GVP Module VII: Multiple Products, Substances and Marketing Authorisation Holders

Introduction

Periodic safety evaluation becomes substantially more complex when an active substance is associated with more than one medicinal product, indication, formulation, marketing authorisation or marketing authorisation holder (MAH).

EU pharmacovigilance arrangements are designed to avoid fragmented safety assessment while preserving the responsibilities of individual MAHs for the products they hold.

The central principle is that PSUR preparation should normally be organised around the active substance and the applicable regulatory scope, rather than around an arbitrary internal product boundary.

For products containing the same active substance, GVP Module VII generally provides for a single PSUR covering the relevant products of the same MAH, unless otherwise specified or agreed with the competent authorities. The report can nevertheless contain separate analyses where differences between indications, routes, dosage forms or dosing regimens are clinically or regulatorily relevant. citeturn0search12turn0search13

Where different MAHs are involved, the EU single-assessment framework allows related PSURs concerning the same active substance or combination to be assessed together through PSUSA where applicable. EMA describes PSUSA as the assessment of PSURs for medicines containing the same active substances or combinations, even where different marketing authorisations and Member States are involved. citeturn0search0

1. Why Multiple-Product Scope Matters

Fragmenting safety evaluation too aggressively can obscure important evidence.

For example, one formulation may generate a signal that is highly relevant to another formulation because both contain the same active substance. Similarly, a safety issue identified in one indication may become relevant to another indication if the exposure, mechanism or affected population overlaps.

Conversely, combining information without recognising clinically important differences can produce misleading conclusions.

The objective is therefore not simply to combine everything. It is to establish the correct scope and then present differences where they matter.

2. The Active Substance as a Core Organising Principle

For PSUR purposes, the active substance is often the principal organising concept.

Where the applicable requirements call for a single PSUR for medicinal products containing the same active substance, the report should cover the relevant authorised indications, routes of administration, dosage forms and dosing regimens rather than treating each product presentation as an independent safety universe.

This principle supports a cumulative safety assessment and reduces unnecessary duplication.

It also means that the internal PSUR process should maintain a reliable inventory of the products and regulatory authorisations falling within scope.

3. One Active Substance, Multiple Product Names

A single active substance may be marketed under different product names.

Different names do not necessarily justify separate safety assessments.

The PSUR scope should instead be determined from the applicable regulatory requirements and authorisations.

The assessment should make clear which products are covered and should not assume that a product-name-based database structure corresponds to the regulatory PSUR scope.

4. Multiple Indications

A medicinal product may be authorised for several indications with materially different:

• disease severity;
• patient populations;
• treatment alternatives;
• exposure duration;
• dose;
• and expected therapeutic benefit.

A single PSUR can cover these indications while still requiring separate presentation or analysis where relevant.

The benefit-risk assessment should not average materially different clinical situations into an uninformative overall conclusion.

5. Multiple Routes of Administration

Different routes can alter:

• systemic exposure;
• local exposure;
• pharmacokinetics;
• patient populations;
• administration errors;
• and the nature of adverse reactions.

Where these differences are safety-relevant, the PSUR should identify and evaluate them appropriately.

The existence of a common active substance does not mean that every safety finding has identical relevance across routes.

6. Multiple Dosage Forms and Regimens

Tablets, injections, infusions, topical preparations and other dosage forms can have materially different safety considerations.

Similarly, a product administered once daily may have a different exposure pattern from one administered intermittently or at a substantially different dose.

Where relevant, the PSUR should distinguish these differences rather than allowing aggregation to conceal clinically meaningful patterns.

7. Different Regulatory Procedures

The same active substance can be associated with marketing authorisations granted through different regulatory routes.

For PSUR purposes, the existence of separate regulatory procedures does not automatically require separate safety evaluations when the applicable rules require a common active-substance PSUR.

The organisation should therefore distinguish:

• the regulatory authorisation pathway;
• the product;
• the active substance; and
• the PSUR assessment scope.

These concepts are related but not interchangeable.

8. Multiple Marketing Authorisations Held by One MAH

An MAH may hold several authorisations containing the same active substance.

The organisation should maintain a controlled mapping between:

Active substance
      ↓
Products
      ↓
Marketing authorisations
      ↓
Indications / formulations / routes
      ↓
PSUR scope

This mapping should be reconciled with the regulatory database and the current EURD framework where applicable.

9. Different MAHs

A more complex situation arises when different MAHs hold authorisations for products containing the same active substance.

Each MAH retains responsibility for its own regulatory obligations, but the EU single-assessment framework can bring related PSURs together for a common regulatory assessment.

EMA states that PSUSA procedures assess PSURs for medicines containing the same active substances or combinations even when they are subject to different marketing authorisations and are authorised in different EU Member States. citeturn0search0

This distinction is fundamental:

Shared regulatory assessment does not mean shared legal responsibility for the underlying pharmacovigilance system.

10. The Single PSUR Principle

GVP Module VII states that, unless otherwise specified by competent authorities, an MAH should prepare a single PSUR for its medicinal products containing the same active substance, covering the authorised indications, routes, dosage forms and dosing regimens. citeturn0search13

This is a regulatory design principle intended to support a coherent cumulative assessment.

It should not be interpreted as an instruction to erase clinically important product differences.

11. When Separate Presentation Is Appropriate

A common PSUR can contain separate sections or analyses where information relating to a particular indication, dosage form, route or dosing regimen requires distinct evaluation.

Examples include:

• a risk limited to an injectable formulation;
• an adverse reaction concentrated in a particular indication;
• an exposure pattern unique to a dosing regimen;
• or a safety issue associated with a route-specific administration process.

The appropriate response is usually segmentation within the assessment, rather than automatic fragmentation of the entire PSUR.

12. Exceptional Separate PSURs

Module VII recognises that exceptional circumstances may justify separate PSURs, for example where different formulations are associated with entirely different indications.

Such separation should not be treated as an internal convenience decision. Agreement with the relevant competent authorities should be obtained where required. citeturn0search13

The general rule should therefore remain a common active-substance assessment unless the regulatory framework provides otherwise.

13. Product Scope Inventory

Before preparing the PSUR, the MAH should establish a controlled scope inventory.

At minimum, the inventory should identify, as applicable:

• active substance or combination;
• product names;
• pharmaceutical forms;
• routes of administration;
• strengths;
• indications;
• dosing regimens;
• marketing authorisations;
• countries of authorisation;
• MAH entities;
• and applicable PSUR frequency and EURD information.

The inventory should have a defined owner and review process.

14. Scope Reconciliation

The scope inventory should be reconciled against authoritative regulatory sources.

Potential sources include:

• the MAH's regulatory database;
• the EU regulatory database;
• the EURD list where applicable;
• product information;
• regulatory correspondence;
• and relevant authorisation records.

A discrepancy should be resolved before the PSUR scope is finalised.

15. Why Product Scope Errors Matter

An incorrect scope can affect every downstream part of the PSUR.

For example, excluding a relevant formulation can result in:

• incomplete exposure assessment;
• missed cases;
• incorrect denominator interpretation;
• incomplete risk characterisation;
• and inappropriate benefit-risk conclusions.

Conversely, including products outside the applicable scope can introduce irrelevant information and complicate the assessment.

16. International Products and the Worldwide Marketing Authorisation Status

The PSUR includes a worldwide marketing authorisation perspective as part of the required report structure.

The MAH should therefore understand which products and authorisations exist globally, not only those within the EU procedure.

International information can be important because regulatory actions, indications and safety findings outside the EU may affect the overall safety assessment and the EU regulatory position.

EMA's current procedural guidance specifically notes that the worldwide marketing authorisation status section applies to both centrally authorised and nationally authorised products. citeturn0search0

17. Different Product Information Across Markets

The same active substance can have different authorised indications or safety wording in different jurisdictions.

The PSUR should distinguish the common safety evidence from region-specific regulatory implementation.

This is one reason the EU regional appendix has an important role in PSURs subject to EU single assessment.

The organisation should avoid treating a global core safety position as though it were automatically identical to every local product information document.

18. Partner and Licensing Arrangements

A product may be marketed through licensing, co-development or distribution arrangements.

The PSUR process should establish:

• who holds the relevant marketing authorisation;
• which party owns the PSUR obligation;
• which party provides safety data;
• how data are reconciled;
• how regulatory actions are communicated;
• and how changes to product information are coordinated.

Contractual arrangements should support, rather than obscure, the legal pharmacovigilance responsibilities of the relevant MAHs.

19. Data From Partners

GVP Module VII specifically provides that partner data should be included and discussed when they may meaningfully contribute to safety, benefit or benefit-risk analyses and may influence the reporting MAH's product information. citeturn0search13

The operational implication is that the PSUR process needs a controlled mechanism for identifying and evaluating partner information rather than relying solely on the MAH's internal database.

20. Multiple MAHs and Data Sharing

Where different MAHs are involved in a common PSUSA, information submitted for the procedure can contribute to the shared regulatory assessment.

EMA's current procedural guidance stresses that responsibility for the quality of submitted documentation remains with the MAH and that PSUR-related submissions are used for the concerned procedure. citeturn0search0

This creates a governance requirement for careful data selection, quality control and appropriate handling of patient-level information.

21. Avoiding Double Counting Across Products

The same underlying safety observation can appear under several products or authorisations.

This can occur where:

• the same active substance is marketed under multiple names;
• a partner transfers the same case;
• a literature publication describes a case already received spontaneously;
• or multiple regulatory databases contain representations of the same event.

The PSUR should distinguish genuine independent evidence from duplicate representations.

22. The Regulatory Assessment Perspective

The reason for harmonising the active-substance assessment becomes especially clear during PSUSA.

EMA describes PSUSA as a mechanism intended to harmonise and strengthen benefit-risk review across the EEA for medicines containing the same active substance or combination. citeturn0search0

A fragmented MAH-by-MAH view could otherwise produce different interpretations of the same underlying safety evidence.

The single-assessment approach allows the regulatory network to consider the evidence across the relevant authorisations.

23. Practical Scenario: Same Substance, Different Indications

Suppose an active substance is authorised for two conditions.

The first indication is for a severe disease with prolonged exposure. The second is for a less severe condition with shorter exposure.

A single PSUR may cover both, but the benefit-risk analysis should consider the different clinical contexts.

A risk that is acceptable in the first population may require a different assessment in the second.

The solution is not necessarily two PSURs. It is an appropriately stratified assessment within the applicable common scope.

24. Practical Scenario: Same Substance, Different Formulations

Consider an active substance available as an oral tablet and an injectable formulation.

The common active substance does not make every safety issue formulation-independent.

For example, an administration-related event associated with injection technique may have little relevance to the oral product. Conversely, a systemic adverse reaction caused by the pharmacological action of the active substance may be relevant to both.

The PSUR should therefore distinguish:

• formulation-specific risks;
• route-specific risks;
• active-substance-related risks; and
• risks arising from the way a particular product is used.

The appropriate analysis is evidence-based rather than determined solely by product structure.

25. Practical Scenario: Different MAHs for the Same Active Substance

Suppose three MAHs market products containing the same active substance in different EU Member States.

The existence of three MAHs does not mean that the EU regulatory network must evaluate three unrelated safety narratives.

Where the PSURs fall within a PSUSA, the relevant reports are assessed together.

Each MAH remains responsible for its own submission and pharmacovigilance obligations, but the regulatory assessment considers the evidence across the relevant products and authorisations.

This distinction should be reflected in contracts, data exchange and governance arrangements.

26. Practical Scenario: One MAH, Several Authorisations

An MAH may hold several authorisations for the same active substance.

The internal PSUR process should identify all relevant authorisations rather than allowing separate business units to prepare disconnected assessments.

A central scope register can prevent omissions and provide a traceable link between the active substance, authorisations and the PSUR.

27. Practical Scenario: Different Safety Profiles by Indication

Suppose a safety event occurs primarily in patients receiving the active substance for one indication.

The PSUR should examine whether this reflects:

• different dose;
• different duration;
• different patient characteristics;
• concomitant treatment;
• disease-related confounding;
• or a genuine indication-specific risk.

The conclusion should not be based solely on the overall pooled reporting frequency.

28. Practical Scenario: A Product Leaves the Market

A product may cease to be marketed in one jurisdiction while the same active substance remains marketed elsewhere.

The organisation should not automatically remove the product from all safety evaluation.

The implications depend on the applicable regulatory scope, exposure and reporting requirements.

Historical information can remain relevant to the cumulative safety assessment even after marketing has stopped.

29. Practical Scenario: A New Product Is Added During the Lifecycle

A new formulation, indication or authorisation may enter the portfolio during a PSUR cycle.

The organisation should establish when it enters the applicable reporting scope and ensure that the relevant exposure and safety information are captured according to the applicable requirements.

This should be controlled through the regulatory change-management process rather than discovered during final drafting.

30. Practical Scenario: Different Product Information Across EU Authorisations

Products containing the same active substance may have differences in their authorised product information.

During an EU single assessment, the MAH must consider the implications of the PSUR findings for the relevant EU product information.

EMA's current procedural guidance explains that proposed EU label changes arising from PSUR data are presented within the EU regional appendix and that the MAH must consider the proposals in the context of the different EU product information. citeturn0search0

A common scientific conclusion therefore does not necessarily mean that every local document can be changed by identical text without regulatory consideration.

31. Practical Scenario: Generic Products

Certain generic, well-established-use, traditional herbal and homeopathic medicinal products are subject to specific PSUR exemptions under EU legislation, subject to defined exceptions.

The exemption should not be interpreted as a general exemption from pharmacovigilance.

Where PSUR submission is required by the marketing authorisation, requested by a competent authority, or otherwise required under the applicable framework, the relevant obligations apply.

The current EURD framework should be checked rather than relying on an assumption based solely on the legal category of the product. GVP Module VII describes these specific arrangements, including circumstances in which PSURs for such products are required. citeturn0search12

32. Generic Product With No Reference Product Currently Marketed

A particularly important situation can arise where a generic remains marketed but the reference medicinal product is no longer marketed.

EU legislation permits competent authorities to request PSURs where pharmacovigilance concerns exist or where there is a lack of PSUR information relating to the active substance after authorisation.

The organisation should therefore maintain an active regulatory assessment of whether a PSUR obligation exists rather than assuming that historical absence of a PSUR means future absence of an obligation. citeturn0search12

33. Combinations of Active Substances

Medicinal products can contain combinations of active substances.

The PSUR scope and EU reference-date framework should be checked for the applicable substance or combination rather than automatically applying the process for a single active substance.

Combination products can require particular care because safety information may relate to:

• one component;
• the combination;
• an interaction between components;
• or the clinical context in which the combination is used.

The scope should therefore be established from the applicable regulatory framework and current EURD information where relevant.

34. Different Doses and Strengths

Different strengths do not automatically require separate PSURs.

The key question is whether the strength or dose materially changes the safety evaluation.

For example, a dose-dependent adverse reaction may require stratified analysis, while a safety issue independent of dose may be more appropriately evaluated cumulatively.

The report should preserve clinically meaningful distinctions without creating unnecessary fragmentation.

35. Data Integration Across Corporate Systems

Large organisations often maintain separate systems for different products or business units.

This creates a risk that the regulatory PSUR scope is wider than the internal data architecture.

A robust process therefore needs controlled integration across:

• safety databases;
• clinical databases;
• regulatory systems;
• literature systems;
• signal-management tools;
• exposure sources;
• and partner data repositories.

The PSUR should be generated from a defined evidence set rather than assembled from disconnected local reports.

36. Scope and Data Lineage

For every material conclusion, the organisation should be able to identify:

Regulatory scope
      ↓
Products / authorisations included
      ↓
Source systems
      ↓
Data extraction
      ↓
Analysis
      ↓
Safety conclusion

This lineage becomes particularly important when multiple MAHs, products or data systems are involved.

37. Governance of Scope Changes

Scope can change during the product lifecycle.

Examples include:

• new indications;
• new formulations;
• acquisitions;
• divestments;
• transfers of marketing authorisation;
• licensing arrangements;
• withdrawal from a market;
• and changes to the EURD list.

These changes should trigger controlled assessment of their effect on the PSUR process.

The responsible pharmacovigilance function should not depend on informal communication from a commercial or regulatory team.

38. Transfer of Marketing Authorisation

When a marketing authorisation is transferred, the parties should establish how ongoing PSUR obligations and relevant historical safety information are managed.

The transfer should address, as applicable:

• responsibility for future submissions;
• access to historical PSURs;
• underlying safety data;
• regulatory correspondence;
• open safety issues;
• ongoing signals;
• RMP interfaces;
• and upcoming DLPs and deadlines.

A transfer that changes legal ownership without transferring the necessary safety context creates an avoidable continuity risk.

39. Mergers and Acquisitions

Corporate transactions can create particularly difficult scope-reconciliation problems.

Two organisations may have different product identifiers, databases, coding conventions and PSUR calendars for the same active substance.

Integration should therefore include a regulatory and pharmacovigilance reconciliation rather than simply moving files between systems.

40. Partner Agreements and PSUR Responsibilities

Contracts should clearly establish responsibilities for:

• data exchange;
• reconciliation;
• literature information;
• signal information;
• PSUR contributions;
• regulatory correspondence;
• product-information changes;
• and urgent safety escalation.

A contractual statement that a partner "supports the PSUR" is not sufficiently precise unless the operational responsibilities are defined.

41. Inspection Scenario: Missing Authorisation

An inspector asks why a particular product was not included in the PSUR.

A defensible answer should not depend on the author's recollection.

The organisation should be able to show:

1. the scope inventory;
2. the regulatory source used;
3. the inclusion/exclusion decision;
4. the date of the decision;
5. review or approval;
6. and the effect on the data analysis.

42. Inspection Scenario: Inconsistent MAH Data

An inspector identifies different product counts in the regulatory database and PSUR project documentation.

The issue may indicate a simple timing difference, but it could also indicate a deeper scope-control problem.

The organisation should be able to reconcile the discrepancy and demonstrate which authoritative source governed the PSUR.

43. Inspection Scenario: Partner Data Excluded

If a partner supplied safety information that was excluded from the PSUR, the organisation should be able to explain the decision.

The assessment should distinguish:

• information not relevant to the report;
• duplicate information;
• information received after the applicable cutoff;
• and information that should have been included but was inadvertently omitted.

The rationale should be documented.

44. Inspection Scenario: Different Conclusions for the Same Active Substance

If separate internal teams reach materially different conclusions about the same active substance, governance should identify why.

Possible explanations include differences in:

• data cutoff;
• product population;
• indication;
• formulation;
• exposure;
• analysis method;
• or scientific interpretation.

The final PSUR should reconcile material differences rather than silently selecting one conclusion.

45. Practical Control Framework

A mature PSUR scope-control process can be organised around six controls:

These controls are complementary to, not substitutes for, the detailed requirements of GVP Module VII and applicable legislation.

46. Key Takeaways

Multiple products and MAHs make PSUR governance more complex, but the regulatory model is designed to preserve a coherent active-substance safety assessment.

The principal lessons are:

• determine PSUR scope from the applicable regulatory framework, not merely internal product structure;
• normally assess relevant products containing the same active substance within the applicable common PSUR scope;
• distinguish common active-substance risks from indication-, formulation-, route- and dose-specific issues;
• maintain a controlled product and authorisation inventory;
• reconcile regulatory scope with safety data sources;
• understand the difference between individual MAH responsibility and EU single assessment;
• manage partner and transfer arrangements explicitly;
• and document scope decisions so they remain inspection-defensible.

The objective is not maximum aggregation. It is the correct regulatory scope with sufficient clinical stratification to preserve the meaning of the evidence.

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 PSUSA procedural guidance and post-authorisation Q&A.
3. European Medicines Agency. Explanatory Note to GVP Module VII.
4. Commission Implementing Regulation (EU) No 520/2012, as amended.
5. Directive 2001/83/EC, as amended.
6. Regulation (EC) No 726/2004, as amended.

Regulatory Note

This article is an educational explanation of PSUR scope across multiple products, active substances and marketing authorisation holders. It does not replace current GVP Module VII, applicable EU legislation, the current EURD list, EMA PSUSA guidance, regulatory decisions or an organisation's approved procedures.

Regulatory requirements and guidance may change. Before preparing or submitting a PSUR, the current applicable regulatory documents, regulatory scope and procedural requirements should be verified.

Examples and inspection scenarios are illustrative unless an authoritative source is specifically identified.