GVP Module VII: PSUR Reference Data and International Safety Information

Introduction

A PSUR cannot be interpreted correctly unless the safety information being evaluated is compared with a clearly defined reference.

The reference information establishes the baseline against which the MAH determines whether information arising during the reporting interval represents a new safety finding, a change to an existing risk, a change in the authorised safety information, or information that does not alter the current understanding of the product.

GVP Module VII therefore gives an important role to reference product information and the reference safety information contained within it or otherwise identified for the purposes of the PSUR.

The PSUR also has an international perspective. A medicinal product may be marketed in multiple countries, with safety information generated from different regulatory environments, formulations, indications, populations and reporting systems. Relevant international safety information can contribute to the EU periodic evaluation and must be assessed in its proper regulatory context.

The objective is not to make every country-specific document identical. The objective is to establish a controlled reference and then evaluate relevant safety information against it consistently.

1. What Is Reference Information?

Reference information is the controlled information against which the safety findings in the PSUR are evaluated.

For PSUR purposes, the reference framework includes two closely related concepts:

• reference safety information, which establishes the baseline for assessing whether reported events are expected or represent changes to the known safety profile; and
• reference product information, which provides the broader product information relevant to the safety and benefit assessment, including the authorised indications and other applicable product information.

These concepts should not be treated as interchangeable database fields. They serve different analytical purposes even when they are contained in the same controlled document.

2. Why a Reference Is Necessary

Without a defined reference, the PSUR team cannot reliably answer basic questions such as:

• Is this adverse reaction already described?
• Has the frequency or seriousness of a known reaction changed?
• Is this a new safety concern?
• Was a warning added during the reporting interval?
• Which authorised indications should be included in the benefit assessment?
• What product information was actually in effect at the DLP?

The reference therefore provides the baseline for comparison.

A strong PSUR process should be able to show which reference information was used, which version applied at the DLP and how changes during the reporting interval were identified.

3. Reference Safety Information

Reference safety information is used to determine whether an adverse reaction is expected for the purposes of the periodic safety evaluation and relevant regulatory reporting framework.

The reference should be sufficiently specific to the product and applicable context.

It may include information such as:

• adverse reactions;
• important warnings and precautions;
• contraindications;
• important interactions;
• and other safety information that forms part of the established reference safety profile.

The exact document used must be identified and controlled.

The reference safety information should not be inferred retrospectively from whichever version happens to be easiest to retrieve during PSUR preparation.

4. Reference Product Information

Reference product information provides the broader regulatory and clinical context for the PSUR.

GVP Module VII allows the MAH to identify an appropriate reference product information document for the PSUR, taking account of the regulatory and product circumstances.

Where a company core data sheet or comparable global core document is used, the MAH should ensure that it appropriately represents the information required for the PSUR, including the authorised indications component where applicable.

Where no suitable company core document exists, the MAH may need to use other national or regional product information, such as an EU SmPC, as appropriate to the circumstances.

The important control is that the selected reference is explicitly identified and justified.

5. Reference Information Is Not Necessarily the EU Label

An international company may maintain several product-information documents.

For example:

Global core document
        │
        ├── US prescribing information
        ├── EU SmPC
        ├── UK product information
        ├── Canadian product information
        └── Other national documents

These documents may differ because of local regulatory requirements, indications, formulations, contraindications, wording or risk-management decisions.

The existence of different labels does not make the PSUR reference meaningless. It means the MAH must define the reference information appropriately and understand which document is being used for which analytical purpose.

6. Version Control at the DLP

The reference information must be version controlled.

The relevant version is not simply the version available when the PSUR author begins drafting. The organisation must establish which version was in effect at the end of the reporting interval and identify significant changes during the interval.

A controlled record should therefore capture, as applicable:

• document name;
• version number;
• effective date;
• jurisdiction;
• indication or formulation covered;
• DLP status;
• and the relationship to the PSUR.

This is essential for traceability.

7. Changes During the Reporting Interval

Reference safety information can change during a reporting interval.

A change may result from:

• a new adverse reaction;
• a new warning or precaution;
• a contraindication;
• an interaction;
• a change in indication;
• new clinical-study findings;
• a regulatory safety action;
• or another important safety finding.

The PSUR should identify significant changes and evaluate their relevance to the safety assessment.

The presence of a label change does not itself determine the conclusion of the PSUR. The change is evidence of a regulatory or scientific development that must be understood in context.

8. The Relationship Between Reference Information and Expectedness

Expectedness and reference safety information are closely connected but should not be confused with the broader concept of whether a safety issue is clinically important.

A reaction can be serious and expected. It can also be serious and unexpected. Expectedness does not determine causality, clinical importance or the overall benefit-risk balance.

For this reason, the reference information should be treated as one component of the PSUR evidence framework rather than as a substitute for scientific evaluation.

9. Different Indications, Formulations and Routes

The reference information must be sufficiently specific where safety or benefit information differs according to:

• indication;
• formulation;
• route of administration;
• strength;
• dosing regimen;
• or population.

For example, a safety finding associated with an injectable formulation should not automatically be interpreted as though it applies identically to every formulation without considering the clinical context.

Similarly, an indication-specific safety issue may require separate consideration from the overall product safety profile.

The PSUR should make such distinctions visible where they materially affect the assessment.

10. International Safety Information

A medicinal product may generate safety information outside the EU before, during or after its EU marketing authorisation lifecycle.

Relevant international information can include:

• individual case safety reports;
• regulatory safety communications;
• label changes;
• clinical studies;
• epidemiological studies;
• literature;
• signal evaluations;
• and regulatory assessments.

The geographic origin of the information does not by itself determine whether it is relevant to the EU PSUR.

The question is whether the information contributes to understanding the safety profile or benefit-risk balance of the product within the scope of the assessment.

11. International Information Does Not Mean Automatic Global Equivalence

International evidence must be interpreted carefully.

A safety finding from another jurisdiction may involve:

• a different indication;
• different dose;
• different formulation;
• different treatment duration;
• different patient population;
• different prescribing practices;
• or different regulatory definitions.

The MAH should therefore determine whether those differences affect the applicability or interpretation of the information for the EU product.

The correct approach is neither to exclude international information automatically nor to assume that every foreign regulatory action applies identically in the EU.

12. Global Safety Database and EU PSUR

Many MAHs maintain a global safety database that contains information from multiple jurisdictions.

This can provide an important source for PSUR preparation, but the global database is not itself the regulatory reference.

The PSUR process must still determine:

• which products are within scope;
• which indications and formulations are relevant;
• which cases belong to the reporting period;
• which reference information applies;
• and how international findings affect the EU safety assessment.

A global database can support the process without replacing regulatory judgement.

13. Regulatory Differences Between Countries

Different authorities may take different regulatory actions in response to similar evidence.

For example, one authority may update a warning while another may request additional evidence before changing its product information.

The PSUR should record relevant international regulatory developments and assess their significance rather than simply creating a list of country-specific actions.

The scientific question is why the action occurred and whether the underlying evidence changes the EU assessment.

14. Reference Information and the DLP

The DLP provides the temporal anchor for determining which version of reference information applies at the end of the reporting interval.

The relationship can be represented as:

Reference information during interval
             ↓
       Changes identified
             ↓
            DLP
             ↓
Reference information in effect at DLP
             ↓
      Periodic evaluation

The PSUR should be able to distinguish changes that occurred during the interval from the final reference state at the DLP.

15. Practical Example: New Warning During the Interval

Suppose an important warning is added to the EU product information three months before the DLP following a regulatory safety assessment.

The PSUR should not simply use the new warning as though it had always been present.

The assessment should establish:

1. what the reference information said at the beginning of the interval;
2. what evidence led to the regulatory change;
3. when the change became effective;
4. what information was available by the DLP; and
5. whether additional analysis or action is required.

This creates a traceable relationship between the safety information, the regulatory action and the PSUR assessment.

16. Practical Example: US Label Change but No EU Change

Suppose a significant warning is added to a US label but the EU SmPC is not changed.

The US action should not automatically be treated as an EU product-information change.

It should nevertheless be assessed as potentially relevant international safety information.

The PSUR team should determine:

• why the US action occurred;
• what evidence supported it;
• whether the evidence is relevant to the EU product;
• whether an EU regulatory assessment has occurred;
• and whether the EU benefit-risk conclusion is affected.

17. Practical Example: Different Formulations

Suppose a safety concern is identified with an intravenous formulation but the MAH also markets an oral formulation.

The PSUR should determine whether the mechanism of the concern is formulation-specific or whether the evidence supports a broader product-level risk.

The reference product information should allow the relevant formulation and route to be identified clearly.

18. Practical Example: Global Case Increase

Suppose the global safety database shows a substantial increase in reports from a country outside the EU.

The increase should not automatically be interpreted as an increase in EU risk.

The assessment should consider:

• exposure in the affected country;
• reporting behaviour;
• local regulatory communications;
• indication and prescribing patterns;
• case characteristics;
• and whether the underlying mechanism is relevant to EU use.

The international increase may nevertheless provide important evidence for the global and EU safety assessment.

Key Takeaways

• A PSUR requires a clearly defined reference against which safety information is evaluated.
• Reference safety information and reference product information serve related but distinct purposes.
• The selected reference information must be explicitly identified and version controlled.
• The version in effect at the DLP is important for the periodic assessment.
• Significant changes during the reporting interval should be identified and assessed.
• International safety information can be highly relevant to an EU PSUR.
• International information should be interpreted in its clinical, regulatory and product context.
• A global safety database supports PSUR preparation but does not replace regulatory assessment.
• Country-specific label differences should be analysed rather than mechanically copied into the EU assessment.
• Differences in indication, formulation, route, population and exposure can materially affect interpretation.

19. Reference Data and the Baseline Safety Profile

The purpose of reference information is not limited to deciding whether an individual adverse reaction is expected.

It establishes the baseline against which the MAH can evaluate whether the product's safety profile has changed.

A useful distinction is:

This prevents the reference document from becoming a static appendix with no analytical function.

20. Reference Safety Information Versus Current Product Information

The document currently authorised in a particular jurisdiction and the reference document selected for PSUR purposes may have different roles.

The PSUR process should therefore maintain a clear distinction between:

• the regulatory product information applicable to a particular marketing authorisation and jurisdiction;
• the reference product information selected for the PSUR;
• and the reference safety information used for safety evaluation.

Where these documents differ, the difference should be understood and documented rather than hidden by treating them as interchangeable.

21. Changes to Reference Safety Information

GVP Module VII specifically requires significant changes to reference safety information during the reporting interval to be identified in the PSUR.

Examples can include changes concerning:

• contraindications;
• warnings and precautions;
• adverse reactions;
• interactions;
• important findings from clinical trials;
• and significant non-clinical findings.

The PSUR should provide sufficient context to explain what changed and why the change matters to the safety evaluation.

A change log alone is insufficient if the underlying safety significance is not understood.

22. Reference Information and Signal Evaluation

Reference information interacts with signal management in both directions.

A new signal may result in a change to the reference safety information. Conversely, a change to reference safety information may provide important context for evaluating subsequent reports.

The PSUR should therefore reconcile relevant changes with the signal-management history.

For example:

Emerging evidence
      ↓
Signal evaluation
      ↓
Regulatory assessment
      ↓
Reference safety information changed
      ↓
PSUR documents the change
      ↓
Cumulative safety evaluation

The PSUR should explain the scientific relationship rather than merely reproducing the chronology.

23. International Regulatory Actions

International regulatory action can be an important safety signal even when the EU regulatory position has not changed.

Relevant actions may include:

• safety warnings;
• contraindications;
• restrictions of use;
• product withdrawals or suspensions;
• Dear Healthcare Professional communications;
• requests for additional studies;
• or regulatory assessments of emerging risks.

The PSUR should consider the underlying evidence and the reason for the action.

The fact that another authority acted is itself information, but it is not necessarily proof that the same regulatory action is required in the EU.

24. International Regulatory Differences as Evidence

Differences between regulatory authorities can arise for legitimate reasons.

Authorities may have access to different data, assess different populations, apply different legal frameworks or reach different conclusions about the balance of evidence.

Therefore, a PSUR should not use a simplistic rule such as:

foreign label change = EU label change

Nor should it use the opposite rule:

no EU label change = foreign action irrelevant

The correct approach is evidence-based assessment of the underlying information.

25. International Data and the EU Population

The relevance of international data depends partly on whether the affected population and use conditions are comparable with those in the EU.

The assessment may consider:

• demographic characteristics;
• genetic or ethnic factors where scientifically relevant;
• healthcare practices;
• treatment patterns;
• diagnostic practices;
• concomitant medication;
• indication;
• dose;
• formulation;
• and exposure duration.

These factors should not be invoked speculatively. They are relevant when there is a scientifically plausible reason that they could affect interpretation of the safety finding.

26. International Exposure and Use Patterns

The PSUR's exposure assessment can include international use where it contributes to understanding the product's overall safety experience.

However, exposure should be interpreted with the same discipline as safety reports.

For example, a large increase in global sales accompanied by an increase in case reports may produce a very different interpretation from an increase in reports without a corresponding change in exposure.

Where use differs materially between jurisdictions, the PSUR should consider whether the difference affects the safety evaluation.

27. Global Core Safety Information

Large MAHs may maintain a global core safety document that serves as a central reference for safety information.

This can improve consistency, but it does not eliminate the need to maintain jurisdiction-specific regulatory information.

A global core document may contain safety information that is not present in every national label, while a national label may contain additional information required by the local authority.

The PSUR team should therefore understand exactly which document is being used as the reference for the report and what its relationship is to local product information.

28. Reference Information and Multiple Products

A single PSUR may cover several products or marketing authorisations where permitted by the applicable regulatory framework.

Where products differ in:

• indication;
• formulation;
• strength;
• route;
• or other clinically relevant characteristics,

the PSUR should identify those differences where they affect the safety evaluation.

A common reference does not justify collapsing clinically distinct evidence into a single undifferentiated analysis.

29. Reference Information for Generic and Established Products

Some products may not have a company core data sheet or other global reference document suitable for the PSUR.

This is particularly relevant for older, generic or locally developed products.

In such circumstances, the MAH should clearly identify the reference information used for the PSUR and ensure that it is appropriate to the product and regulatory context.

The absence of a global document does not remove the need for a controlled reference.

30. Reference Information and Product Lifecycle Changes

The reference information can change as the product lifecycle develops.

Examples include:

• new indications;
• new formulations;
• new strengths;
• new routes of administration;
• safety-related variations;
• line extensions;
• and withdrawal of indications.

The PSUR process should be connected to regulatory lifecycle management so that the reference information used in the safety assessment remains current.

31. Reference Information and RMP Changes

Changes in the RMP and changes in reference safety information may be related but are not synonymous.

A new or changing risk may lead to changes in the RMP, product information, both, or neither, depending on the evidence and regulatory decision.

The PSUR should therefore reconcile relevant RMP developments with reference-information changes without assuming that one automatically determines the other.

32. What Should Be Controlled?

A mature PSUR process should maintain a controlled record of:

1. the selected reference product information;
2. the reference safety information;
3. the versions in effect during the reporting interval where relevant;
4. the version in effect at the DLP;
5. significant changes during the interval;
6. the rationale for selecting the reference information;
7. relevant international product-information changes;
8. and the relationship between those changes and the PSUR conclusions.

This provides the traceability needed for both scientific review and inspection.

33. Common Failure: Using the Wrong Version

An author retrieves the current EU SmPC while preparing a PSUR several months after the DLP.

The current SmPC contains a safety warning that was added after the DLP.

If the author uses the current document without checking its effective date, the historical PSUR analysis may incorrectly imply that the warning was already present during the reporting period.

The corrective control is version and effective-date verification.

34. Common Failure: Treating a Foreign Label as an EU Regulatory Decision

A US authority changes its product information.

The PSUR author copies the US change into the EU product-information section and states that the EU safety information changed.

That is incorrect unless the EU regulatory position actually changed.

The US action should instead be represented as relevant international information and evaluated for its implications for the EU product.

35. Common Failure: Ignoring International Information

An MAH's global safety group identifies a significant safety concern outside the EU, but the EU PSUR team excludes it because no EU case has been received.

That approach is too narrow.

The absence of EU reports does not establish that international evidence is irrelevant. The information should be assessed for its applicability to the EU product and population.

36. Common Failure: Treating the Reference as Static

A PSUR team copies the reference product information from the previous PSUR and does not reconcile changes during the current reporting interval.

This can obscure important safety developments and weaken the relationship between regulatory actions and the periodic safety assessment.

Reference information should be actively controlled, not inherited blindly from the previous report.

37. Inspection Perspective

Inspectors may ask:

• What reference safety information did you use?
• Why was that document selected?
• Which version was applicable at the DLP?
• How did you identify changes during the reporting interval?
• How did you evaluate international regulatory actions?
• How did you determine whether foreign safety information was relevant to the EU product?
• How did you reconcile the PSUR reference with local product information?
• How did you ensure that post-DLP changes were not incorrectly attributed to the reporting interval?

The organisation should be able to answer these questions from controlled records rather than relying on individual author recollection.

38. QPPV Oversight

The QPPV should be able to understand how reference information affects the conclusions presented in the PSUR.

This does not mean that the QPPV must personally maintain every product-information version. It means that the PV system should provide sufficient governance and escalation to ensure that material reference-information changes are recognised and appropriately evaluated.

Particular attention should be given to:

• significant new safety information;
• international regulatory actions;
• discrepancies between global and EU safety information;
• and changes that could affect the benefit-risk conclusion.

39. Practical Control Framework

A simple operational control can be built around five questions:

1. What is our reference?
           ↓
2. Which version applies at the DLP?
           ↓
3. What changed during the interval?
           ↓
4. What relevant international information emerged?
           ↓
5. What does all of this mean for the EU safety assessment?

This framework is simple enough to operationalise while preserving the scientific judgement required by the PSUR.

40. Key Takeaways

Reference information is the baseline against which the PSUR evaluates changes in the safety profile.

The selected reference should be explicit, appropriate, version controlled and traceable to the DLP.

International safety information should be considered based on its evidentiary and clinical relevance, not merely its geographical origin.

International regulatory actions are important evidence but do not automatically establish the EU regulatory position.

Differences in indication, formulation, route, population, exposure and regulatory context can change the meaning of an international safety finding.

The strongest PSUR processes connect reference-information control, international safety surveillance, signal management, regulatory lifecycle management and the final benefit-risk assessment.

41. When Reference Information Changes the Interpretation of a Case

The reference safety information provides an important classification baseline, but the PSUR should still evaluate the clinical meaning of individual cases and aggregated evidence.

For example, an adverse reaction may be listed in the reference safety information but become more frequent, more severe or associated with a previously unrecognised population. Its listed status does not end the assessment.

Conversely, an event may not be listed but may have insufficient evidence to establish a new causal association.

The PSUR therefore asks a broader question than expectedness:

Has the totality of evidence changed the understanding of the safety profile or benefit-risk balance?

42. Reference Information and Signal Closure

A signal may be closed without changing the reference safety information.

That conclusion can be scientifically important because it explains why a suspected new risk was not incorporated into the established safety information.

Similarly, a signal may remain under evaluation at the DLP without a regulatory change having occurred.

The PSUR should accurately represent the status of the evidence and avoid presenting unresolved scientific questions as established risks.

43. Reference Information and Regulatory Variations

Safety-related variations can modify the authorised product information.

The PSUR should be able to trace the relationship between:

Safety evidence
      ↓
Regulatory assessment
      ↓
Variation / regulatory decision
      ↓
Updated product information
      ↓
PSUR reference information
      ↓
Periodic safety evaluation

This relationship is particularly important when a change occurs shortly before the DLP.

The effective date, regulatory basis and scope of the change should be clear.

44. Multiple Reference Documents

Some products require more than one reference document because the safety and authorised-indication information may not be contained in a single document.

Where this occurs, the MAH should identify the documents explicitly and explain their respective roles.

The objective is not to force all reference information into one file. The objective is to create an unambiguous reference framework for the PSUR.

45. Reference Information and the PSUR Sections

Reference information has implications for several parts of the PSUR rather than only one section.

Depending on the applicable PSUR structure, it can affect:

• changes to reference safety information;
• estimated exposure and use patterns;
• signals and risks;
• safety evaluation;
• benefit-risk analysis;
• and proposed actions.

The same regulatory change may therefore appear in more than one analytical context, but the presentation should remain consistent.

46. International Safety Information and Case Processing

International safety information may enter the MAH through several operational channels.

Examples include:

• the global safety database;
• affiliates;
• license partners;
• literature monitoring;
• regulatory intelligence;
• clinical development;
• and external vendors.

The PSUR should rely on controlled processes that reconcile these sources where necessary.

A foreign case should not be counted as a separate observation merely because the same underlying case entered through multiple organisational pathways.

47. International Safety Information and Literature

International literature can provide evidence that is particularly important when the EU product has limited exposure or when a safety issue is recognised first in another market.

The PSUR assessment should consider the publication's:

• population;
• exposure;
• product and formulation;
• outcome;
• study design;
• comparator where applicable;
• and methodological limitations.

The geographic location of the publication should not be used as a surrogate for evidentiary quality.

48. International Safety Information and Studies

Global clinical and observational studies may contain information relevant to an EU PSUR even when only part of the study population is exposed to the EU-authorised product or indication.

The assessment should establish which findings are applicable and identify important differences in:

• product exposure;
• dose;
• indication;
• population;
• study setting;
• and treatment duration.

This avoids both over-generalisation and unjustified exclusion.

49. International Safety Information and Risk Management

International safety information can influence risk-management decisions.

For example, a safety concern identified outside the EU may lead to:

• further signal evaluation;
• additional data collection;
• changes to the RMP;
• a regulatory variation;
• additional risk-minimisation measures;
• or continued monitoring without immediate regulatory change.

The PSUR should explain the relationship between the evidence and the resulting action where that relationship is relevant to the periodic assessment.

50. When International Information Is Not Applicable

Not every international safety finding will be relevant to the EU product.

A finding may have limited applicability because the foreign product has:

• a substantially different active ingredient or formulation;
• a different indication;
• a materially different dose;
• a different exposure population;
• or a use pattern that is not relevant to the EU authorisation.

The exclusion should nevertheless be based on an appropriate assessment rather than an automatic geographic rule.

Where a potentially important international finding is excluded, the rationale should be documented.

51. Avoiding Retrospective Reconstruction

Reference-information reconciliation should occur as part of the routine PV and regulatory processes, not only when a PSUR deadline approaches.

A mature process should capture significant changes when they occur.

This reduces the risk that the PSUR team discovers months later that:

• a warning changed;
• an international authority issued a safety communication;
• a formulation changed;
• an indication was withdrawn;
• or a global safety document was revised.

The PSUR should then use controlled records rather than reconstructing history from emails and individual memory.

52. Data Lineage

A defensible PSUR should provide a traceable chain from source information to conclusion.

For reference information, this can be represented as:

Regulatory document
      ↓
Controlled version
      ↓
Effective date
      ↓
DLP applicability
      ↓
PSUR analysis
      ↓
Conclusion / action

For international safety information:

International source
      ↓
Scientific / regulatory assessment
      ↓
Applicability to EU product
      ↓
Integration into PSUR evidence
      ↓
Benefit-risk conclusion

Traceability is particularly important when the evidence is later challenged during an inspection or regulatory assessment.

53. Inspection Scenario: Wrong Reference Version

An inspector asks why a PSUR describes a warning as being present throughout the reporting period when the warning was introduced only shortly before the DLP.

The organisation should be able to produce:

• the earlier reference version;
• the updated version;
• effective dates;
• the regulatory decision or variation;
• and the PSUR analysis showing how the change was considered.

If these records cannot be reconciled, the issue is not simply a writing error. It may indicate a weakness in the interface between regulatory information management and pharmacovigilance.

54. Inspection Scenario: Foreign Regulatory Action

An inspector asks why a major foreign regulatory warning was absent from the PSUR.

The appropriate response is not automatically that the warning was not applicable to the EU.

The organisation should demonstrate that the foreign action was identified, assessed for relevance and either incorporated into the PSUR or excluded with a documented rationale.

The important evidence is the decision process.

55. Inspection Scenario: Global Database and EU PSUR Reconciliation

An inspector identifies that the global safety database contains substantially more reports than the dataset used for a particular PSUR analysis.

The organisation should be able to explain:

• the PSUR scope;
• the data cut-off;
• product and indication filters;
• duplicate handling;
• exclusion criteria;
• and reconciliation controls.

A difference in dataset size is not necessarily an error. An unexplained difference is a control weakness.

56. Governance Metrics

Useful process metrics can include:

• percentage of reference documents reconciled before the PSUR project starts;
• percentage of significant reference changes captured within the required process timeframe;
• number of unresolved discrepancies at PSUR initiation;
• number of international regulatory actions requiring escalation;
• and number of reference-data discrepancies identified during QC.

Metrics should measure process control rather than reward the absence of identified issues.

57. What Good Practice Looks Like

A well-controlled PSUR process has a simple characteristic: the authors do not have to guess what the reference information was.

The system should make it possible to determine:

• what document was selected;
• why it was selected;
• which version applied;
• what changed during the interval;
• what relevant international information emerged;
• how applicability was assessed;
• and how the evidence influenced the final conclusion.

This is the practical meaning of traceability.

58. Final Practical Checklist

Before finalising the PSUR, the team should be able to answer yes to the following:

• Is the reference product information explicitly identified?
• Is the reference safety information explicitly identified?
• Are the relevant versions controlled?
• Is the DLP version confirmed?
• Are significant changes during the interval identified?
• Are relevant international safety findings included?
• Have international regulatory actions been assessed?
• Have differences between jurisdictions been considered where relevant?
• Have formulation, indication and population differences been considered?
• Can important exclusions be explained?
• Are global and EU datasets reconciled where necessary?
• Can the final safety conclusion be traced to the evidence?

59. Key Takeaways

Reference data are not administrative attachments to the PSUR. They establish the baseline against which changes in the safety profile are interpreted.

International safety information is part of the broader evidence base and should be assessed according to scientific and regulatory relevance rather than geography.

The most important operational controls are explicit reference selection, version control, DLP verification, change tracking, international-safety surveillance, reconciliation and documented judgement.

The final PSUR should make it possible for another qualified reviewer to reconstruct why the organisation reached its safety conclusions from the reference information and evidence available at the time.

References

1. European Medicines Agency. Good Pharmacovigilance Practices (GVP), Module VII — Periodic Safety Update Report.
2. European Medicines Agency. Periodic safety update reports (PSURs), including current procedural guidance and PSUR Repository information.
3. European Medicines Agency. GVP Module VII explanatory note, current revision.
4. European Commission. Commission Implementing Regulation (EU) No 520/2012, as amended, including requirements concerning PSUR content and reference information.
5. International Council for Harmonisation. ICH E2C(R2): Periodic Benefit-Risk Evaluation Report (PBRER).
6. European Medicines Agency. Current GVP guidance and revision information.

Regulatory Note

This article is an educational explanation of reference information and international safety information in the EU PSUR. It does not replace current GVP Module VII, applicable EU legislation, EMA procedural guidance, the PSUR Repository requirements or an organisation's approved procedures.

GVP guidance and EU pharmacovigilance legislation are subject to revision. The current applicable regulatory sources should be verified before preparing or submitting a PSUR.

Examples in this article are illustrative unless an authoritative source is specifically identified.