What Happens When Member States Disagree During an MRP or DCP?

Introduction

The mutual recognition procedure (MRP) and decentralised procedure (DCP) are designed to allow Member States to reach a coordinated regulatory position on a medicinal product. Most procedural issues are resolved through assessment, questions, responses and discussion between the Reference Member State (RMS), Concerned Member States (CMSs) and applicant.

A more serious situation arises when a Member State cannot approve the assessment report, the summary of product characteristics, the labelling or the package leaflet because it considers that there is a potential serious risk to public health.

This is not simply another regulatory question.

Under Article 29 of Directive 2001/83/EC, such a disagreement is formally referred to the coordination group. The Member States must use their best endeavours to reach agreement, and the applicant must be given an opportunity to make its views known. If agreement is not reached within the applicable period, the matter is referred onward for the Union-level procedure provided for in the Directive. citeturn0search0turn0search1

The purpose of this article is to explain the mechanism and, particularly, the distinction between an ordinary scientific discussion and a legally significant disagreement.

1. Disagreement Is an Exception to the Normal MRP/DCP Process

The normal structure of an MRP or DCP assumes that the participating authorities can arrive at an agreed regulatory position.

The RMS leads and coordinates the assessment, while CMSs review the scientific and regulatory conclusions. The applicant responds to questions and provides evidence needed to resolve outstanding issues.

A disagreement becomes exceptional when a CMS cannot approve the relevant assessment or product information on the grounds of a potential serious risk to public health.

The legal trigger is therefore narrower than simply saying that two authorities have different opinions.

A difference in scientific emphasis, a request for clarification or disagreement over wording does not automatically constitute an Article 29 disagreement.

2. The Legal Basis: Article 29 of Directive 2001/83/EC

Article 29 provides the principal legal mechanism for disagreement during the relevant MRP/DCP process.

Article 29(1) provides that, where a Member State cannot approve the assessment report, SmPC, labelling or package leaflet on grounds of a potential serious risk to public health, it must give a detailed explanation of its position to the RMS, the other CMSs and the applicant. The points of disagreement are then referred to the coordination group. citeturn0search0

Article 29(2) provides the legal basis for Commission guidelines defining a potential serious risk to public health. The Commission guideline published in 2006 explains the exceptional nature of this mechanism and the circumstances in which it may be invoked. citeturn0search28

Article 29(3) requires the Member States involved to use their best endeavours to reach agreement within the coordination group and requires that the applicant be given an opportunity to make its views known orally or in writing. If agreement is reached, the RMS records the agreement, closes the procedure and informs the applicant. citeturn0search1

If agreement cannot be reached within the applicable period, Article 29(4) provides for immediate escalation to the Agency for the subsequent procedure under Articles 32, 33 and 34. citeturn0search1

3. What Counts as the Trigger?

The trigger should be stated precisely.

It is not:

"The CMS disagrees with the RMS."

It is closer to:

The CMS cannot approve the relevant regulatory position because it considers that there is a potential serious risk to public health.

This distinction matters because Article 29 is an exceptional mechanism.

The Commission guideline on potential serious risk to public health was developed specifically to define the circumstances in which a CMS can refuse recognition or approval on this basis. citeturn0search28

A regulatory professional should therefore avoid using the term "Article 29 disagreement" loosely for every unresolved comment during an MRP or DCP.

4. From Scientific Comment to Formal Point of Disagreement

The transition can be understood as a series of steps:

RMS assessment
       ↓
CMS review
       ↓
Scientific / regulatory question
       ↓
Discussion and applicant response
       ↓
Issue resolved
       │
       └───────────────┐
                       │ unresolved qualifying concern
                       ↓
       CMS identifies potential serious
              risk to public health
                       ↓
       Detailed statement of reasons
                       ↓
          Referral to coordination group

This sequence is important because the formal disagreement is not normally the first step in the scientific discussion.

The authorities and applicant should have an opportunity to understand and address the underlying issue before it becomes a formal point of disagreement, subject to the specific procedural circumstances.

5. The CMS Must Explain Its Position

Article 29 requires a detailed exposition of the reasons for the CMS position.

This is more demanding than recording a general statement such as "safety concern" or "insufficient evidence".

The regulatory record should make it possible to understand:

• what scientific or regulatory issue is disputed;
• why the issue is considered significant;
• how the issue relates to the potential serious risk to public health;
• what evidence supports the concern;
• and what aspect of the proposed regulatory position cannot be accepted.

The detailed reasoning is important for the subsequent coordination-group discussion and, if necessary, the later Union-level procedure.

6. The RMS Does Not Decide the Disagreement Alone

The RMS remains the coordinating authority during the procedure, but it cannot resolve a formal Article 29 disagreement simply by declaring the CMS position incorrect.

The matter is referred to the coordination group so that the participating Member States can seek agreement within the established legal framework.

This is a direct consequence of the RMS/CMS model discussed in the preceding article:

The RMS leads the procedure; it does not possess unilateral authority to extinguish a qualifying CMS objection.

The coordination mechanism exists precisely because the participating Member States have been unable to reach the required common position through the ordinary procedure.

7. The Role of the Coordination Group

The coordination group is the next level of structured discussion.

For human medicines, this is the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh).

The objective is still to reach agreement rather than immediately move every disagreement to a Union scientific committee.

Article 29(3) expressly requires the Member States concerned to use their best endeavours to reach agreement. The applicant must also be allowed to make its views known orally or in writing. citeturn0search1

This stage is therefore both regulatory and scientific.

It is not merely an administrative appeal against the RMS.

8. The Applicant's Role

The applicant remains an active participant in resolving the disagreement.

The applicant may need to provide:

• additional scientific evidence;
• clarification of the dossier;
• revised product information;
• a proposed risk-management approach;
• responses to specific points raised by the Member States;
• or an explanation of why the available evidence supports the proposed regulatory position.

Article 29(3) expressly provides the applicant with an opportunity to make its point of view known orally or in writing. citeturn0search0

The applicant should therefore treat the disagreement as a controlled regulatory process rather than as a bilateral dispute with one national authority.

9. The Importance of the Regulatory Record

Once a disagreement becomes formal, the quality of the regulatory record becomes particularly important.

The record should allow a later reviewer to reconstruct:

1. the original scientific issue;
2. the RMS assessment;
3. the CMS concern;
4. the evidence supporting the concern;
5. the applicant's response;
6. the discussion within the coordination group;
7. the eventual agreement or escalation;
8. and the resulting regulatory decision.

This record can become important long after the original procedure has closed because the regulatory conclusion may influence later variations, safety assessments or product-information changes.

10. Potential Serious Risk to Public Health Is a Defined Regulatory Concept

The phrase should not be interpreted as ordinary clinical language.

The Commission's guideline on the definition of a potential serious risk to public health was specifically developed for Article 29(1) and (2) of Directive 2001/83/EC. It describes the exceptional circumstances in which a Member State may refuse recognition or approval on this basis. citeturn0search28

Consequently, a regulatory team should not create its own informal threshold for invoking Article 29.

The relevant legal text and applicable Commission guidance should be reviewed when determining whether a concern meets the legal concept.

11. Disagreement Does Not Automatically Mean the Product Is Unsafe

A formal Article 29 disagreement means that a Member State considers that the applicable regulatory position cannot be accepted on the grounds of a potential serious risk to public health.

It does not by itself establish that the medicine is unsafe.

The purpose of the subsequent procedure is to obtain a structured scientific and regulatory assessment of the disagreement and reach a legally operative outcome.

This distinction is important in communications with management, safety committees and other internal stakeholders. A disagreement is a regulatory event; it should not be described as a confirmed safety conclusion unless the competent scientific and regulatory assessment has established that conclusion.

12. What Happens if the Member States Reach Agreement?

If the Member States reach agreement within the coordination-group stage, the RMS records the agreement, closes the procedure and informs the applicant. Article 28(5) then applies to the resulting national decisions. citeturn0search1

The practical lesson is that not every Article 29 disagreement proceeds to a CHMP-level procedure.

The coordination-group stage is a genuine opportunity to resolve the disagreement.

Key Takeaways

1. Not every difference of opinion during MRP or DCP is an Article 29 disagreement.
2. The key legal trigger is a CMS's inability to approve the relevant regulatory position on grounds of a potential serious risk to public health.
3. The CMS must provide detailed reasons for its position.
4. The disagreement is referred to the coordination group.
5. The Member States must use their best endeavours to reach agreement.
6. The applicant must be given an opportunity to present its views orally or in writing.
7. The RMS coordinates the process but cannot unilaterally extinguish a qualifying CMS objection.
8. If agreement is reached, the RMS records the agreement and closes the procedure.
9. If agreement is not reached within the applicable period, Article 29 provides for escalation to the Union-level procedure.
10. A regulatory disagreement should not be described as proof that a medicine is unsafe unless the subsequent scientific and regulatory assessment establishes that conclusion.

References

1. European Parliament and Council. Directive 2001/83/EC on the Community code relating to medicinal products for human use, as amended, Articles 28–29. Primary legal basis for MRP/DCP and the formal disagreement mechanism. citeturn0search0turn0search1
2. European Commission. Guideline on the definition of a potential serious risk to public health in the context of Article 29(1) and (2) of Directive 2001/83/EC (2006/C 133/05). Guidance defining the exceptional concept underlying Article 29 disagreements. citeturn0search28
3. Heads of Medicines Agencies / CMDh. Best Practice Guide on the handling of MRP/DCP procedures. Current procedural guidance on the handling of potential serious risks to public health and coordination of disagreement. citeturn0search27
4. CMDh. CMDh Referrals and procedural guidance. Current material concerning disagreements referred to CMDh under Article 29 and related provisions. citeturn0search13

Regulatory Note

This article is an educational explanation of disagreement during EU mutual recognition and decentralised procedures for human medicinal products. It does not constitute legal advice and does not replace the current consolidated Directive 2001/83/EC, current Commission guidance, CMDh procedural guidance or procedure-specific regulatory documents.

The concept of a potential serious risk to public health is a specific regulatory concept and should be assessed against the applicable legal and guidance framework rather than an internally created definition.

Where a live disagreement is being managed, the current legislation and procedure-specific documents take precedence. Particular care should be taken to distinguish routine scientific discussion, formal Article 29 disagreement and subsequent Union-level referral procedures.

13. What Happens When Agreement Cannot Be Reached?

If the Member States cannot reach agreement within the coordination-group stage, Article 29(4) provides for escalation to the Agency for the subsequent Union procedure under Articles 32, 33 and 34 of Directive 2001/83/EC.

This is an important boundary in the regulatory architecture. The issue is no longer confined to the ordinary MRP/DCP coordination process. It enters a Union-level procedure in which the scientific and regulatory question is assessed under the provisions governing that procedure.

The escalation should therefore not be described simply as an "appeal" against the CMS or RMS. It is a statutory transition from one regulatory mechanism to another.

14. The Difference Between Article 29 and the Subsequent Union Procedure

Article 29 addresses the disagreement arising during the MRP/DCP framework. Articles 32–34 establish the subsequent Union-level procedure.

This distinction matters because the responsible bodies and procedural mechanics change.

At the MRP/DCP stage, the RMS, CMSs, applicant and coordination group are central to the process. Following escalation, the Agency and the relevant scientific committee become part of the Union-level assessment under the Directive.

The regulatory professional should therefore track the procedure as a sequence rather than treating "Article 29" as the name of the entire process.

MRP / DCP
    |
    v
CMS concern
    |
    v
Potential serious risk to public health
    |
    v
Article 29 coordination-group stage
    |
    +---- agreement ----> procedure closes
    |
    v
No agreement
    |
    v
Union-level procedure under Articles 32–34

15. What the Union-Level Procedure Is Intended to Achieve

The Union-level procedure provides a mechanism for obtaining a common Union position when the participating Member States cannot resolve the qualifying disagreement themselves.

The scientific question is therefore examined beyond the national coordination stage.

For regulatory professionals, this illustrates an important principle of EU medicines regulation: national regulatory disagreement can, under defined legal conditions, be transformed into a Union-level scientific and regulatory question.

The purpose is not simply to determine which Member State was correct. The purpose is to reach the regulatory outcome provided for by Union law.

16. The Scientific Question Must Remain Clearly Defined

When a disagreement escalates, the quality of the issue definition becomes particularly important.

The regulatory record should distinguish between:

• the original scientific evidence;
• the RMS conclusion;
• the CMS objection;
• the reason the objection was considered a potential serious risk to public health;
• the applicant's response;
• the points that remained unresolved;
• and the precise question requiring Union-level assessment.

Poor issue definition can make a complex procedure harder to assess because multiple questions become mixed together.

A strong regulatory record instead allows the scientific question to be stated in a form that can be independently evaluated.

17. The Applicant During Escalation

The applicant's role does not disappear when the disagreement moves beyond the coordination group.

The applicant should maintain a controlled position on the scientific evidence, product information and benefit-risk implications and should respond through the procedural mechanisms applicable to the Union-level assessment.

The internal organisation should also ensure that Regulatory Affairs, Pharmacovigilance, Medical, Clinical and other relevant functions work from the same evidence base.

A formal disagreement can expose inconsistencies that may have been less visible during routine procedure management. For example, the pharmacovigilance assessment, clinical interpretation and proposed product-information wording should not contradict one another.

18. Regulatory Communication During a Disagreement

A formal disagreement should be managed as a controlled regulatory process.

Internal communications should distinguish clearly between:

• established regulatory facts;
• the authority's stated concern;
• the applicant's interpretation;
• scientific hypotheses under assessment;
• and the final regulatory conclusion.

This distinction is particularly important when communicating with senior management. A CMS concern is not necessarily the final scientific conclusion, and an escalation is not itself proof of an adverse benefit-risk determination.

The wording used in internal records should therefore remain proportionate to the evidence and the procedural stage.

19. Implications for Pharmacovigilance

A disagreement concerning safety can have direct implications for the pharmacovigilance system.

The QPPV and relevant PV functions should understand the issue sufficiently to determine whether it affects:

• signal management;
• ongoing safety evaluation;
• risk-management activities;
• product information;
• safety communications;
• aggregate reporting;
• or other pharmacovigilance processes.

The existence of an Article 29 disagreement does not itself determine the final PV action. The action should follow the evidence, the regulatory assessment and the applicable legal requirements.

Where the issue concerns a potential new risk or a change in the understanding of an existing risk, the pharmacovigilance assessment should remain scientifically independent while being appropriately aligned with the regulatory procedure.

20. A Practical Case-Management Framework

For an MAH, a useful internal framework is:

This framework is not a substitute for the statutory procedure. It is an internal governance tool for maintaining traceability.

21. Why the Potential Serious Risk Concept Should Be Used Carefully

The phrase "potential serious risk to public health" can sound broader than its legal use.

It should not become a general label for any important safety concern.

The applicable Commission guidance should be consulted when assessing whether the legal criteria are met. The organisation should document the reasoning rather than relying on an informal internal threshold.

This is particularly important because invoking the formal disagreement mechanism has procedural consequences.

22. What a QPPV Should Know About an Article 29 Disagreement

The QPPV does not need to become the procedural owner of an MRP or DCP disagreement merely because the issue concerns safety.

However, the QPPV should have sufficient oversight to understand:

• what safety issue is being discussed;
• what evidence supports it;
• what regulatory position is being considered;
• what product-information consequences are possible;
• what risk-management measures may be affected;
• and what the final regulatory outcome means for the pharmacovigilance system.

The QPPV's perspective is therefore one of pharmacovigilance oversight and regulatory interface, not substitution for the regulatory-procedure owner.

23. What Happens to the National Authorisations?

The practical consequence of the final procedure must be considered in relation to the national marketing authorisations involved.

The legal effect of the final regulatory outcome depends on the procedure and the applicable provisions of the Directive. The organisation should therefore not assume that a generic description of an Article 29 disagreement tells it exactly how a particular national authorisation will be changed.

The final legally operative documents should be reviewed to determine:

• the required product-information changes;
• the relevant national decisions or implementation steps;
• any conditions or measures imposed;
• and the applicable implementation requirements.

This is another reason to distinguish scientific conclusions from legal decisions and implementation actions.

24. A Complete Regulatory Timeline

A useful way to reconstruct a disagreement is to build a procedural timeline:

Application / existing authorisation
          ↓
RMS assessment
          ↓
CMS review
          ↓
Scientific issue identified
          ↓
Applicant response / discussion
          ↓
Qualifying CMS disagreement
          ↓
Article 29 referral to coordination group
          ↓
Best endeavours to reach agreement
          ↓
      +---+---+
      |       |
   Agreement  No agreement
      |       |
      v       v
 Procedure   Union-level
  closes     procedure
              |
              v
        Final regulatory
            outcome
              |
              v
       National implementation

This timeline is particularly useful during audits, inspections and internal governance reviews because it separates procedural events from scientific conclusions.

25. Common Mistakes in Managing an Article 29 Disagreement

Calling every CMS objection an Article 29 referral

The legal trigger is specific. Ordinary scientific questions and drafting comments should not be labelled as formal Article 29 disagreements without establishing the applicable criteria.

Treating the CMS as having made the final safety conclusion

A CMS objection initiates or contributes to a regulatory assessment. It is not automatically the final scientific determination.

Treating escalation as proof of product failure

Escalation means that the disagreement could not be resolved at the coordination-group stage under the applicable framework. It does not itself establish an unfavourable benefit-risk balance.

Ignoring the applicant's role

The applicant has an explicit opportunity to present its views and should manage the evidence and responses as a coordinated regulatory submission.

Losing the distinction between scientific and legal outcomes

A scientific recommendation, committee conclusion, Commission decision or national implementation action may have different legal significance. The exact document should be identified.

Failing to involve pharmacovigilance appropriately

Where the disagreement concerns safety, PV should understand the issue and its potential consequences without taking over ownership of the regulatory procedure.

26. Relationship to the Next Article

The next article, Potential Serious Risk to Public Health: How It Is Assessed, examines the specific concept that determines whether a CMS concern can qualify for the formal Article 29 pathway.

That distinction is important because the disagreement mechanism cannot be understood correctly without understanding its legal trigger.

Key Takeaways

1. Article 29 disagreement is an exceptional mechanism within MRP/DCP.
2. A qualifying CMS concern can move from ordinary procedure management to coordination-group discussion.
3. The Member States must use their best endeavours to reach agreement.
4. The applicant has an explicit opportunity to present its views.
5. If agreement is reached, the procedure can close at the coordination-group stage.
6. If agreement cannot be reached within the applicable period, Article 29(4) provides for escalation to the Union-level procedure under Articles 32–34.
7. Escalation is a change in regulatory mechanism, not simply an appeal against the RMS.
8. The scientific question should remain clearly defined throughout the escalation.
9. A formal disagreement is not itself proof that a medicine is unsafe or has an unfavourable benefit-risk balance.
10. The QPPV should maintain appropriate pharmacovigilance oversight while Regulatory Affairs retains responsibility for the regulatory procedure.
11. Final implementation should be based on the legally operative outcome and applicable national requirements.

References

1. European Parliament and Council. Directive 2001/83/EC on the Community code relating to medicinal products for human use, as amended, Articles 28–29 and 32–34. Primary legal basis for the MRP/DCP disagreement mechanism and subsequent Union-level procedure.
2. European Commission. Guideline on the definition of a potential serious risk to public health in the context of Article 29(1) and (2) of Directive 2001/83/EC (2006/C 133/05). Commission guidance on the legal concept that triggers the formal disagreement pathway.
3. CMDh. Current procedural guidance concerning Mutual Recognition and Decentralised Procedures. Current guidance on RMS/CMS coordination, disagreement and referral mechanisms.
4. European Medicines Agency. Referral procedures for human medicines. Current explanatory and procedural material concerning Union-level referrals.
5. European Medicines Agency. Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh). Current information concerning CMDh's role in nationally authorised medicines.

Regulatory Note

This article is an educational explanation of disagreement during MRP and DCP and the transition from the Article 29 coordination-group stage to the subsequent Union-level procedure. It does not constitute legal advice and does not replace the current consolidated Directive 2001/83/EC, Commission guidance, CMDh guidance or procedure-specific regulatory documents.

The precise legal effect of a disagreement and its final outcome depends on the applicable legislation and the documents governing the individual procedure. The phrase "potential serious risk to public health" should be assessed using the applicable legal and Commission guidance framework rather than an internally created definition.

For a live procedure, the current legislation, formal regulatory communications, procedure-specific timetable and legally operative decision take precedence over this general educational explanation.