GVP Module VIII: Imposed and Non-Imposed PASS

Introduction

The distinction between an imposed PASS and a non-imposed PASS is fundamental because it determines the regulatory framework within which the study operates. It is not simply a description of how strongly a regulator encouraged the study.

A PASS is any study relating to an authorised medicinal product that is conducted to identify, characterise or quantify a safety hazard, confirm the safety profile, or measure the effectiveness of risk-management measures. A PASS can be interventional or non-interventional. GVP Module VIII applies to both, with particular emphasis on non-interventional PASS. citeturn0search12

For non-interventional PASS, the key distinction is between studies undertaken voluntarily by a marketing authorisation holder and studies conducted pursuant to an obligation imposed by an EU competent authority. The regulatory consequences are different even when the scientific question is similar. citeturn0search12turn0search0

The distinction therefore needs to be established early in study planning. Once the legal status is known, the organisation can determine the applicable protocol, submission, assessment, reporting and follow-up requirements.

1. The Basic Distinction

At its simplest:

The distinction should be documented rather than inferred from the study's scientific importance.

A study can be highly important to the RMP and still be non-imposed. Conversely, an imposed study may arise from a specific regulatory obligation rather than from a routine RMP activity.

2. Where the Distinction Comes From

The legal framework for post-authorisation safety studies is distributed across EU legislation and GVP guidance.

Directive 2001/83/EC, Regulation (EC) No 726/2004 and Commission Implementing Regulation (EU) No 520/2012 contain provisions governing PASS. GVP Module VIII explains how these provisions operate in pharmacovigilance practice. citeturn0search12turn0search3

For non-interventional PASS imposed by an EU competent authority, Articles 107n to 107q of Directive 2001/83/EC establish specific procedures for protocol submission, assessment and final results. These procedures are therefore not simply recommendations adopted by individual companies. citeturn0search13turn0search0

This is why an organisation should determine legal status before selecting its operational pathway.

3. Categories of Non-Interventional PASS

GVP Module VIII identifies several categories of non-interventional PASS undertaken by MAHs:

1. a PASS imposed as an obligation associated with a marketing authorisation;
2. a PASS imposed as a specific obligation for a marketing authorisation granted under exceptional circumstances;
3. a PASS included in the RMP to investigate a safety concern or evaluate risk-minimisation effectiveness; and
4. a PASS conducted voluntarily by the MAH. citeturn0search12

The third category is particularly important because an RMP can contain a PASS without the study being an authority-imposed obligation. The presence of a PASS in an RMP therefore does not, by itself, answer the question of whether the study is imposed.

4. RMP Inclusion Does Not Automatically Mean Imposition

An RMP describes how identified or potential risks and missing information are managed. A study may be included in the RMP because the MAH has determined that additional evidence is needed. That does not necessarily mean that an authority has imposed the study as a legal obligation.

The organisation should therefore distinguish:

• the RMP rationale for the study;
• the regulatory source of any obligation;
• the category of PASS; and
• the procedural consequences that follow from that category.

This prevents an RMP entry from being treated as evidence of a legal obligation when the underlying regulatory record does not support that conclusion.

5. What Makes a PASS Imposed?

An imposed PASS arises where the competent authority establishes an obligation requiring the MAH to conduct the study.

For example, an EU competent authority may impose a non-interventional PASS as a condition of a marketing authorisation or as a specific obligation in a conditional marketing authorisation or a marketing authorisation under exceptional circumstances. citeturn0search0

The legal source of the obligation should be identifiable in the regulatory record. A robust system should therefore be able to answer: What document or regulatory action created the obligation?

The answer should not simply be "the RMP" or "the safety department requested the study".

6. What Is a Non-Imposed PASS?

A non-imposed PASS is a study that is not subject to an authority-imposed PASS obligation. It may nevertheless be scientifically important, included in the RMP, requested during regulatory dialogue, or conducted to answer a significant safety question.

EMA states that voluntary PASS are sponsored or conducted by MAHs on their own initiative and that non-imposed studies requested in RMPs fall within the voluntary category. EMA also recommends that companies submit protocols and study reports for voluntary PASS in the same manner as imposed PASS, although this is not mandatory. citeturn0search0

The recommendation to follow the same approach should not be confused with the legal obligation applicable to an imposed PASS.

7. Why Legal Status Matters Operationally

The imposed/non-imposed distinction affects more than terminology. It can determine:

• whether the Articles 107n–107q procedure applies;
• which authority receives the protocol or final report;
• whether regulatory assessment is mandatory;
• the applicable regulatory timetable;
• how protocol amendments are handled;
• how final results are submitted; and
• how the organisation demonstrates fulfilment of a regulatory commitment.

These consequences make classification an early governance decision rather than a field to be completed at the end of study planning.

8. The Same Scientific Question Can Produce Different Regulatory Pathways

Consider a study intended to determine whether a known adverse reaction occurs more frequently in a particular population.

The scientific question can be identical in two situations: the authority may impose the study because the evidence is considered insufficient, or the MAH may voluntarily conduct it to resolve an uncertainty identified through its own pharmacovigilance activities.

The study design may therefore look very similar while the regulatory pathway differs. Scientific design and legal status answer different questions.

9. Imposed PASS: Regulatory Control of the Protocol

For an imposed non-interventional PASS within the EU Article 107n–107q framework, the draft protocol is submitted for regulatory assessment through the applicable process.

The regulatory assessment provides an opportunity for the authority to determine whether the proposed design can address the required safety question. Protocol development is therefore both a scientific activity and, for an imposed study, part of the regulatory control system.

10. Imposed PASS: Final Results

The final results of an imposed non-interventional PASS are subject to the applicable regulatory procedure.

EMA's current procedural guidance specifies that only study reports considered final by the MAH should be submitted under the Article 107n–107q framework. Finality is connected to completion of the analytical dataset required for the primary analyses. Where the dataset is incomplete or data collection continues, the Agency should be contacted before submitting the final report. citeturn0search0

An interim analysis and a final study report are therefore not interchangeable regulatory documents.

11. Non-Imposed PASS: Different Does Not Mean Uncontrolled

The absence of an imposed obligation does not reduce the MAH's responsibility for scientific quality.

A voluntary or RMP PASS still requires appropriate governance, protocol control, data quality, scientific review, safety assessment, documentation and integration with the pharmacovigilance system.

The difference is the source and legal status of the obligation, not whether the study should be professionally managed.

12. The RMP Interface

A PASS may be included in the RMP because the study is necessary to address a safety concern or evaluate risk-minimisation effectiveness. If the study is imposed, the regulatory obligation and RMP entry should be reconciled. If it is non-imposed, the RMP should accurately describe the study and its purpose without implying a legal obligation that does not exist.

The RMP should therefore not be used as the sole source for determining the legal status of a PASS.

13. A Practical Classification Test

Before approving a PASS plan, the organisation can work through a simple sequence:

Is there a PASS?
      ↓
Is the study non-interventional?
      ↓
Was the study imposed by an EU competent authority?
      ↓
What regulatory instrument created the obligation?
      ↓
If not imposed, is it included in the RMP?
      ↓
If not, is it voluntary?
      ↓
Which procedural and documentation requirements follow?

This sequence keeps scientific purpose, RMP status and legal obligation separate.

14. The Importance of the Regulatory Record

The classification should be supported by evidence.

For an imposed study, the organisation should identify the regulatory basis of the obligation and connect it to the current protocol, RMP and internal commitment tracker. For a non-imposed study, it should demonstrate why it is classified as voluntary or RMP-related and what expectations apply.

This evidence becomes particularly important when responsibility transfers between teams or when the study continues over several years.

15. Common Classification Error: "RMP PASS = Imposed PASS"

A PASS can be present in an agreed RMP without being an authority-imposed PASS. Treating every RMP study as imposed can lead to inappropriate assumptions about mandatory submission procedures, regulatory timelines and commitment closure.

The correct approach is to identify the legal source of the obligation first and then determine how the RMP records the study.

16. Common Classification Error: "Voluntary = Optional to Complete"

Voluntary does not mean that the organisation can disregard a study once it has been started.

If the MAH has undertaken the study to answer an important safety question, it remains responsible for managing the study appropriately and assessing the resulting evidence. If the study is included in the RMP, the organisation should also consider the consequences of failing to generate the evidence described in the agreed risk-management strategy.

The absence of an imposed legal obligation does not eliminate scientific or governance responsibility.

Key Takeaways

The imposed/non-imposed distinction is fundamentally about regulatory status, not scientific importance.

An imposed non-interventional PASS arises from an authority-created obligation and can therefore be subject to the specific EU procedures in Articles 107n–107q. A PASS included in an RMP is not automatically imposed. Voluntary and RMP-related non-imposed studies remain subject to appropriate MAH governance and scientific responsibility. citeturn0search0turn0search13

The safest operational approach is to establish the legal source of the study obligation first, then determine the applicable procedural pathway, and only afterwards map the study into the RMP and internal governance framework.

References

1. European Medicines Agency. GVP Module VIII — Post-authorisation safety studies, Revision 3.
2. European Medicines Agency. Post-authorisation safety studies (PASS): current procedural guidance and questions and answers.
3. European Medicines Agency. GVP Module VIII Addendum I — Requirements and recommendations for submission of information on non-interventional PASS.
4. Directive 2001/83/EC, as amended, particularly Articles 107m–107q.
5. Regulation (EC) No 726/2004, as amended.
6. Commission Implementing Regulation (EU) No 520/2012, as amended.
7. European Medicines Agency. GVP Module V — Risk management systems.

Regulatory Note

This article distinguishes legal requirements from EMA guidance and recommended operational practice. The classification of an individual PASS should be established from the current regulatory record and applicable legislation rather than inferred from the study title, RMP alone or internal terminology.

Regulatory procedures and guidance may change. Current EU legislation and EMA procedural guidance should therefore be verified before applying this framework to an active study.