GVP Module VIII Addendum I: Submission of Information on Non-Interventional PASS

Introduction

A non-interventional PASS generates several regulatory documents during its lifecycle: a protocol, possible substantial amendments, progress information and a final study report. Their submission is not governed by one universal workflow. The applicable route depends on the study's regulatory status, the product, the Member States involved and the nature of the document being submitted.

GVP Module VIII Addendum I provides the detailed framework for submitting information on non-interventional PASS. It deliberately distinguishes legal requirements from recommendations and must be read with the underlying legislation, GVP Modules V and VIII, and current EMA and national procedural guidance. citeturn2search12turn3search0

The first practical lesson is therefore that classification precedes submission. Before deciding where a document goes, the MAH needs to establish why the study exists and what regulatory procedure applies.

1. Regulatory Status Determines the Submission Path

A non-interventional PASS may be imposed by an EU competent authority, included in an EU-agreed RMP without being imposed, or conducted voluntarily. These categories do not create identical legal obligations.

For imposed PASS, the legislation provides specific procedures for protocols, substantial amendments and final study reports. For voluntary studies, national procedures may still apply, and GVP recommendations may create additional expectations. Addendum I therefore cannot be reduced to a single submission checklist. citeturn2search12turn4search0

The internal record for a study should consequently establish its regulatory category before the submission calendar is created.

2. Legal Requirements, Recommendations and Internal Controls

Addendum I explicitly distinguishes legal requirements, identified by "shall", from recommendations, identified by "should". citeturn6search0

That distinction should survive into the MAH's procedures. A statutory deadline, an EMA recommendation and an internally selected quality-control deadline may all appear in the same operational calendar, but they should not be represented as having the same legal status.

A useful submission control therefore records the legal basis, applicable authority, deadline, route and evidence of completion for each milestone. An MAH may choose a more conservative internal control than the legal minimum, but it should remain possible to identify which requirement is regulatory and which is operational practice.

3. Registration Is Not Regulatory Submission

GVP Module VIII recommends registration of non-interventional PASS conducted voluntarily in the EU and those included in an EU-agreed RMP. Registration should occur before the study starts or as early as possible. citeturn6search0

Registration and regulatory submission are nevertheless different controls. Addendum I states that uploading protocols, progress reports and final reports to the EU PAS Register is not itself a legal submission obligation and cannot be the only channel for submitting documents to competent authorities or the Agency. citeturn6search0

EMA's current PASS material now refers to the HMA-EMA catalogue of real-world data studies, which replaces the EU PAS Register as the public catalogue. The regulatory principle remains the same: transparency registration should not be confused with transmission under the applicable legal procedure. citeturn7search3

The two controls should be cross-referenced so that an inspector can determine both that the study record was maintained and that required regulatory submissions were actually made.

4. The Protocol Starts the Submission Lifecycle

For an imposed non-interventional PASS, the draft protocol enters the applicable Article 107n procedure. Current EMA procedural guidance specifies the submission context for centrally authorised products and the treatment of protocol amendments. citeturn7search6

For voluntary studies, the protocol remains a controlled scientific document, but the regulatory submission requirements depend on the applicable category and national procedure. Category 3 PASS, for example, has specific RMP and submission implications. citeturn4search0

The practical consequence is that an SOP should not simply instruct staff to "submit the protocol to EMA". It should first determine the regulatory status, competent authority and applicable route.

5. Substantial Amendments Require Regulatory Reasoning

A substantial amendment can alter the scientific question, population, exposure, outcome definition or analysis and can therefore affect the regulatory basis on which the study was accepted.

For imposed PASS, Addendum I expressly addresses submission of an updated protocol following a substantial amendment through the Article 107n–107o framework. citeturn2search12turn7search6

A sound amendment process therefore connects:

proposed change → scientific assessment → regulatory determination → approved protocol version → implementation.

This prevents a common control failure in which the study team implements a scientifically sensible change and only afterwards asks whether regulatory review was required.

6. The Final Report Is a Regulatory Milestone

The final report provides the evidence on which the scientific and, for imposed PASS, regulatory assessment can be based. It should therefore be distinguished from internal study close-out.

For an imposed non-interventional PASS, the final report is subject to the applicable Article 107p procedure, with a statutory submission period of twelve months after the end of data collection. citeturn2search12

The organisation should consequently track separately:

• end of data collection;
• analysis and quality control;
• final report approval;
• regulatory submission;
• regulatory assessment;
• implementation of the outcome; and
• closure of resulting commitments.

Calling all of these "study completion" hides important controls.

7. A Lifecycle Model

The submission architecture can be understood as a continuous lifecycle:

Study classification
        ↓
Legal obligation / recommendation
        ↓
Registration and transparency
        ↓
Protocol submission, where applicable
        ↓
Amendment control
        ↓
Progress information, where required or requested
        ↓
Final study report
        ↓
Regulatory assessment, where applicable
        ↓
Implementation and follow-up

This model is more useful than a static document checklist because every later step depends on the classification established at the beginning.

8. The Minimum Regulatory Record

For each non-interventional PASS, the MAH should be able to establish from controlled records:

The purpose is not administrative complexity. It is to make the regulatory reasoning reproducible.

9. Why Current Procedures Must Be Checked

GVP Module VIII Addendum I Rev. 3 came into effect in June 2020. Its national-procedure information should therefore be treated as a regulatory reference that must be checked against current national requirements rather than as a permanently current national-procedure directory. citeturn3search1

EMA's current PASS guidance has also evolved operationally. From January 2025, MAHs should use IRIS when managing PASS after the original submission; EMA states that IRIS and the existing submission gateway continue to serve different functions. citeturn7search2

This is an important governance principle: an internal procedure should identify the current authoritative route at the time of submission rather than hard-code a historical portal or workflow.

References

1. European Medicines Agency. GVP Module VIII Addendum I — Requirements and recommendations for the submission of information on non-interventional post-authorisation safety studies (Rev. 3).
2. European Medicines Agency. GVP Module VIII — Post-authorisation safety studies (Rev. 3).
3. European Medicines Agency. Post-authorisation safety studies (PASS), including current procedural questions and answers.
4. European Medicines Agency. GVP Module V — Risk management systems.
5. Commission Implementing Regulation (EU) No 520/2012, as amended.
6. Directive 2001/83/EC, as amended.

Regulatory Note

This article distinguishes legal requirements, EMA recommendations and operational practice. Current national requirements and EMA procedural instructions should be verified when applying the framework to an actual PASS.

10. Imposed PASS: The EU Procedure

For an imposed non-interventional PASS, the submission pathway is determined by the legal basis of the obligation and the product's authorisation status. The draft protocol, an updated protocol following a substantial amendment and the final study report are subject to the procedures specified in the pharmacovigilance legislation. citeturn2search12

For centrally authorised products, current EMA procedural guidance identifies specific CTD locations and procedures for imposed PASS documents. Draft protocols are submitted in the applicable post-authorisation procedure, while final reports are handled through the Article 107q procedure. citeturn7search6

The important principle is that the regulatory submission is part of the PASS assessment process. It is not simply transmission of a finished scientific document. The authority's assessment can lead to further regulatory consequences, so the MAH needs to preserve the connection between the submitted document, the regulatory procedure and the eventual outcome.

11. Progress Reports Are Different From Final Reports

A progress report answers a different question from a final report. It documents the status of the study and, where relevant, interim information rather than providing the final scientific assessment.

For imposed PASS, national competent authorities may require progress reports under the applicable legal framework. The Addendum identifies national procedures for such reports and states that progress reports should also be submitted to the Agency for centrally authorised products. citeturn5search0

The national list in Rev. 3 is historical procedural information and should not be treated as an immutable current directory. Current national requirements should be verified when a real submission is prepared.

This distinction also matters operationally. A progress report should not be treated as a substitute for a final report, and a final report should not be delayed merely because an internal project tracker has not classified an interim milestone correctly.

12. Voluntary PASS Has a Different Legal Architecture

Voluntary non-interventional PASS include category 3 studies and other non-interventional PASS conducted voluntarily by the MAH. They are not automatically subject to the same EU-level procedure as an imposed PASS. citeturn4search0

For voluntary studies, the final study report is subject to national submission procedures within twelve months of the end of data collection under the framework described in Addendum I. Competent authorities may also require submission of the protocol and progress reports through national procedures. citeturn4search0

For category 3 studies, the protocol also has an RMP interface, and progress information should be submitted to the Agency for centrally authorised products in the circumstances described by the Addendum. citeturn5search0

The practical lesson is that voluntary does not mean unregulated. It means that the legal pathway differs from that of an imposed PASS. National requirements, RMP commitments, transparency expectations and the MAH's own pharmacovigilance obligations can still create significant controls.

13. National Procedures Are Part of the EU Operating Model

A multinational PASS can involve a combination of EU-level and national requirements. The fact that a study is governed by GVP does not eliminate the need to determine what a particular Member State requires for a study conducted on its territory.

This is particularly important for voluntary studies, for which Addendum I identifies national requirements for protocol and progress-report submissions. citeturn4search0

A multinational submission matrix should therefore distinguish at least:

• Member State;
• competent authority;
• study status;
• document type;
• submission requirement;
• legal or procedural basis;
• deadline;
• submission route;
• local language requirement, if applicable;
• confirmation of receipt;
• and follow-up obligation.

The matrix is an operational tool, not a substitute for the underlying national rule. Its value is that it makes the organisation's interpretation and execution visible.

14. National Variants of a Common Protocol

A multinational PASS may require national adaptations because of differences in national law or implementation requirements. Current EMA procedural guidance describes national variants as regional appendices to the main protocol where necessary. citeturn7search6

This creates an important document-control issue. The organisation needs to know which elements constitute the common scientific protocol and which are national adaptations. A local amendment should not unintentionally alter the common scientific design without appropriate assessment.

The controlled relationship can therefore be represented as:

Common protocol
      ↓
Scientific/regulatory approval
      ↓
National implementation appendices
      ↓
Local execution
      ↓
Consolidated study evidence

Where a national change affects a core scientific element, the organisation should reassess whether it is still a local implementation difference or a substantial change to the study itself.

15. The RMP Interface Does Not Replace the Submission Procedure

For a PASS included in an RMP, the protocol and its milestones are part of the risk-management system. That does not mean that attaching the protocol to an RMP automatically satisfies every separate submission obligation.

For category 3 studies, Addendum I states that the protocol should also be submitted with the RMP according to GVP Module V. citeturn5search0

For imposed studies, current EMA guidance similarly distinguishes the initial regulatory submission from later inclusion of the endorsed protocol in the RMP at the appropriate regulatory opportunity. citeturn7search6

The operational consequence is that RMP control and regulatory-submission control should be linked but not merged. One demonstrates lifecycle risk-management governance; the other demonstrates compliance with the applicable submission procedure.

16. Electronic Submission Is a Process, Not a Portal Name

Electronic systems change. The regulatory obligation does not necessarily change when the system used to transmit information changes.

EMA currently states that from January 2025 MAHs should use IRIS when managing PASS after the original submission, while IRIS and the existing submission gateway coexist for different functions. citeturn7search2

This means an SOP should describe the regulatory transaction first and the electronic mechanism second. A durable control might state that the responsible function must submit the document through the EMA-designated electronic route applicable at the time, with the procedure and current technical guidance verified before submission.

That is more resilient than embedding a portal name into a permanent workflow.

17. Submission Evidence Is Part of the Pharmacovigilance Record

The submitted document alone does not necessarily prove that the regulatory transaction was completed. A controlled submission record should allow the organisation to reconstruct what was submitted, when, under which procedure and with what outcome.

For a significant PASS, useful evidence can include:

• approved submitted document;
• submission package or delivery record;
• submission date;
• procedure or application identifier;
• acknowledgement or confirmation;
• regulatory correspondence;
• authority questions and responses;
• final assessment or decision;
• and evidence of implementation.

The precise record set depends on the procedure. The governing principle is traceability: the organisation should not have to rely on individual memory to reconstruct the regulatory history.

18. When a Submission Is Rejected, Returned or Requires Correction

A technical rejection or procedural correction does not necessarily mean that the scientific document itself is defective. It may indicate an administrative, validation or technical problem.

The organisation should distinguish the type of problem because the response differs. A technical transmission failure may require resubmission through the same route. A deficiency identified by an authority may require scientific or regulatory action. A disagreement about the applicable procedure may require escalation to regulatory affairs and pharmacovigilance governance.

The important control is that the original deadline remains visible while the issue is resolved. A failed transmission should not silently become a missed regulatory milestone.

19. Submission Responsibility Across Functions

PASS submissions commonly involve several functions: study operations, epidemiology, statistics, pharmacovigilance, regulatory affairs and external service providers. Dividing tasks does not divide regulatory accountability into independent fragments.

Responsibilities should therefore distinguish preparation from approval and transmission. The scientific team may own the content, regulatory affairs may manage the procedure, and pharmacovigilance governance may assess the safety implications, while the MAH retains overall responsibility for compliance.

The QPPV does not need to perform every submission task. The governance system should, however, ensure that material safety information and significant regulatory consequences are visible to the appropriate pharmacovigilance oversight function. GVP Module VIII recommends QPPV or delegate involvement in relevant PASS protocol review and sign-off. citeturn2search15

20. Submission Calendars Should Reflect Regulatory Dependencies

A useful calendar does more than list dates. It represents dependencies.

For example:

Regulatory obligation
        ↓
Protocol deadline
        ↓
Scientific review
        ↓
Regulatory submission
        ↓
Authority assessment
        ↓
Study conduct
        ↓
Data collection end
        ↓
Final report deadline
        ↓
Regulatory assessment
        ↓
Implementation

Internal review deadlines should be placed before the regulatory deadline with sufficient contingency. The calendar should also identify dependencies that can change the expected date, such as a substantial amendment, delayed data availability, authority request or technical submission problem.

21. A Submission Decision Example

Consider a category 3 non-interventional PASS conducted voluntarily by an MAH for a centrally authorised medicine. The study is included in the EU RMP but was not imposed as an obligation.

The correct reasoning is not "because it is in the RMP, it follows the imposed PASS procedure". Instead:

1. establish that the study is voluntary/category 3;
2. identify the RMP obligation and its milestones;
3. determine the applicable national submission requirements;
4. apply the relevant transparency and EMA expectations;
5. maintain the protocol and study records under controlled procedures;
6. submit progress or final information where required or requested; and
7. assess the results for their effect on the RMP and wider pharmacovigilance system.

This example illustrates why study status, RMP status and submission status must remain separate concepts.

22. The Central Governance Principle

The strongest submission process does not ask staff to remember a long list of portals and dates. It gives them a controlled decision path that begins with the regulatory status of the study and ends with evidence that the applicable obligation was fulfilled.

That makes the process more robust when regulations, electronic systems or national procedures change.

References

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

Regulatory Note

The national-procedure information in GVP Module VIII Addendum I reflects its applicable version and should not be treated as a substitute for checking current national requirements. Current EMA procedural and electronic-submission guidance should be verified for each real transaction.

23. Inspection Readiness: Reconstructing the Submission Decision

An inspector evaluating PASS submissions may be less interested in seeing a large collection of transmission receipts than in understanding whether the organisation had an effective process for determining what had to be submitted.

A strong evidence chain should allow the organisation to move from the study's regulatory classification to the resulting submission obligation and then to the evidence that the obligation was fulfilled:

Study status
     ↓
Legal / procedural basis
     ↓
Required document
     ↓
Authority and route
     ↓
Deadline
     ↓
Approved submission
     ↓
Confirmation / correspondence
     ↓
Regulatory outcome
     ↓
Implementation / closure

This chain is particularly important when several functions participate in the process. It demonstrates that the submission was the result of a controlled decision rather than an informal exchange between individuals.

24. Illustrative Failure: The Register Record Is Complete but the Submission Is Missing

An inspector finds a complete public PASS record containing the protocol and final report but cannot find evidence that the required regulatory submission was made through the applicable authority procedure.

The organisation may initially argue that the documents are publicly available, but that does not answer the regulatory question. Registration and legal submission are distinct controls. Addendum I expressly states that EU PAS Register uploading cannot be the only submission channel. citeturn6search0

The appropriate corrective analysis would therefore examine why the organisation's process allowed transparency registration to be treated as evidence of regulatory submission.

25. Illustrative Failure: The Wrong PASS Category Was Used

A study is included in an RMP and the team automatically treats it as an imposed PASS. It therefore follows an imposed-study procedure even though no competent authority imposed the study.

The problem is not necessarily the use of a more conservative process. The deeper weakness is that the regulatory classification was never explicitly established.

A mature process should record the basis for the classification and the resulting submission pathway. If the organisation chooses to follow the recommended submission approach for a voluntary PASS, that operational choice should still be distinguishable from a legal imposition.

EMA explicitly recommends that companies submit protocols and study reports for voluntary PASS in the same manner as imposed PASS, while stating that this is not mandatory. citeturn7search2

26. Illustrative Failure: A Substantial Amendment Was Implemented Too Early

A study team changes the primary outcome because the original outcome becomes impractical. The amendment is scientifically justified and the new protocol is eventually submitted, but data collection under the amended design began before the applicable regulatory review was completed.

The inspection issue is the sequencing of the controls. Scientific justification does not automatically remove a regulatory requirement for prior submission or assessment.

The evidence should show when the change was proposed, when its regulatory significance was determined, when approval or acknowledgement was obtained where required, and when implementation began.

27. Illustrative Failure: A Final Report Was Submitted but the Deadline Was Miscalculated

The MAH can demonstrate a final report submission but calculates the twelve-month period from final report approval rather than the end of data collection.

For imposed PASS, the statutory reference point is the end of data collection. citeturn2search12

This illustrates why a regulatory calendar should derive deadlines from the legally defined event rather than from an internal project milestone.

28. Illustrative Failure: National Requirements Were Copied From an Old Matrix

A multinational study follows a national submission matrix created several years earlier. The matrix still reflects historical requirements, even though the relevant national procedure has changed.

The underlying problem is not merely an outdated spreadsheet. It is a governance failure in which a secondary operational record has been allowed to become the source of regulatory truth.

The matrix should instead point to the current authoritative requirement and record when that requirement was verified.

29. Illustrative Failure: The Submission Exists but the Submitted Version Cannot Be Identified

The organisation can demonstrate that a report was transmitted but has several versions of the report in its document system and cannot establish which version was actually submitted.

This creates a data-integrity and traceability problem. A submission record should identify the controlled document version, submission date and procedure identifier so that the regulatory transaction can be reconstructed.

The issue is especially important when the document was changed during late review or following a regulatory query.

30. Illustrative Failure: Regulatory Correspondence Is Not Linked to the Study

The authority's questions and the MAH's responses exist in an email archive, but the PASS record does not identify them or show how the resulting actions were tracked.

The weakness is not necessarily that the correspondence was conducted by email. It is that the regulatory history is fragmented.

A mature process links substantive regulatory correspondence to the study record and ensures that resulting commitments are assigned, monitored and closed.

31. The QPPV Perspective

The QPPV's role is primarily one of pharmacovigilance oversight rather than document transmission. For a significant PASS, the QPPV or delegate should nevertheless be able to understand the study's regulatory status, its major milestones and the consequences of its results.

Relevant questions include:

• Was the study correctly classified?
• Is the study linked to an important RMP commitment?
• Were significant protocol changes appropriately assessed?
• Could an interim finding alter the safety profile?
• Was the final report submitted through the correct procedure?
• What did the authority conclude?
• Does the outcome affect the RMP, signal management, PSUR, product information or risk minimisation?
• Are resulting actions controlled through the quality system?

The QPPV should not need to personally execute each submission. The governance system should make these answers accessible and reliable.

32. Submission Controls as Part of the PV Quality System

The submission process belongs within the wider pharmacovigilance quality system because a failure in transmission can undermine an otherwise scientifically sound study.

Relevant quality controls include:

• defined roles and responsibilities;
• regulatory-calendar ownership;
• document control;
• submission verification;
• contingency arrangements;
• escalation of delays;
• vendor oversight;
• reconciliation of regulatory commitments;
• records retention;
• and periodic review of the effectiveness of the process.

These controls should be proportionate to risk. A small voluntary study with no regulatory milestone does not require the same escalation architecture as an imposed PASS linked to an important safety concern.

33. From Submission Compliance to Effective Pharmacovigilance

Submission compliance is necessary, but it is not the endpoint of PASS governance.

The more complete chain is:

Correct classification
        ↓
Correct submission
        ↓
Reliable study evidence
        ↓
Scientific assessment
        ↓
Regulatory assessment where applicable
        ↓
Risk-management decision
        ↓
Implementation
        ↓
Effectiveness / continued monitoring

A submission process that ends at the transmission receipt is therefore incomplete. The final report may generate regulatory action, a change to the RMP, a new signal-management activity, additional risk minimisation or a reasoned conclusion that no change is required.

The submission system should make the hand-off into those downstream processes visible.

34. Practical Minimum Evidence Set

For a significant non-interventional PASS, a practical inspection-ready record should normally make it possible to locate, as applicable:

1. regulatory classification;
2. regulatory obligation or RMP basis;
3. protocol and approved versions;
4. amendment assessments and regulatory decisions;
5. study registration record;
6. submission records;
7. progress information and authority requests;
8. final study report;
9. regulatory assessment and correspondence;
10. resulting actions;
11. evidence of implementation;
12. closure or continuing monitoring.

This is not a claim that every item is independently required by GVP in every study. It is an illustrative evidence model for demonstrating controlled implementation.

35. A Mature Operating Model

The mature model treats the PASS submission process as a controlled regulatory lifecycle rather than a series of document transfers.

The study is first classified. That classification determines which obligations and recommendations apply. The organisation then creates the regulatory calendar, maintains the required transparency record, prepares and submits documents through the applicable routes, manages authority interaction and preserves the evidence trail. The resulting scientific and regulatory conclusions are then connected to the broader pharmacovigilance system.

This approach has an important advantage: when the regulatory environment changes, the organisation can update the decision rules without rebuilding the entire process from memory.

36. Final Review Questions

Before a PASS submission is considered complete, the responsible team should be able to answer:

1. What is the regulatory status of the study?
2. What legal requirements apply?
3. Which recommendations have been adopted operationally?
4. What document is being submitted?
5. Which authority must receive it?
6. What event determines the deadline?
7. Which electronic or national route is currently applicable?
8. What evidence proves submission?
9. What regulatory questions or outcomes followed?
10. What downstream pharmacovigilance actions resulted?
11. Has implementation been verified?
12. Can the complete history be reconstructed independently of the individuals who managed the study?

These questions are deliberately broader than a transmission checklist because effective compliance requires both correct submission and controlled follow-through.

Key Takeaways

GVP Module VIII Addendum I is best understood as a framework connecting the PASS lifecycle to regulatory submission obligations. Its most important practical distinction is between what the law requires, what EMA recommends and what the MAH chooses to implement as internal control.

Registration, regulatory submission, RMP inclusion and electronic transmission are related but distinct concepts. Imposed and voluntary PASS also require different reasoning, particularly where national procedures are involved.

The strongest submission process therefore begins with classification, derives the applicable obligation, controls each regulatory milestone and preserves an evidence chain through assessment and implementation. That is what turns a document-submission process into an effective pharmacovigilance control.

References

1. European Medicines Agency. GVP Module VIII Addendum I — Requirements and recommendations for the submission of information on non-interventional post-authorisation safety studies (Rev. 3).
2. European Medicines Agency. Post-authorisation safety studies (PASS), including current procedural questions and answers.
3. European Medicines Agency. GVP Module VIII — Post-authorisation safety studies (Rev. 3).
4. European Medicines Agency. GVP Module I — Pharmacovigilance systems and quality systems.
5. European Medicines Agency. GVP Module V — Risk management systems.
6. Commission Implementing Regulation (EU) No 520/2012, as amended.
7. Directive 2001/83/EC, as amended.

Regulatory Note

This article distinguishes legal requirements, EMA recommendations and illustrative operational practice. National requirements and current EMA procedures should be verified for each actual PASS submission. The inspection scenarios are hypothetical unless a specific authoritative inspection source is cited.