Global Marketing Authorisation Holder with Affiliate MAHs

Many multinational pharmaceutical companies maintain a single global Company Core Data Sheet (CCDS) and Company Core Safety Information (CCSI), while individual marketing authorisations are held by affiliated legal entities in different countries.

Although multiple legal Marketing Authorisation Holders may exist, the organisation generally maintains one global scientific position regarding the recognised safety profile of the medicinal product.

In these situations, the Reference Safety Information used within the PBRER is normally derived from the current global CCSI rather than from any individual country's approved product information.

Regional implementation of the revised safety information may occur at different times because approval depends upon local regulatory procedures.

Consequently, temporary differences between the global RSI and individual national labels should be expected and do not necessarily indicate inconsistency.

The report should identify the RSI version used for the aggregate evaluation while recognising that implementation within individual jurisdictions may still be ongoing.

Independent Licensing Partners

Licensing arrangements require careful consideration because responsibilities for maintaining product information may differ between contractual partners.

Some licensing agreements require all partners to implement harmonised global safety information following revision of the CCDS.

Other agreements permit regional adaptation according to local regulatory requirements.

Authors should therefore determine which Reference Safety Information forms the basis of the PBRER and ensure that important differences arising from contractual responsibilities are understood before describing changes during the reporting interval.

Commercial details of the licensing agreement are generally unnecessary unless they influence interpretation of the Reference Safety Information or explain differences in implementation between regions.

Medical Review Consideration

Confirm that the Reference Safety Information used throughout the PBRER corresponds to the agreed global safety reference and not inadvertently to a regional product label.

Different Regional Implementation Dates

One of the most common situations encountered during preparation of a global PBRER is variation in the timing of implementation.

For example, the Company Core Safety Information may be revised in January.

European implementation may occur in March.

United States approval may occur in June.

Several smaller markets may not complete implementation until later in the year.

These differences are expected within global pharmacovigilance systems.

The purpose of this section is therefore not to document every national implementation date but to identify the Reference Safety Information applicable at the data lock point and summarise the important scientific changes introduced during the reporting interval.

Where regional implementation differs substantially and influences interpretation of the benefit-risk profile, a concise explanation should be provided.

Acquisition, Divestment and Marketing Authorisation Transfer

Corporate transactions may result in transfer of responsibility for maintaining the Reference Safety Information.

Examples include acquisition of product portfolios, divestment of mature brands, transfer of marketing authorisations or integration following company mergers.

The important consideration is not the commercial transaction itself but whether responsibility for maintaining the Reference Safety Information changed during the reporting interval.

Where responsibility has changed, the report should explain which version of the Reference Safety Information formed the basis of the current PBRER and describe any important transitional arrangements affecting interpretation of cumulative safety information.

Generic Products and Biosimilars

Manufacturers of generic medicines and biosimilars frequently align product information with the reference medicinal product while remaining subject to national regulatory approval processes.

Implementation of safety-related changes may therefore occur at different times between the reference product and related products.

Where these differences are relevant to interpretation of the aggregate safety evaluation, they should be described objectively without implying that temporary implementation differences necessarily represent different scientific conclusions.

The emphasis should remain on the Reference Safety Information applicable to the product covered by the PBRER.

Multiple Indications and Formulations

Some medicinal products have several authorised indications, formulations or routes of administration, each with different recognised safety information.

Authors should ensure that changes to the Reference Safety Information are described with sufficient precision to identify the affected indication, formulation or patient population.

For example, a new contraindication applicable only to an oncology indication should not be described as though it applies universally across all approved uses of the medicinal product.

Similarly, safety information affecting only a prolonged-release formulation should not be presented as a class-wide change unless supported by the available evidence.

Inspection Insight

During inspections, reviewers frequently assess whether organisations have robust global governance processes for maintaining the Company Core Safety Information and ensuring that important safety updates are communicated consistently across affiliated Marketing Authorisation Holders, licensing partners and regional regulatory organisations. The PBRER should therefore clearly identify the scientific reference used throughout the report and avoid ambiguity regarding the applicable RSI version.

Managing Reference Safety Information Throughout the Reporting Interval

One of the more challenging aspects of preparing a PBRER is determining how changes to the Reference Safety Information should be handled when they occur during the reporting interval.

Unlike static reference documents, the Company Core Data Sheet (CCDS) and Company Core Safety Information (CCSI) evolve continuously as new safety information becomes available. Consequently, aggregate report authors frequently prepare PBRERs covering periods during which one or more revisions to the Reference Safety Information have already occurred.

The objective of this section is not to describe every document revision but to identify the version of the Reference Safety Information used for the scientific evaluation and explain important changes introduced during the reporting interval.

Which Version of the RSI Should Be Used?

The Reference Safety Information applicable to the PBRER should be identified clearly.

Where the Reference Safety Information has changed during the reporting interval, the report should identify:

• the version used as the reference for the PBRER;
• the effective date of that version;
• the important safety changes introduced;
• the sections of the PBRER affected by those changes.

This allows regulators to understand the scientific framework used throughout the report.

The objective is transparency rather than documenting every editorial revision made to the Company Core Data Sheet.

Changes Introduced During the Reporting Interval

The reporting interval may contain several revisions to the Company Core Safety Information.

Not every revision requires detailed discussion.

The emphasis should remain on changes that influence interpretation of the medicinal product's recognised safety profile.

Examples include:

• addition of important identified risks;
• addition of important potential risks;
• new contraindications;
• important warnings and precautions;
• clinically significant adverse reactions;
• major changes to use in pregnancy or lactation;
• significant paediatric safety information;
• important monitoring recommendations.

Minor editorial revisions, harmonisation of terminology or formatting changes generally require little discussion unless they materially influence scientific interpretation.

Multiple RSI Versions Within the Reporting Interval

Some reporting intervals span several revisions of the Company Core Data Sheet.

For example, an important safety signal identified early in the reporting interval may result in revision of the Company Core Safety Information several months before the Data Lock Point.

In these situations, authors should explain clearly which version formed the basis of the scientific evaluation while summarising the important changes introduced during the interval.

Readers should never be left uncertain regarding which recognised safety information was considered current during preparation of the report.

Where necessary, brief explanation of the timing of important revisions may assist interpretation of subsequent signal evaluations and benefit-risk discussions.

Ongoing Label Updates at the Data Lock Point

Preparation of a PBRER frequently coincides with ongoing implementation of safety-related label changes.

For example, revision of the Company Core Safety Information may have been completed, while regulatory approval of corresponding national product information remains under review in several countries.

This situation is common within global pharmacovigilance and should not be interpreted as inconsistency.

The report should identify the applicable Reference Safety Information while explaining, where relevant, that implementation into regional product information remained ongoing at the Data Lock Point.

The emphasis should remain on the scientific reference standard rather than the administrative status of individual regulatory submissions.

Global Core Safety Information and Regional Product Information

Global safety governance and regional regulatory implementation frequently operate on different timelines.

A multinational company may maintain a single global Company Core Safety Information while individual affiliates submit corresponding updates according to national regulatory requirements and local implementation schedules.

Consequently, temporary differences between the Company Core Safety Information and nationally approved product information are expected.

The PBRER should clearly identify the Reference Safety Information used throughout the report while avoiding unnecessary description of every regional implementation milestone unless these differences influence interpretation of the safety evaluation.

Partner Companies Operating Different Implementation Timelines

Licensing partners and regional Marketing Authorisation Holders may implement agreed safety updates at different times because approval processes differ between regulatory authorities.

Where a common global Company Core Safety Information exists, temporary implementation differences do not necessarily represent disagreement regarding the underlying scientific conclusions.

Instead, they usually reflect differences in national regulatory procedures.

Where partners maintain independent product information under separate contractual arrangements, authors should ensure that the Reference Safety Information applicable to the PBRER is identified clearly and that important regional differences affecting interpretation of the aggregate safety evaluation are described objectively.

Commercial responsibilities should only be discussed where they are necessary to understand differences in the Reference Safety Information or its implementation.

Governance Considerations

Preparation of the PBRER requires close collaboration between pharmacovigilance, regulatory affairs, safety physicians and product label management functions.

Although governance models differ between organisations, effective preparation generally depends upon:

• clear identification of the applicable Reference Safety Information;
• documented version control;
• traceability of safety-related revisions;
• communication of important CCDS updates to relevant functions;
• consistency between aggregate reports and product information management activities.

These governance activities support preparation of scientifically consistent aggregate reports and facilitate regulatory review.

Inspection Insight

During inspections, organisations may be expected to demonstrate which version of the Company Core Safety Information formed the basis of aggregate safety evaluations, how important safety updates were governed internally and how consistency was maintained between global safety positions and regional implementation activities.

Writing High-Quality RSI Narratives

The purpose of this section is to explain how the recognised safety profile of the medicinal product evolved during the reporting interval. It should not become a regulatory submission history or a catalogue of every editorial revision made to the Company Core Data Sheet.

High-quality narratives focus on scientifically meaningful changes to the Reference Safety Information and explain their significance to the remainder of the PBRER.

For every important change, the reader should understand:

• what changed;
• why the change was introduced;
• when the change became part of the Reference Safety Information;
• whether the change influences interpretation of later sections of the report.

Detailed discussion of the supporting evidence belongs within the Signal Evaluation, Characterisation of Risks or Benefit-Risk sections rather than here.

Present Changes Chronologically

Where several important revisions occurred during the reporting interval, present them in chronological order.

This allows regulators to understand how the recognised safety profile evolved over time and how new scientific evidence translated into revisions of the Reference Safety Information.

Where several related revisions arose from the same safety concern, they should normally be discussed together rather than as isolated document revisions.

Focus on Scientifically Important Changes

Not every update to the Company Core Safety Information warrants discussion within the PBRER.

The emphasis should remain on revisions that materially affect the recognised safety profile.

Examples include:

• addition of new adverse reactions;
• important revisions to frequency classifications;
• new contraindications;
• important precautions or warnings;
• significant interactions;
• changes affecting pregnancy, lactation or paediatric use;
• important monitoring recommendations;
• reclassification of important identified or potential risks.

Routine editorial corrections, formatting changes or harmonisation of terminology generally do not require detailed discussion unless they alter scientific interpretation.

Maintain Consistency Throughout the Report

Changes described within the RSI section should be reflected consistently throughout the remainder of the PBRER.

For example:

• newly recognised adverse reactions should be considered during signal evaluation where appropriate;

• important identified risks should be reflected within risk characterisation;

• revised monitoring recommendations should align with discussions of risk minimisation;

• important benefit-risk implications should be discussed within the integrated benefit-risk evaluation.

Readers should never encounter conflicting descriptions of the recognised safety profile in different sections of the report.

Common Mistakes

Several recurring deficiencies are observed during preparation and review of this section.

One of the most frequent errors is confusing the Reference Safety Information with regional product information. Although related, these documents serve different regulatory purposes and should not be used interchangeably.

Another common mistake is presenting every editorial revision as though it represents a significant safety change. This obscures genuinely important developments and reduces the overall clarity of the report.

Authors should also avoid describing regional implementation history in excessive detail. The objective is to identify the applicable Reference Safety Information rather than document every national variation submission.

Failure to identify the RSI version used for the scientific evaluation is another important deficiency. Readers should always be able to determine the reference document against which the cumulative safety data have been assessed.

Finally, inconsistencies between the RSI section and later discussions of risks, signals or benefit-risk evaluation frequently generate avoidable regulatory questions during assessment.

Inspection and Regulatory Assessment Considerations

Regulatory assessors expect the Reference Safety Information section to establish a clear scientific baseline for interpretation of the remainder of the PBRER.

During assessment, reviewers may verify:

• that the applicable RSI version has been identified clearly;
• that important safety-related revisions have been summarised accurately;
• that changes described are consistent with later discussions within the report;
• that important risks added to the RSI are reflected appropriately throughout the benefit-risk evaluation;
• that regional implementation differences have been described objectively where relevant.

During pharmacovigilance inspections, inspectors may also review:

• governance of CCDS and CCSI revisions;
• version control procedures;
• traceability of safety-related changes;
• communication of revised core safety information to affiliates and licensing partners;
• alignment between aggregate reporting and product information management processes.

Organisations should therefore maintain documentation demonstrating how changes to the Company Core Safety Information were evaluated, approved, communicated and incorporated into aggregate safety reports.

Inspection Insight

Inspectors are not only interested in the final Reference Safety Information. They frequently review the governance process used to evaluate new safety information, approve changes to the core safety documents and ensure consistent implementation across the organisation.

Key Takeaways

The Reference Safety Information provides the scientific baseline against which cumulative safety information is evaluated throughout the PBRER.

This section should identify the applicable RSI version, summarise clinically important safety-related revisions introduced during the reporting interval and explain how those changes influence interpretation of the medicinal product's evolving benefit-risk profile.

High-quality reports distinguish clearly between global Reference Safety Information and regional product information, describe significant scientific changes rather than editorial revisions and maintain consistency throughout the remainder of the aggregate report.

Continue Reading

• [[reference-safety-information-in-pharmacovigilance]]
• [[writing-the-estimated-exposure-section-in-a-pbrer]]
• [[writing-the-data-in-summary-tabulations-section-in-a-pbrer]]
• [[writing-the-signal-evaluation-section-in-a-pbrer]]
• [[benefit-risk-evaluation]]
• [[risk-management-plans]]

References

Primary Regulatory References

1. ICH E2C(R2): Periodic Benefit-Risk Evaluation Report.

2. European Medicines Agency. Good Pharmacovigilance Practices (GVP) Module VII – Periodic Safety Update Report.

3. Commission Implementing Regulation (EU) No 520/2012.

4. Directive 2001/83/EC.

5. Regulation (EC) No 726/2004.

Supporting Regulatory Guidance

1. EMA Questions & Answers on PSURs and PBRERs.

2. EMA Procedural Guidance for PSUSA.

3. Relevant PRAC guidance relating to product information updates and benefit-risk evaluation.

Scientific References

1. CIOMS Working Group reports relating to benefit-risk evaluation and aggregate safety reporting.

2. Relevant peer-reviewed publications discussing core safety information, aggregate reporting and regulatory labelling governance.