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What Does the Marketing Authorisation Holder Do During an EMA Referral?

How an MAH organises, responds to and implements an EMA referral, including the interaction between regulatory affairs, pharmacovigilance, medical, quality and other functions.

Audio Lesson 22 min

What Does the Marketing Authorisation Holder Do During an EMA Referral?

Introduction

An EU referral is not only a procedure conducted by regulators. It is also a major regulatory event for the marketing authorisation holder (MAH).

Once a referral begins, the MAH must organise its response within a defined legal and scientific framework. The company may need to assemble evidence, analyse new and existing data, answer questions from the relevant committee, coordinate multiple internal functions, provide written or oral explanations where permitted, and prepare for the regulatory consequences of the eventual outcome.

The exact obligations depend on the legal basis and scope of the referral. An Article 20 pharmacovigilance procedure for centrally authorised medicines is not identical to an Article 31 referral involving nationally authorised medicines, and an urgent Union procedure under Article 107i has its own procedural framework.

The common principle is nevertheless straightforward:

The MAH is an active participant in the scientific and regulatory process, but it does not control the regulatory conclusion.

The company's task is to provide a complete, accurate and scientifically defensible assessment of the evidence, respond to the formal regulatory questions, and ensure that the resulting regulatory requirements are implemented appropriately.

This article focuses on the practical role of the MAH during the referral itself. It does not attempt to reproduce the detailed scientific assessment performed by PRAC, which is addressed separately in How PRAC Assesses a Safety Issue During an EMA Referral.

The first mistake an MAH can make is to treat every referral as though it were operationally identical.

Before deciding how to respond, the company must establish:

These are not merely administrative details. They determine what the company is being asked to address and how its response enters the regulatory process.

For example, EMA's current Article 20 pharmacovigilance guidance states that an Article 20 pharmacovigilance procedure applies to centrally authorised medicinal products when the procedure arises from pharmacovigilance data, and that the European Commission initiates the procedure. The MAH cannot itself trigger that procedure.

Similarly, current Article 31 guidance explains that MAH submissions are made available to the PRAC rapporteur and co-rapporteur for assessment and that the subsequent pathway depends in part on whether centrally authorised products are included.

The MAH therefore begins by understanding which regulatory process it is actually participating in.

2. The Referral Becomes a Controlled Company Programme

A referral should normally be treated as a controlled cross-functional regulatory programme rather than as an ordinary safety assessment.

This does not mean creating unnecessary bureaucracy. It means establishing clear ownership for activities that may have different scientific, regulatory and operational consequences.

Depending on the referral, relevant functions can include:

The precise organisational structure is an MAH decision. EU legislation does not prescribe a universal internal referral team.

What must be controlled is the work and accountability, not the organisational chart.

3. Establish One Authoritative Regulatory Record

A referral generates multiple versions of information: the original safety assessment, new analyses, drafts, responses to questions, regulatory correspondence, meeting materials and final approved documents.

The MAH should therefore establish one controlled regulatory record for the procedure.

At minimum, the record should allow the company to identify:

  1. the formal referral notification;
  2. the current procedural timetable;
  3. the questions and outstanding issues;
  4. submitted responses;
  5. supporting analyses and reports;
  6. regulatory correspondence;
  7. internal approval records;
  8. oral-explanation materials where applicable;
  9. the committee recommendation or opinion;
  10. the final regulatory decision or position; and
  11. implementation evidence.

The purpose is not simply document storage. It is traceability.

A future reviewer should be able to determine what the company knew, what it submitted, who approved the submission and what regulatory conclusion followed.

4. Appoint the Right Regulatory Contact

EMA procedures provide specific mechanisms for communication with the MAH.

The company should ensure that the designated contact is correctly identified and that regulatory correspondence is routed through the controlled process specified for the procedure.

For example, current EMA Article 20 pharmacovigilance guidance states that the QPPV is the default contact for correspondence, although the QPPV may designate another contact or representative in accordance with the procedure. EMA also states that documents sent to the designated contact constitute effective receipt for procedural purposes.

Current EMA guidance for other referral types can specify different arrangements. The MAH should therefore follow the contact mechanism for the individual procedure rather than assuming that one internal model applies to every referral.

This is particularly important because a missed communication can have procedural consequences when the applicable timetable is already running.

5. Understand the Formal Regulatory Question

The most important document after initiation is often not the company's historical safety assessment. It is the formal question the committee has been asked to answer.

The company should translate that question into a controlled response plan.

For each question, the team should identify:

This prevents a common failure mode: producing a large amount of scientifically interesting information that does not directly answer the regulatory question.

A referral submission should be responsive before it is expansive.

6. Reconstruct the Safety Evidence Before Arguing the Conclusion

The MAH should begin by reconstructing the evidence base.

Depending on the referral, this can include:

The objective is to establish a common evidence base across the internal functions contributing to the response.

The company should be able to distinguish between:

what is known, what is inferred, what remains uncertain, and what the company recommends.

This distinction becomes particularly important when the MAH's preferred conclusion differs from the emerging regulatory assessment.

7. The Pharmacovigilance Function Is Central, but It Is Not the Whole Response

For a pharmacovigilance referral, PV will usually provide a substantial part of the scientific evidence and interpretation.

The QPPV and PV organisation may need to coordinate:

However, a referral response should not automatically be treated as a PV document owned by PV alone.

The regulatory question may also involve clinical benefit, epidemiology, dosing, product use, risk-management measures, product information, manufacturing or other matters.

The strongest response therefore combines specialist expertise while retaining one coherent regulatory position.

8. The QPPV's Position in the Referral

The QPPV has a particularly important perspective because the referral may test whether the company's pharmacovigilance system has identified and appropriately evaluated the issue.

The QPPV should understand:

The QPPV should not be expected to personally perform every analysis. The responsibility is to maintain appropriate oversight of the pharmacovigilance system and its interface with the regulatory response.

A useful distinction is:

The referral response is a company submission; the QPPV's responsibility is to ensure that the pharmacovigilance contribution is scientifically sound, appropriately governed and consistent with the pharmacovigilance system.

9. Do Not Confuse Regulatory Strategy With Scientific Evidence

An MAH inevitably considers regulatory strategy during a referral. It may need to assess possible outcomes and their consequences for the product.

But regulatory strategy should not change the underlying evidence.

A scientifically defensible process separates:

For example, a company may prefer a targeted risk-minimisation measure rather than a broader restriction. That is a legitimate regulatory position to evaluate. It should not lead to selective presentation of evidence supporting the preferred option.

The credibility of the response depends heavily on this separation.

10. The MAH's First-Day Questions

When a referral is formally communicated, the internal team should be able to answer a short set of questions quickly:

Question Why it matters
What is the legal basis? Establishes the regulatory framework.
Which products are in scope? Defines the evidence and implementation population.
Which committee is assessing the issue? Establishes the scientific pathway.
What is the formal question? Defines the response objective.
What is the timetable? Controls every subsequent activity.
Who is the EMA contact? Prevents communication failures.
Who owns the scientific response? Establishes accountability.
What evidence already exists? Establishes the starting point.
What information is missing? Identifies immediate analytical work.
What regulatory consequences are plausible? Enables controlled contingency planning.

This is a management framework, not a statutory checklist.

The actual procedural requirements must be taken from the documents governing the individual referral.

11. Build the Response Around the Questions, Not the Company's Narrative

Once the evidence base has been reconstructed, the MAH should build the submission around the questions that the committee must answer.

A useful response architecture is:

Regulatory question
       ↓
Evidence relevant to the question
       ↓
Analysis
       ↓
Limitations and uncertainty
       ↓
Scientific conclusion
       ↓
Regulatory implication
       ↓
Company position

This structure prevents two opposite problems: under-answering, where a conclusion is provided without sufficient evidence, and over-answering, where large quantities of data are supplied without explaining their relevance.

The objective is not to maximise the amount of information submitted. It is to make the relevant evidence understandable, reproducible and decision-useful.

12. Reanalyse the Evidence When the Referral Requires It

A referral can require analyses that were not part of the company's routine pharmacovigilance activities.

For example, the committee may require an updated cumulative case review, subgroup analysis, refined exposure denominator, additional epidemiological analysis, assessment of a particular risk factor, analysis of dose or duration relationships, or evaluation of a competing explanation for observed events.

The MAH should document the analytical question before performing the analysis.

A new analysis should have a clear objective, defined data sources and transparent methods. Post-hoc analysis should not be presented as though it had been prospectively planned when it was not.

Where an analysis has important limitations, those limitations should be stated explicitly.

A transparent analysis with acknowledged limitations is more useful to a regulator than an apparently definitive analysis whose assumptions are hidden.

13. Maintain One Scientific Position Across Functions

Large referral teams create a particular risk: different specialists may produce technically correct analyses that imply different conclusions.

For example, Epidemiology may conclude that an observational association is uncertain, while Pharmacovigilance considers the clinical case pattern persuasive. Medical Affairs may emphasise the severity of the event, while Regulatory Affairs is considering the proportionality of possible restrictions.

These perspectives are not necessarily contradictory. They answer different questions.

The MAH therefore needs a process that integrates the perspectives into one coherent scientific position.

This does not mean forcing every function to use identical language. It means ensuring that the final submission does not contain unexplained contradictions.

A useful internal review asks:

If the regulator reads each section independently, will the overall scientific interpretation remain coherent?

14. Regulatory Writing Is Part of the Scientific Work

A referral response should not be treated as a transcription exercise.

The structure and wording of the submission affect how the evidence can be understood.

A strong regulatory response should make it easy to identify:

Important qualifications should not be hidden in appendices while the main text presents an unqualified conclusion.

At the same time, the submission should avoid unnecessary repetition. If the same evidence is discussed in several sections, the relationship between those discussions should be clear.

The objective is not rhetorical persuasion. It is accurate transmission of the company's scientific assessment to the committee.

15. Internal Medical and Scientific Review

The referral response should pass through appropriate scientific review before submission.

The reviewers required will depend on the subject matter. A complex safety referral may require review by pharmacovigilance physicians, epidemiologists, statisticians, clinicians, toxicologists, clinical pharmacologists or other specialists.

The review should test more than grammar and consistency.

Scientific reviewers should ask:

These questions are particularly important where the MAH's position differs from the regulator's emerging interpretation.

16. Regulatory Governance and Sign-Off

Scientific authorship and regulatory accountability are related but distinct.

The company should define who has authority to approve the final response before submission.

The exact governance model is company-specific. It may include a referral steering committee, senior safety governance, regulatory leadership, medical leadership and appropriate quality or legal review.

The key controls are clear ownership, documented review, version control, approval before submission and preservation of the submitted version.

A referral can evolve rapidly. Draft analyses may be superseded by new data, and draft positions may change after regulatory questions are received.

The final submitted document must therefore be identifiable and retrievable independently of later drafts.

17. Responding to PRAC Questions and Outstanding Issues

Questions from PRAC or the rapporteur are an important part of the assessment process.

The MAH should establish a controlled process for each question:

Question received
      ↓
Interpret the exact question
      ↓
Assign scientific owner
      ↓
Identify required data
      ↓
Perform analysis
      ↓
Medical/scientific review
      ↓
Regulatory writing
      ↓
Cross-functional review
      ↓
Final approval
      ↓
Submission

The response should answer the question that was asked.

If the question contains an assumption that the MAH considers incorrect, the response should identify the issue clearly and then provide the evidence supporting the alternative interpretation.

Simply refusing the premise of a question can leave the underlying regulatory concern unanswered.

18. When the MAH Does Not Have the Requested Data

A regulator may request information that the MAH cannot provide in the requested form.

The appropriate response is not to manufacture certainty.

The MAH should explain what data are available, what data are unavailable, why the requested information cannot be provided, whether a valid alternative analysis is possible, and what uncertainty remains as a consequence.

For example, spontaneous-reporting systems may not provide a reliable denominator for calculating an incidence rate. The company should not generate a precise incidence estimate simply because a precise number would be easier to communicate.

A transparent limitation can itself be an important part of the scientific answer.

19. New Evidence During the Referral

A referral does not necessarily freeze the evidence base at the moment of initiation.

New cases, literature, study results or other relevant information can emerge while the procedure is ongoing.

The MAH must therefore have a process for identifying potentially important new evidence and determining how it should be incorporated into the regulatory response.

The appropriate handling depends on the procedure and the significance of the information. Not every new case requires a formal amendment to the submission, but material evidence cannot simply be ignored because the original dossier has already been submitted.

The company should be able to explain when the new information became available, how it was assessed, whether it changes the scientific interpretation, and how and when it was communicated through the applicable regulatory process.

This is an important connection between the referral and the ongoing pharmacovigilance system.

20. Oral Explanations

Where the applicable procedure provides an opportunity for an oral explanation, the MAH should treat it as an extension of the scientific submission rather than as a separate advocacy exercise.

The most effective oral explanation usually concentrates on the issues that remain material after the written assessment.

The company should be prepared to explain:

The oral presentation should not introduce unsupported claims simply because they were absent from the written dossier.

Where new information is relevant, its procedural status should be clear.

21. Preparing for More Than One Regulatory Outcome

The MAH should avoid building its internal programme around one assumed outcome.

Possible outcomes may include no regulatory change, product-information changes, additional risk-minimisation measures, changes to the RMP or pharmacovigilance activities, restrictions on use, suspension or revocation where legally applicable, or another measure provided for by the applicable framework.

The exact options vary by procedure.

Contingency planning allows the company to assess operational consequences without confusing a possible outcome with the actual regulatory decision.

For example, if a restriction could materially affect supply, manufacturing, distribution or educational materials, the relevant functions can prepare implementation scenarios while the scientific assessment is still underway.

The important control is to label these as contingency scenarios, not as regulatory requirements.

22. Regulatory Disagreement With the MAH's Position

The purpose of the referral is not to obtain agreement between the regulator and the MAH at every stage.

The MAH may reach a different scientific conclusion from the rapporteur or committee.

A disagreement should therefore be expressed scientifically.

A useful structure is:

  1. identify the specific conclusion being challenged;
  2. state the evidence on which the MAH relies;
  3. explain the methodological or interpretive issue;
  4. acknowledge evidence supporting the alternative view;
  5. explain why the MAH considers its interpretation better supported; and
  6. describe the regulatory consequence the company considers appropriate.

This is substantially stronger than stating that the regulator has misunderstood the evidence.

23. What the MAH Should Not Do

Several behaviours can weaken an otherwise strong referral response.

Do not minimise the concern simply because the evidence is uncertain

Uncertainty is not the same as absence of risk.

Do not present a plausible mechanism as proof of clinical causality

Mechanistic plausibility is one component of evidence, not necessarily the conclusion.

Do not selectively exclude unfavourable evidence

Conflicting evidence should be acknowledged and explained.

Do not treat historical regulatory conclusions as permanently controlling

New evidence can legitimately change the benefit-risk assessment.

Do not allow internal functions to submit contradictory positions

Specialist differences should be resolved or explicitly characterised before the final response.

Do not confuse a preferred outcome with the evidence

The scientific assessment must remain independent of the company's commercial preference.

Do not wait for the final decision before planning implementation

Contingency planning can begin early, provided it is clearly distinguished from the legally operative outcome.

24. Referral Governance as a QPPV Issue

From the QPPV perspective, the referral should be connected to the established pharmacovigilance quality system.

The company should be able to demonstrate that the referral response is consistent with the safety information available within the pharmacovigilance system and that material developments during the procedure are appropriately assessed.

The QPPV should pay particular attention to situations where:

These circumstances may require broader review of the pharmacovigilance system, not merely completion of the referral submission.

25. The MAH Response as an Evidence Chain

A useful way to assess the quality of the company's response is to follow the evidence chain from source to conclusion:

Raw safety information
        ↓
Validated data
        ↓
Analysis
        ↓
Clinical/scientific interpretation
        ↓
Uncertainty
        ↓
Benefit-risk assessment
        ↓
Regulatory position
        ↓
Submitted response

Each transition should be understandable.

If the final regulatory position cannot be traced back to the evidence, the response is weak regardless of how polished the writing appears.

Conversely, a response can be scientifically strong even when the evidence is uncertain, provided the uncertainty is accurately represented and the regulatory conclusion is proportionate to the evidence.

26. The MAH Does Not Own the Outcome

The MAH owns its submission and its regulatory responsibilities. It does not own the committee's conclusion.

This distinction is fundamental.

A company can provide a rigorous analysis, disclose limitations, answer every question and propose a proportionate regulatory measure while still receiving a regulatory outcome different from the one it recommended.

That does not make the submission unsuccessful.

The quality of the MAH response should be judged by whether it provided the regulator with a complete, accurate and scientifically defensible basis for assessment and whether the company complied with the resulting regulatory obligations.

27. From Referral Response to Implementation

The MAH's work changes character once the regulatory outcome becomes clear.

During assessment, the principal task is evidence and scientific response.

After the decision, the principal task becomes controlled implementation and lifecycle follow-up.

The transition can be represented as:

Referral initiation
      ↓
Evidence reconstruction
      ↓
Scientific analysis
      ↓
Regulatory response
      ↓
Committee assessment
      ↓
Regulatory outcome
      ↓
Implementation
      ↓
Ongoing pharmacovigilance

The same safety issue can therefore generate work across several different company systems over an extended period.

This is why referral management should be treated as a lifecycle regulatory activity rather than as a single submission exercise.

28. Practical MAH Referral Checklist

Before each major procedural milestone, the MAH can ask:

Area Control question
Legal basis Are we working to the correct procedure?
Scope Have all affected products and indications been identified?
Evidence Is the evidence base current and complete?
Analysis Are methods, assumptions and limitations documented?
PV Is the response consistent with the pharmacovigilance system?
Medical Is the clinical interpretation adequately reviewed?
Epidemiology Are relevant study findings and limitations addressed?
Regulatory Does the submission answer the formal question?
Governance Has the final document received appropriate approval?
Communication Is the designated regulatory contact controlled?
New information Has material new evidence been assessed?
Contingency Are possible outcomes understood without being treated as final?
Implementation Are the likely operational consequences understood?

This is a practical management tool rather than a legal checklist. The applicable procedure-specific requirements always take precedence.

Key Takeaways

  1. The MAH is an active participant in an EU referral, not merely the recipient of a regulatory decision.
  2. The first task is to establish the legal basis, scope, timetable and formal regulatory question.
  3. A referral requires controlled cross-functional governance, but EU legislation does not prescribe one universal internal organisational structure.
  4. The response should be built around the questions the committee must answer.
  5. Evidence, interpretation, uncertainty and the company's preferred regulatory position should remain distinguishable.
  6. Pharmacovigilance is central to a pharmacovigilance referral, but the response may require substantial input from medical, epidemiological, regulatory and other specialist functions.
  7. The QPPV should maintain appropriate oversight of the pharmacovigilance contribution and its consistency with the PV system.
  8. Questions and outstanding issues should be answered directly, with transparent treatment of data limitations.
  9. Material new evidence arising during the referral must be assessed through the ongoing pharmacovigilance and regulatory processes.
  10. Oral explanations, where applicable, should clarify the scientific record rather than substitute for it.
  11. The MAH should prepare for possible regulatory outcomes without treating a contingency scenario as a final regulatory requirement.
  12. A regulator may reach a different conclusion from the MAH without that difference, by itself, demonstrating a pharmacovigilance-system failure.
  13. Once the regulatory outcome is established, the MAH's focus shifts from assessment to controlled implementation and continued pharmacovigilance.

The next article turns from the MAH's overall role to one of the most visible consequences of a referral: how the outcome changes the SmPC, Package Leaflet and Risk Management Plan.

References

  1. European Parliament and Council. Regulation (EC) No 726/2004, as amended. EUR-Lex. Legal framework for centrally authorised medicinal products, EMA and the centralised pharmacovigilance procedure.
  2. European Parliament and Council. Directive 2001/83/EC, as amended. EUR-Lex. Legal framework for medicinal products for human use and applicable referral provisions.
  3. European Medicines Agency. Questions and answers: Article 20 pharmacovigilance procedures. Current EMA procedure-specific information concerning centrally authorised medicines, MAH participation and communications.
  4. European Medicines Agency. Questions and answers: Article 31 pharmacovigilance referrals. Current EMA procedure-specific information concerning MAH submissions, assessment, questions and subsequent regulatory pathways.
  5. European Medicines Agency. Questions and answers: Urgent Union procedures (Article 107i). Current information concerning urgent Union pharmacovigilance procedures.
  6. European Medicines Agency. Referral procedures for human medicines. Current overview of referral mechanisms and procedural information.
  7. European Medicines Agency. Pharmacovigilance Risk Assessment Committee (PRAC). Current information on PRAC's responsibilities and role in pharmacovigilance referrals.
  8. European Medicines Agency. Good Pharmacovigilance Practices (GVP), Module IX — Signal Management. Current guidance concerning signal detection, validation, analysis and management.
  9. European Medicines Agency. Good Pharmacovigilance Practices (GVP), Module V — Risk Management Systems. Current guidance concerning risk-management systems and risk-minimisation measures.
  10. European Medicines Agency. Good Pharmacovigilance Practices (GVP), Module I — Pharmacovigilance systems and their quality systems. Current guidance relevant to pharmacovigilance governance, quality and oversight.
  11. European Medicines Agency. Procedural guidance and current referral timetables. Current procedural material should be consulted for the specific referral, submission requirements and applicable deadlines.

Regulatory Note

This article is an educational explanation of the marketing authorisation holder's role during an EU referral. It is not legal advice and does not replace the applicable legislation, current EMA procedural guidance, GVP, national competent-authority requirements or the formal documents governing an individual referral.

The exact responsibilities, submission requirements, contacts, deadlines, opportunities for oral explanation, re-examination rights and implementation arrangements depend on the legal basis and individual procedure.

The article deliberately describes internal MAH governance as a practical operating model rather than as a set of statutory organisational requirements. EU legislation does not prescribe a universal corporate referral team or a single internal governance structure.

Examples and checklists are educational aids. They should not be interpreted as creating additional legal obligations.

For an active referral, the current legislation, formal referral notification, questions referred, procedure-specific timetable, EMA communications, adopted committee documents and final legally operative regulatory instrument should take precedence over this general explanation.

29. What Good Referral Management Looks Like

A well-managed referral is not defined by the company obtaining the regulatory outcome it wanted. It is defined by the quality and integrity of the company's participation in the procedure.

The MAH should be able to demonstrate a clear chain from the regulatory question to the evidence reviewed, the analyses performed, the scientific conclusions reached, the position submitted and the actions taken after the outcome.

That chain should remain understandable even when the evidence is uncertain or the regulator ultimately reaches a different conclusion.

Three characteristics are particularly important.

Scientific completeness

The company has considered the relevant evidence, including evidence that does not support its preferred interpretation.

Procedural discipline

The company has complied with the applicable submission requirements, communications and procedural timetable.

Lifecycle control

The company has translated the regulatory outcome into appropriate changes to its pharmacovigilance, risk-management and regulatory systems.

These characteristics are more important than the size of the referral team or the volume of material submitted.

30. The MAH and the Principle of Regulatory Traceability

Regulatory traceability is particularly important during a referral because the scientific assessment can evolve rapidly.

A question may lead to a new analysis. That analysis may change the company's interpretation. A subsequent regulatory assessment may identify another uncertainty. The company may then provide an additional explanation before the committee reaches its conclusion.

The final record should preserve that evolution without making it impossible to determine which position was current at each stage.

A mature referral process therefore distinguishes clearly between:

This is not merely document-management discipline. It allows the MAH to reconstruct its own decision-making if the referral is later reviewed during an inspection, audit, litigation or another regulatory procedure.

31. What the QPPV Should Take Forward After the Referral

The QPPV should regard the referral outcome as information about the pharmacovigilance system itself, not only about the individual product.

A referral can reveal strengths or weaknesses in:

The appropriate response depends on what the referral demonstrates.

A regulator reaching a different scientific conclusion from the MAH does not automatically mean that the PV system was deficient. Conversely, a referral can expose a genuine process weakness even when the final regulatory action is relatively limited.

The QPPV should therefore ask a broader question after closure:

What does this referral tell us about the capability of our pharmacovigilance system to detect, evaluate, communicate and act on emerging risks?

That question converts a single regulatory event into organisational learning.

32. A Referral Is Not a Negotiation in the Commercial Sense

The MAH may advocate for a particular regulatory approach, but an EU referral should not be understood as a commercial negotiation between the company and the regulator.

The committee's task is to assess the scientific and regulatory issues within its legal remit.

The company's responsibility is to provide evidence and explain its interpretation.

The resulting decision may therefore differ from the company's proposal even when the company has participated fully and transparently.

This distinction is particularly important for internal governance. Senior management should understand that a referral response is not simply an exercise in defending the existing label or minimising commercial impact.

The scientific record must remain the foundation of the response.

33. A Practical End-to-End Model for the MAH

The complete MAH workflow can be represented as follows:

1. Referral received
          ↓
2. Confirm legal basis and scope
          ↓
3. Establish governance and contacts
          ↓
4. Interpret formal questions
          ↓
5. Reconstruct evidence base
          ↓
6. Identify gaps and perform analyses
          ↓
7. Integrate PV, medical, epidemiological and other expertise
          ↓
8. Draft scientifically coherent responses
          ↓
9. Quality and governance review
          ↓
10. Submit through the applicable EMA process
          ↓
11. Respond to further questions / outstanding issues
          ↓
12. Provide oral explanation where applicable
          ↓
13. Monitor emerging evidence and regulatory assessment
          ↓
14. Assess the final regulatory outcome
          ↓
15. Implement the legally operative requirements
          ↓
16. Update PV, RMP, product information and other systems as required
          ↓
17. Monitor effectiveness and remaining safety questions

Not every referral will contain every step in exactly this order. The model is a practical representation of the MAH's lifecycle responsibilities rather than a statutory procedural timetable.

34. Final Perspective

The marketing authorisation holder occupies a distinctive position during an EU referral.

It has access to the product's internal safety and clinical evidence and is responsible for maintaining the pharmacovigilance and regulatory systems surrounding the medicine. At the same time, it is not the body that determines the Union regulatory outcome.

The quality of the MAH's contribution therefore depends on balancing two responsibilities:

scientific candour — presenting the evidence accurately, including uncertainty and evidence that may weaken the company's preferred position; and

regulatory discipline — responding to the formal procedure, maintaining traceability, meeting applicable requirements and implementing the final outcome correctly.

For the QPPV, the referral is also a test of whether the pharmacovigilance system can function under regulatory pressure without losing scientific independence, data integrity or operational control.

A strong MAH referral process does not attempt to control the conclusion. It ensures that the conclusion is reached on the basis of the best information the company can provide, and that whatever regulatory outcome follows is incorporated into the product's continuing lifecycle management.

References

  1. European Parliament and Council. Regulation (EC) No 726/2004, as amended. Legal framework for Union procedures for the authorisation, supervision and pharmacovigilance of medicinal products and for the European Medicines Agency.
  2. European Parliament and Council. Directive 2001/83/EC, as amended. Community code relating to medicinal products for human use, including pharmacovigilance and referral provisions.
  3. European Medicines Agency. Questions and answers: Article 20 pharmacovigilance procedures. Current operational guidance for centrally authorised medicines, including MAH submissions, questions, assessment reports and oral explanations.
  4. European Medicines Agency. Questions and answers: Article 20 non-pharmacovigilance procedures. Current operational guidance for Article 20 procedures involving quality, efficacy and other non-pharmacovigilance concerns; updated July 2026.
  5. European Medicines Agency. Questions and answers: Article 31 pharmacovigilance referrals. Current operational information for MAHs participating in Article 31 pharmacovigilance referrals.
  6. European Medicines Agency. Questions and answers: Article 31 non-pharmacovigilance referrals. Current operational information on MAH submissions and assessment in Article 31 non-pharmacovigilance procedures.
  7. European Medicines Agency. Referral procedures: human medicines. Current overview of EU referral mechanisms and the principal referral pathways.
  8. European Medicines Agency. Good Pharmacovigilance Practices (GVP), Module I — Pharmacovigilance systems and their quality systems. Current guidance relevant to PV-system governance, quality and oversight.
  9. European Medicines Agency. Good Pharmacovigilance Practices (GVP), Module IX — Signal Management. Current guidance concerning signal detection, validation, analysis, prioritisation and management.
  10. European Medicines Agency. Good Pharmacovigilance Practices (GVP), Module V — Risk Management Systems. Current guidance concerning risk-management systems and risk-minimisation measures.
  11. European Medicines Agency. Dossier requirements for centrally authorised products and referral procedures. Current procedural and submission requirements should be checked for the individual procedure.

Regulatory Note

This article is an educational explanation of the role of the marketing authorisation holder during an EU referral. It is not legal advice and does not replace the applicable EU legislation, current EMA procedural guidance, GVP, national competent-authority requirements or the formal documents governing an individual procedure.

The article intentionally distinguishes statutory and procedure-specific requirements from practical recommendations for internal MAH governance. EU legislation does not prescribe a single corporate referral team, universal internal approval structure or one mandatory project-management model.

The examples, workflow diagrams and checklists are educational operating models. They should not be interpreted as additional legal obligations.

Procedure-specific requirements can change. In particular, EMA operational guidance and submission arrangements may be updated independently of the underlying legislation. For an active referral, the current referral notification, applicable legal basis, procedure timetable, EMA communications, questions and outstanding issues, current submission requirements, committee documents and final legally operative decision should take precedence over this article.

Where this article refers to a QPPV's involvement, that discussion concerns appropriate pharmacovigilance oversight and governance. It does not mean that the QPPV personally owns every regulatory, medical, quality or operational activity associated with a referral.

The central principle is that the MAH remains responsible for the quality and integrity of the information it submits and for complying with the regulatory outcome, while the competent EU bodies retain responsibility for the scientific assessment and regulatory decision within their respective legal mandates.

Revision History

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A practical explanation of how an EMA referral can change the SmPC, Package Leaflet, labelling and Risk Management Plan, and how the MAH implements and governs those changes.

EMA Referral Types Explained: Article 20, Article 31, Article 107i and Article 30

A textbook guide to distinguishing Article 20, Article 31, Article 107i and Article 30 referrals in EU medicines regulation, with particular attention to pharmacovigilance, Union interest, urgency, harmonisation and the roles of PRAC, CHMP and CMDh.

Last reviewed: 2026-08-24