Writing the Changes to Reference Safety Information Section in a PBRER

The section on changes to reference safety information establishes the safety reference against which much of the PBRER is interpreted. Its purpose is not to reproduce a label history. It should tell the assessor which reference information underpins the report, what scientifically meaningful safety changes occurred during the reporting interval, and whether those changes affect interpretation elsewhere in the PBRER.

Purpose and Regulatory Framework

The PBRER format is defined by ICH E2C(R2). In the European Union, the corresponding PSUR format and content are implemented through Commission Implementing Regulation (EU) No 520/2012 and GVP Module VII — Periodic safety update report (Rev. 1).

ICH E2C(R2) and GVP Module VII distinguish the reference information used for safety evaluation from the many local labels that may exist worldwide. The report should make the reference basis clear enough that an assessor can understand which safety information was regarded as established when evaluating interval and cumulative evidence.

This section therefore performs two linked functions:

1. define the applicable reference baseline; and
2. describe important changes to that baseline during the reporting interval.

Reference Safety Information in the PBRER Context

The terminology used by organisations varies. A company may maintain a Company Core Data Sheet (CCDS) containing a Company Core Safety Information (CCSI) section, while individual jurisdictions maintain their own approved product information.

For PBRER purposes, the relevant reference information should be identified according to the applicable ICH/EU framework and the reporting product. The author should not assume that a national SmPC, US Prescribing Information or internal company label automatically serves as the global reference merely because it is familiar to the writing team.

The report should clearly identify:

• the reference document used;
• its version or effective date where relevant;
• the authorised indication context relevant to benefit evaluation; and
• any important change during the reporting interval that affects the recognised safety profile.

Why the Reference Baseline Matters

The reference baseline affects interpretation across the PBRER. A change in recognised safety information may influence:

• whether an adverse reaction is considered newly characterised;
• how completed signals are described;
• how important risks are evaluated;
• whether risk minimisation has changed;
• whether regulatory actions are considered significant; and
• how the integrated benefit-risk assessment is framed.

The author should therefore treat the section as a cross-report control point, not as an isolated regulatory-history paragraph.

What Counts as a Meaningful Change

The section should focus on safety changes with scientific or clinical significance. Depending on the product, these may include:

• addition or substantial revision of an adverse reaction;
• a new contraindication;
• a materially strengthened warning or precaution;
• a clinically important interaction;
• a major change concerning pregnancy, lactation or a special population;
• a new monitoring recommendation;
• a meaningful change in risk characterisation; or
• another safety-related revision that changes how the product is understood or used.

Purely editorial changes, formatting changes and terminology harmonisation usually do not require detailed discussion unless they alter the scientific meaning.

The Author's First Question: What Was the Applicable Version?

Before drafting, the author should establish the chronology of reference-information versions across the reporting interval and at the data lock point.

A simple evidence map may include:

The exact internal records are organisation-specific. What matters is that the final narrative can be traced to controlled source information.

Handling Multiple Versions During the Reporting Interval

A reporting interval may span more than one version of the reference information. The author should not collapse these versions into a single undated description if doing so would obscure when the recognised safety profile changed.

A practical narrative normally states:

• which important change occurred;
• when it became part of the reference information;
• which safety issue drove it; and
• whether it affected later interpretation in the report.

The objective is chronology with scientific meaning, not exhaustive version history.

Global Reference Information and Local Product Information

Global core safety information and nationally approved product information can legitimately differ for periods of time because regulatory procedures and implementation dates vary by jurisdiction. A temporary difference does not by itself mean that the underlying scientific position is inconsistent.

Where regional differences matter, the author should explain them precisely. For example, a warning may have entered the company core information during the interval while the corresponding variation remained under review in some countries at the DLP.

The section should distinguish:

• the reference information used for the PBRER;
• the status of important local implementation where it affects interpretation; and
• any genuine scientific divergence between jurisdictions, if such divergence exists.

It should not become a country-by-country regulatory tracker.

Licensing, Multiple MAHs and Corporate Change

Products may be marketed through affiliates, licensing partners or different MAHs. Acquisitions and transfers can also change responsibility for product information.

The relevant question for the PBRER is not the commercial structure itself but whether that structure affects:

• which reference information applies;
• access to safety-related label history;
• completeness of interval changes; or
• interpretation of regional differences.

Commercial detail should be included only when it explains the scientific or regulatory context.

Multiple Indications, Formulations and Populations

A safety-information change may apply only to a particular indication, formulation, route or patient population. The narrative should therefore avoid broad statements that imply universal applicability.

For example, if a new monitoring requirement applies only to patients receiving a specific formulation, the text should identify that scope. Precision matters because later risk and benefit-risk sections may be indication- or population-specific.

Relationship With Actions Taken for Safety Reasons

A safety-related label change can appear in both the reference-information section and the Actions Taken for Safety Reasons section, but the two sections answer different questions.

• The reference-information section explains what changed in the safety reference baseline.
• The actions section explains what significant safety action occurred during the interval.

The wording should be coordinated without duplication. A major warning update may be introduced briefly as a safety action and described here as a change to the reference information, while the supporting evidence is analysed later in the signal or risk section.

Relationship With Signal and Risk Evaluation

Changes to reference information should be traceable to the scientific reasoning that justified them.

If a new adverse reaction was added following signal evaluation, the later signal/risk sections should explain the evidence and conclusion. If an important warning was strengthened because the severity or susceptible population was better characterised, the risk-evaluation section should explain that evolution.

This creates a logical chain:

new evidence → signal/risk evaluation → safety conclusion → reference-information change → benefit-risk consequence, if any.

Writing the Narrative

A concise entry for each important change should normally answer four questions:

1. What changed?
2. When did it change?
3. Why did it change?
4. Where is the supporting scientific evaluation discussed?

The section should avoid detailed case narratives, full study summaries or long causal arguments. Those belong in the appropriate scientific evaluation sections.

Illustrative Example

Suppose cumulative evidence supported recognition of severe hypoglycaemia in a newly exposed patient subgroup, leading to a revised warning during the interval.

A weak entry would say:

The CCDS was updated for hypoglycaemia.

A stronger entry would identify the relevant version/date, explain that the warning was strengthened for the defined subgroup following cumulative evaluation, and direct the reader to the later risk discussion. That gives the assessor chronology, scope and scientific context without duplicating the evaluation.

Practical Review Method

Before finalising the section, reconcile it against the controlled source documents and the rest of the PBRER. A practical review sequence is:

1. confirm the reference document and version used;
2. identify every scientifically meaningful interval change;
3. exclude purely editorial changes unless they affect interpretation;
4. confirm the timing and scope of each change;
5. identify any material regional implementation difference;
6. reconcile each change with Actions Taken for Safety Reasons;
7. reconcile each change with signal and risk conclusions;
8. confirm consistency with the integrated benefit-risk evaluation and conclusions; and
9. ensure that no proposed change is described as already approved or implemented.

Potential Writing Failure Modes

The following are illustrative writing failures, not inspection findings.

Inspection and Governance Considerations

Inspection interest usually lies in whether important changes to safety information are controlled, traceable and propagated appropriately across the pharmacovigilance system. An inspector may ask how a major core-safety change was initiated, approved, communicated, tracked and reflected in aggregate reporting.

That does not create a universal requirement for a specific global label committee, fixed approval cadence or QPPV signature on every core-label change. Governance should be sufficient to demonstrate controlled decision-making and implementation.

Possible questions include:

• Which reference information was used for this PBRER?
• How was the version confirmed?
• Which safety changes occurred during the interval?
• What evidence supported those changes?
• How were affiliates or partners informed?
• How were local implementation differences tracked?
• How did the change flow into the PSUR/PBRER, RMP and product information?

Practical Authoring Checklist

1. Is the applicable reference information identified unambiguously?
2. Is the version/effective date clear where relevant?
3. Are only scientifically meaningful changes emphasised?
4. Is each change described with correct scope and timing?
5. Are regional differences explained only where they matter?
6. Are licensing or MAH arrangements discussed only when relevant to interpretation?
7. Does the section avoid duplicating the detailed signal/risk assessment?
8. Is each important change consistent with Actions Taken for Safety Reasons?
9. Are signal, risk and benefit-risk sections aligned with the revised reference information?
10. Are proposals, approvals and implementation states distinguished accurately?

Relationship With Other QPPV.com PBRER Articles

For the overall PBRER structure see [[understanding-the-structure-of-a-pbrer]]. For the wider regulatory framework see [[pbrer-guide]]. For detailed authoring across all sections see [[how-to-write-a-pbrer]]. Related specialist articles include [[writing-the-actions-taken-for-safety-reasons-section]], [[writing-the-evaluation-of-risks-and-new-information-section-in-a-pbrer]] and [[writing-the-integrated-benefit-risk-evaluation-section-in-a-pbrer]].

Key Takeaways

The reference-information section establishes the safety baseline used throughout the PBRER and describes meaningful changes to that baseline during the reporting interval.

It should not become a complete label history or a country-by-country variation tracker.

The author should distinguish global reference information from local implementation and describe only those regional differences that matter to interpretation.

Every important safety-information change should be scientifically traceable to signal/risk evaluation and procedurally consistent with the actions and conclusions described elsewhere in the report.

References

1. International Council for Harmonisation. ICH E2C(R2): Periodic Benefit-Risk Evaluation Report (PBRER). Step 4, 15 November 2012.
2. International Council for Harmonisation. ICH E2C(R2) Questions and Answers. Last update 31 March 2014.
3. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module VII — Periodic safety update report (Rev. 1). EMA/816292/2011 Rev. 1.
4. European Medicines Agency. Periodic safety update reports (PSURs). Current procedural guidance.
5. European Union. Commission Implementing Regulation (EU) No 520/2012, as amended.
6. European Union. Directive 2001/83/EC, as amended.
7. European Union. Regulation (EC) No 726/2004, as amended.

Regulatory Note

This article explains authoring of the PBRER/PSUR section describing changes to reference safety information. It distinguishes the regulatory requirement to identify the applicable reference basis and important interval changes from organisation-specific label-governance structures. As of 9 September 2026, GVP Module VII Rev. 1 remains the published EMA module; current PSUR procedural guidance should be checked for live submissions.