (EU) and Risk Evaluation and Mitigation Strategies (US).

PSUR and Risk Management Plan (RMP) Relationship

The European Medicines Agency requires Risk Management Plans for most new marketing authorization applications. The RMP identifies important identified risks, important potential risks, and missing information.

PSUR-RMP Integration Points:

When RMP Updates Trigger:

• PSUR identifies new important identified risk or important potential risk
• Missing information has been addressed through newly available data
• Post-authorization safety study completed during reporting period
• Effectiveness evaluation suggests risk minimization measures inadequate

PSUR and REMS (US) Relationship

For products with FDA-mandated Risk Evaluation and Mitigation Strategies, the periodic safety report must address REMS performance.

REMS Assessment Report vs. PSUR:

Regulatory Inspections: PSUR as Assessment Tool

Health authorities use submitted PSURs to assess a company's pharmacovigilance system compliance and may conduct inspections based on PSUR findings.

What Inspectors Evaluate in PSURs

Completeness and Timeliness:

• Were PSURs submitted on time for all products?
• Are all required sections present and complete?
• Is the reporting period correct based on IBD or other specified schedule?

Data Quality:

• Are adverse event numbers consistent with safety database?
• Is literature search systematic, comprehensive, and documented?
• Are exposure estimates reasonable and methodology explained?

Signal Management:

• Were appropriate signal detection methods applied?
• Are signals from previous PSURs tracked with documented outcomes?
• Is signal prioritization and evaluation scientifically sound?

Benefit-Risk Assessment:

• Is the integrated benefit-risk analysis supported by data presented?
• Are conclusions reasonable given the safety and efficacy data?
• Are regulatory action recommendations appropriate?

Cross-Functional Coordination:

• Is clinical development data integrated (trial safety updates)?
• Are risk management plan and REMS activities addressed?
• Is there evidence of medical and regulatory oversight?

Common PSUR Inspection Findings

PSUR Automation and Technology Solutions

The complexity and volume of PSUR data have driven adoption of specialized pharmacovigilance software and automation tools.

Technology Solutions for PSUR Preparation

Automation Opportunities

High-Value Automation:

• Summary tabulation generation from safety database
• Literature search execution and duplicate removal
• Exposure data extraction from sales systems
• Standard text population (e.g., marketing authorization tables, previous PSUR summaries)
• Cross-reference verification between sections

Requires Human Expertise:

• Signal evaluation and causality assessment
• Integrated benefit-risk analysis
• Regulatory action recommendations
• Medical review and interpretation of clinical significance
• Quality review of conclusions and consistency

Data Integration Challenges

Common Data Sources for PSUR:

• Safety database (adverse event cases)
• Clinical trial management systems (ongoing trial safety data)
• Medical information systems (patient inquiries, off-label use reports)
• Literature monitoring services (published case reports, epidemiology studies)
• Regulatory intelligence databases (label changes, Dear Healthcare Provider letters)
• Sales and distribution systems (exposure data)
• Quality systems (product complaints, manufacturing deviations)

Integration Barriers:

• Different data formats and structures across systems
• Multiple regional or legacy databases requiring reconciliation
• Inconsistent coding (e.g., different MedDRA versions, in-house terms)
• Access and permission limitations across systems
• Real-time synchronization vs. periodic data extracts

Key Takeaways

Next Steps

Understanding periodic safety update report requirements is essential for maintaining pharmacovigilance compliance and ensuring continuous monitoring of your product's benefit-risk profile throughout its lifecycle.

Organizations managing regulatory submissions benefit from automated validation tools that catch errors before gateway rejection. Assyro's AI-powered platform validates eCTD submissions against FDA, EMA, and Health Canada requirements, providing detailed error reports and remediation guidance before submission.

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