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Listedness, Expectedness and Reference Safety Information

Explains why listedness and expectedness are not interchangeable, how the applicable reference changes between post-authorisation ICSRs, PBRERs and clinical trials, and how pharmacovigilance systems should control reference documents, versions and global-local differences.

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Listedness, Expectedness and Reference Safety Information

A safety case can be described as expected, unexpected, listed or unlisted, but those words have no reliable meaning unless the assessor also identifies the regulatory purpose and the reference document being used.

This is the central idea of the subject. The same adverse reaction may be listed in a company core safety document, absent from a national label, expected under a clinical-trial Reference Safety Information section, and still relevant to a new signal because its severity or outcome has changed. None of those conclusions is contradictory if each is tied to the correct framework.

Confusion arises when organisations treat “listed” and “expected” as interchangeable database labels or use one global reference document for every safety decision. Current ICH guidance deliberately separates the concepts. ICH E2D(R1) uses regional or local product labelling when discussing post-authorisation unexpectedness and states that unlisted is not the term for ICSR reporting; ICH E2C(R2), by contrast, uses the Company Core Safety Information as the reference for listed/unlisted status in periodic reporting.

Clinical trials add a third context. Under the EU Clinical Trials Regulation, Reference Safety Information in the Investigator's Brochure—or an applicable Summary of Product Characteristics when it serves as the Investigator's Brochure—supports determination of which adverse reactions are expected for the investigational medicinal product.

The practical skill is therefore not memorising four labels. It is choosing the right question, the right reference and the right version before making the classification.

Purpose and Scope

This article explains the relationship between:

The article focuses on the conceptual and governance framework rather than reproducing every regional submission rule. Where reporting obligations differ by jurisdiction, the applicable law and current regulatory guidance remain controlling.

The subject is especially important for organisations that operate globally, because one product can have several legitimate safety references at the same time. A central safety database may therefore contain more than one classification for the same reaction depending on the purpose of the assessment.

The First Principle: Define the Regulatory Question Before Selecting the Reference

A classification is only defensible when the question comes first.

Consider four different questions:

Regulatory question Typical classification Reference concept
Is this post-authorisation reaction consistent with the product labelling applicable in this country or region? Expected / unexpected Regional or local product labelling
Is this reaction contained in the company core safety information used for periodic reporting? Listed / unlisted CCSI or other defined PBRER RSI
Is this serious adverse reaction expected for an investigational medicinal product in a clinical trial? Expected / unexpected Clinical-trial RSI in the IB or applicable SmPC
Does new evidence change the known safety profile or create a new aspect of a known risk? Signal/risk evaluation, not merely listedness All relevant evidence, not one label alone

The last row is important. Reference information is a baseline, but pharmacovigilance does not stop at the baseline. A reaction can already be described in the reference information and still generate a signal if its frequency, severity, outcome, population, dose relationship, timing or clinical presentation changes materially.

The sequence should therefore be:

What decision am I making?
        ↓
Which regulatory framework governs that decision?
        ↓
Which reference document is specified or appropriate?
        ↓
Which version applied at the relevant date?
        ↓
Is the reported reaction consistent with that reference?
        ↓
What regulatory or pharmacovigilance consequence follows?

Starting with the label “expected” or “listed” and only later asking which document was used reverses the logic.

Regulatory Framework

Several regulatory layers intersect in this area.

ICH E2D(R1): Post-Approval ICSR Management

ICH E2D(R1) is the current harmonised guideline for post-approval safety data and individual case safety reports. It came into effect in the EU on 18 March 2026.

For post-authorisation ICSR purposes, E2D(R1) describes an adverse event or adverse drug reaction as unexpected when it is not included in the relevant regional or local product labelling, or when its nature, severity or specificity is not consistent with the term or description in that labelling. It also explains that a fatal outcome can make an otherwise labelled reaction unexpected if fatal outcome is not represented appropriately.

E2D(R1) explicitly distinguishes this from unlistedness, stating that “unlisted” is not the ICSR-reporting term and refers instead to classification against the CCSI under ICH E2C.

This is a conceptual boundary with practical consequences: local expectedness and global listedness answer different questions.

ICH E2C(R2): Periodic Benefit-Risk Evaluation

ICH E2C(R2) defines the PBRER framework and its reference product information.

The guideline describes the CCDS as a company-prepared document containing safety information as well as information on indications, dosing, pharmacology and other product information. The safety information contained within it is the CCSI.

For periodic reporting, the CCSI is the reference by which reactions are classified as listed or unlisted. ICH E2C(R2) is explicit that the CCSI is not the reference by which expected/unexpected status is determined for expedited reporting.

Where a CCDS or CCSI does not exist, ICH E2C(R2) allows another clearly specified reference product information source, such as an appropriate national or regional label.

EU GVP and EU Pharmacovigilance Law

EU pharmacovigilance law and GVP determine the actual EU reporting obligations.

Under the current post-authorisation framework, marketing authorisation holders submit serious suspected adverse reactions to EudraVigilance within 15 days and EU non-serious suspected adverse reactions within 90 days. Expectedness is therefore not a gate that exempts serious post-authorisation ICSRs from EU submission.

This is an important distinction from older or non-EU mental models in which “serious + unexpected” is treated as the universal formula for expedited post-marketing reporting.

EMA has stated that GVP modules affected by ICH E2D(R1) will be revised and that, in the interim, the E2D(R1) guidance should be applied as far as it affects GVP, together with the EU implementation strategy and current EU requirements.

EU Clinical Trials Regulation

Clinical-trial safety reporting is governed by a different framework.

Regulation (EU) No 536/2014 defines how the Investigator's Brochure and clinical-trial Reference Safety Information support determination of expected adverse reactions. When the Investigator's Brochure is not an SmPC, it must contain a clearly identifiable RSI section. For an authorised investigational medicinal product used in accordance with the terms of its marketing authorisation, the approved SmPC serves as the Investigator's Brochure under the Regulation.

The trial context therefore uses expected/unexpected terminology, but the reference and regulatory purpose differ from post-authorisation expectedness.

Core Documents and What They Represent

The terminology becomes easier when each document is understood by function.

Company Core Data Sheet

The Company Core Data Sheet is a company-controlled global reference document. ICH E2C describes it as containing safety information together with other product information such as indications, dosing and pharmacology.

It is not itself a national marketing authorisation.

A CCDS may be used to promote a consistent global company position, but national authorities can require different wording, different restrictions, different indications or different safety information.

Company Core Safety Information

The Company Core Safety Information is the safety subset of the CCDS.

Its regulatory importance in ICH E2C is that it provides the reference for deciding whether an adverse reaction is listed or unlisted for periodic reporting of marketed products.

A useful shorthand is:

CCDS = broader company core product information
CCSI = safety information within the CCDS

The shorthand is useful, but it should not obscure governance. The CCSI must be version controlled, maintained through a formal safety and labelling process, and linked to the evidence and decisions that support changes.

Regional or Local Product Labelling

Regional or local product labelling is the authorised product information applicable in a jurisdiction.

In the EU, the SmPC is the principal professional product information document. Other regions use their own authorised prescribing information.

For E2D(R1) post-authorisation unexpectedness, this regional or local labelling is the relevant reference.

This means that a reaction can be:

That is not necessarily a data-quality problem. It can be a legitimate consequence of different regulatory histories and implementation timelines.

Reference Safety Information in a PBRER

ICH E2C(R2) uses Reference Safety Information as the relevant safety information contained within the PBRER reference product information.

If the reference product information is the CCDS, the RSI is the CCSI.

If there is no CCDS or CCSI, another clearly specified national or regional product information document may be used as the reference.

The critical controls are therefore:

Reference Safety Information in a Clinical Trial

The same acronym, RSI, is also used in clinical development.

This is not merely a different copy of the post-marketing CCSI.

Clinical-trial RSI is the reference used to determine which adverse reactions are expected for the investigational medicinal product in the trial. Under the EU Clinical Trials Regulation, it is contained in a clearly identifiable section of the Investigator's Brochure when the IB is not an SmPC.

The distinction matters because an organisation can legitimately maintain:

Marketed-product CCSI / PBRER RSI
                and
Clinical-trial RSI for an investigational programme

for the same active substance at the same time.

The next sections apply these concepts to post-authorisation cases and aggregate reporting, where the difference between expectedness and listedness becomes operationally important.

Expectedness in Post-Authorisation ICSR Assessment

Expectedness is not a general judgement that an event was foreseeable.

Under ICH E2D(R1), the assessment is tied to the applicable regional or local product labelling. The reported reaction should be compared with the wording and clinical meaning of that reference.

A reaction is not made expected merely because:

Each of those facts may be relevant to causality or signal evaluation. None substitutes automatically for the applicable local reference.

Expectedness Is More Than a Term Match

A mechanistic text search is not sufficient.

E2D(R1) states that the nature, severity and specificity of the reported reaction must be consistent with the regional or local product labelling. Outcome can also change the assessment.

Suppose a label includes “rash”.

A report of a mild, self-limited rash may be represented adequately by that wording. A report of a severe blistering mucocutaneous syndrome should not automatically be classified as expected simply because “rash” appears somewhere in the product information.

The clinical concept matters.

The same principle applies when the label contains a broad term but the case describes a materially different syndrome, severity or complication.

Fatal Outcomes Require Specific Attention

ICH E2D(R1) adds an important operational clarification: an ADR included in regional or local product labelling should be considered unexpected when the ICSR reports a fatal outcome unless the labelling specifically indicates that the ADR may be associated with fatal outcome.

This prevents a broad listed term from absorbing a clinically different outcome.

For example, if a label describes a reversible hepatic reaction but does not indicate that fatal hepatic failure can occur, a fatal case should not be treated mechanically as expected simply because liver injury is mentioned somewhere in the label.

The assessment should be based on the actual wording and clinical scope of the reference.

Class Effects Are Not Automatically Product-Specific Expected Reactions

Product information sometimes discusses reactions associated with a pharmacological class.

E2D(R1) states that a class ADR should not automatically be considered expected when reported for an individual medicinal product.

The reason is straightforward: a class association is not necessarily equivalent to a product-specific established adverse reaction.

The assessor should determine whether the product-specific labelling actually represents the reaction for that medicine and whether the reported event is consistent with that description.

Expectedness Is Independent of Seriousness and Causality

Three different questions are commonly collapsed into one:

Question Assessment
Does the event meet a regulatory seriousness criterion? Seriousness
Is the reaction consistent with the applicable reference? Expectedness
Does the available evidence support a causal relationship? Causality

A reaction can therefore be:

Likewise, an unexpected reaction is not automatically caused by the product, and an expected reaction can still have weak individual-case causality.

Keeping the dimensions separate prevents regulatory classifications from becoming substitutes for medical judgement.

Expectedness and EU Post-Authorisation Reporting

In the EU, expectedness should not be used as a filter to decide whether a serious suspected post-authorisation adverse reaction is submitted.

Article 107 of Directive 2001/83/EC requires marketing authorisation holders to submit serious suspected adverse reactions occurring in the Union or in third countries within 15 days of knowledge. It also requires submission of non-serious suspected adverse reactions occurring in the Union within 90 days.

The current EU rule is therefore based primarily on seriousness and geography, not on an expected/unexpected gate for serious post-authorisation cases.

This produces an important practical distinction:

Expectedness classification
        ≠
EU serious ICSR submission eligibility

Expectedness can still be relevant to case assessment, regulatory interpretation, signal management and global reporting obligations. It simply should not be imported into the EU submission decision as though EU law reported only serious unexpected post-marketing cases.

A global pharmacovigilance system should therefore avoid one universal rule such as:

submit only if serious and unexpected.

That rule would be incorrect for current EU post-authorisation reporting.

Listedness and the Company Core Safety Information

Listedness asks a different question.

Under ICH E2C(R2), the CCSI is the company reference used to determine whether an ADR is listed or unlisted for periodic reporting of marketed products.

The concept supports global aggregate evaluation because the CCSI provides a company-wide safety baseline even when local labels differ.

A reaction is not “listed” merely because it appears in any document somewhere in the organisation. The classification must be tied to the controlled CCSI or other explicitly selected PBRER RSI.

Why Listedness Exists

A global PBRER can cover a medicine authorised in many jurisdictions.

If every case were classified only against its local label, the aggregate report would contain multiple local regulatory baselines that could obscure the company's global scientific position.

The CCSI provides a stable core reference against which the company can evaluate whether reactions are already represented in its recognised core safety information.

This does not make the CCSI superior to national product information. It serves a different purpose.

The relationship is better represented as:

Global aggregate baseline → CCSI / PBRER RSI
Local regulatory baseline  → national or regional authorised labelling

Both can be valid simultaneously.

Reference Product Information in the PBRER

ICH E2C(R2) requires the PBRER reference product information to support both the safety and benefit evaluation.

A common option is the CCDS, which can contain:

When the CCDS is used, the CCSI forms the RSI for the risk sections.

Where there is no CCDS or CCSI, ICH E2C(R2) permits another clearly specified source, such as a national or regional product information document.

This is particularly relevant for:

The important point is not that every company must create the same type of core document. The important point is that the PBRER should identify which reference information is being used and why.

Version Control and the Data Lock Point

Reference information changes over time.

A PBRER is therefore not simply compared with “the current label” available when the author starts drafting.

ICH E2C(R2) states that the MAH should identify an appropriate reference product information document and use the version current at the end of the reporting interval, while describing significant changes made during the interval.

This creates a chronology that should be reconstructable:

Date Safety-reference event
Start of reporting interval Existing CCSI/RSI version in force
During interval New safety evidence assessed
During interval Core safety wording revised
Data lock point Controlled reference version identified
After DLP but before submission Important late-breaking change considered where applicable

A reviewer should be able to determine which version supported each aggregate conclusion.

Retrospectively applying a later CCSI version to all historical cases can distort listedness and obscure when the company first recognised a reaction.

Global Core Information and Local Labels Can Diverge

Divergence between the CCSI and a local label is not inherently evidence of non-compliance.

It can arise because:

The control problem is not the existence of differences. The control problem is not knowing which differences exist, why they exist or which reference should be used for a particular decision.

A mature process should maintain a traceable relationship between:

Safety evidence
   ↓
Company core safety decision
   ↓
CCSI/CCDS revision
   ↓
Regional regulatory submissions
   ↓
Local authorised label
   ↓
Case and aggregate classifications using the applicable version

A Global-Local Example

Assume a new adverse reaction, myocarditis, is added to a company's CCSI on 1 June.

Country A approves the corresponding local label update on 20 June.

Country B is still reviewing the variation on 30 June.

A serious myocarditis case is received on 25 June.

The classifications can legitimately differ:

Assessment Country A Country B
Listedness against CCSI Listed Listed
Expectedness against local label Expected, if the approved wording represents the case Potentially unexpected, if the local label has not yet incorporated the reaction
EU serious ICSR submission Required within applicable timeframe Required within applicable timeframe

The example shows why storing only one binary “expected” field without reference metadata can be misleading.

At minimum, the organisation needs to know:

Listedness Does Not Close a Signal

A listed reaction can still require signal evaluation.

The relevant new information might concern:

The signal question is not:

Is this term already in the CCSI?

It is:

Does the new information suggest a new causal association or a new aspect of a known association that warrants further evaluation?

Listedness can therefore be one input to signal evaluation, but it is not a signal-closure rule.

Medical Coding and Reference Matching

MedDRA coding and expectedness/listedness assessment are connected but should not be collapsed.

The coded Preferred Term represents the clinical information in the case. The reference document may use different medical wording.

A medically sound assessment may require review of:

Automated lexical matching can support retrieval, but a simple rule such as “PT appears in label = expected” can fail when:

This is why reference matching should remain medically interpretable and auditable.

The next section turns to clinical trials, where the same word “expectedness” is used but the governing reference is different.

Clinical-Trial Reference Safety Information

Clinical-trial safety reporting uses a development-specific reference framework.

Under Regulation (EU) No 536/2014, the Investigator's Brochure provides investigators and others involved in the trial with the information needed to understand the investigational medicinal product, the rationale for the study and important safety monitoring requirements.

When the Investigator's Brochure is not an SmPC, it must contain a clearly identifiable section called Reference Safety Information.

That RSI describes how to determine which adverse reactions are expected for the investigational medicinal product and addresses the nature and frequency of those reactions.

This reference supports the clinical-trial assessment of unexpectedness and therefore contributes to the determination of suspected unexpected serious adverse reactions (SUSARs) together with seriousness and causal relationship.

The logic is:

Serious adverse event
        ↓
Is a causal relationship at least suspected?
        ↓
Serious adverse reaction
        ↓
Is the reaction expected against the trial RSI?
        ↓
Expected SAR or SUSAR, subject to the applicable clinical-trial rules

This is not the same decision as post-authorisation expectedness against a national marketed-product label.

When the SmPC Serves as the Investigator's Brochure

The EU Clinical Trials Regulation provides an important simplification for authorised investigational medicinal products.

If the investigational medicinal product is authorised and used in accordance with the terms of the marketing authorisation, the approved SmPC serves as the Investigator's Brochure under the Regulation.

If use in the trial differs from the authorised conditions, the SmPC must be supplemented with relevant non-clinical and clinical information supporting the investigational use.

For a multinational clinical trial using nationally authorised products where SmPCs differ between Member States, the sponsor selects one SmPC for the whole trial, choosing the one best suited to ensure participant safety.

This can produce a trial-level reference that is deliberately different from the label used for post-authorisation expectedness in a particular country.

The reference is selected for the clinical trial as a whole, not reconstructed case by case from every national label.

The Investigator's Brochure Is a Controlled Safety Document

The clinical-trial RSI should not be treated as an informal list of known events.

Its content determines whether a serious suspected adverse reaction is expected or unexpected for the trial.

The EU Clinical Trials Regulation also requires the Investigator's Brochure to be updated when new and relevant safety information becomes available and reviewed by the sponsor at least annually.

Operationally, this requires control over:

If the RSI changes after a new risk is recognised, historical cases should not be silently reclassified as though the new version had always existed.

The chronology of recognition matters.

Expectedness in the DSUR

ICH E2F provides the Development Safety Update Report framework.

The DSUR should specify the document and version used as Reference Safety Information for determining expectedness for relevant tabulations where national or regional requirements require such classification.

This establishes a development-programme analogue to the PBRER requirement for explicit reference control.

The two reports therefore share a general principle:

Periodic report
   ↓
Identify reference document
   ↓
Identify version
   ↓
Describe important changes
   ↓
Interpret interval and cumulative safety data against that controlled baseline

The actual reference differs because the PBRER addresses marketed-product benefit-risk while the DSUR addresses the evolving safety of a development programme.

One Acronym, Different Regulatory Functions

“RSI” is often used as though it referred to one universal document. It does not.

A more accurate map is:

Context What RSI means operationally Typical source
PBRER / marketed-product aggregate reporting Safety information within the selected reference product information CCSI within CCDS, or another specified product-information source
Clinical trial / SUSAR assessment Safety information used to determine expected adverse reactions for the investigational medicinal product RSI section of IB or an applicable SmPC
DSUR Reference document/version used for development safety expectedness and periodic presentation Development-programme RSI, normally aligned with the IB framework

The term therefore has to be interpreted from its regulatory context.

An SOP that simply says “check the RSI” without defining which RSI applies is incomplete.

Parallel Development and Marketing Can Produce Different Classifications

A medicinal product can be marketed for one indication while still being studied in another indication, dose, formulation or population.

In that situation, the organisation may simultaneously maintain:

The same clinical event can then be classified differently for different regulatory purposes.

Example: Different Development Population

A product is marketed in adults and is being studied in paediatric patients.

A reaction is already described in the adult SmPC and CCSI, so it is listed and may be expected in the marketed setting.

The paediatric trial RSI may contain more specific wording because the event behaves differently in children.

A paediatric case with a more severe phenotype might therefore be unexpected for the clinical trial even though the broad reaction is known in marketed adults.

The apparent contradiction disappears when the reference, population and purpose are made explicit.

Example: New Trial Finding Before Marketed-Label Update

A new serious reaction emerges in an ongoing study.

The sponsor updates the clinical-trial RSI after regulatory approval of the change, but the company core and local marketed labels have not yet been revised.

During the transition:

One clinical concept can therefore have three different regulatory statuses at the same time.

This is precisely why classification should never be stored without its reference context.

Important Special Situations

Several recurring situations test the boundaries between the frameworks.

Same Reaction, Different Severity

The local label includes “neutropenia”.

A case describes prolonged grade 4 neutropenia with life-threatening sepsis.

The assessor should determine whether the label wording adequately represents that severity and clinical course. The presence of the broad reaction term alone does not decide expectedness.

In a clinical trial, the same question is asked against the trial RSI, not automatically against the marketed label.

Same Reaction, Fatal Outcome

The reference includes a reaction but does not indicate that fatal outcome can occur.

Under E2D(R1), a fatal post-authorisation case should be treated as unexpected unless the regional or local labelling specifically represents fatal outcome.

The same principle of clinical specificity is relevant when assessing trial RSI: the wording should reflect the nature and severity that is considered expected.

Class Warning

The label states that a class of medicines has been associated with an event but does not identify the event as an established adverse reaction for the specific product.

E2D(R1) states that class ADRs should not automatically be considered expected for an individual medicinal product.

Medical and regulatory review should determine whether the product-specific wording actually supports expectedness.

Local Label Updated Before the CCSI

A national authority can require a safety change before the company adopts equivalent global core wording.

A reaction may therefore be expected locally but remain unlisted against the CCSI.

The difference should be visible and govern the appropriate local versus aggregate classification.

CCSI Updated Before a Local Label

A company may add a reaction to the CCSI while a local variation is still pending.

The reaction becomes listed globally but can remain unexpected against the unchanged local label.

This is one of the clearest demonstrations that listedness and expectedness are not synonyms.

Reference Change During the Reporting Period

A PBRER reporting interval may span more than one CCSI version.

The report should identify the relevant reference and describe significant changes during the interval.

A DSUR can face the same issue with IB/RSI versions.

The solution is not to force one retrospective classification across the entire interval. It is to preserve the version chronology and explain how changes affect interpretation.

Cross-Framework Decision Table

The following table summarises which reference should normally be considered first.

Decision Primary reference concept Key caution
Post-authorisation ICSR expectedness under ICH E2D(R1) Regional/local product labelling Do not substitute the CCSI automatically
EU post-authorisation ICSR submission EU law and current GVP Serious cases are not exempt because they are expected
PBRER listedness CCSI or other specified PBRER RSI Listedness is an aggregate-reporting construct
PBRER benefit-risk interpretation Reference product information plus total evidence RSI is a baseline, not the whole benefit-risk evaluation
Clinical-trial expectedness / SUSAR assessment Trial RSI in IB or applicable SmPC Use the controlled trial reference version
DSUR expectedness presentation Specified development RSI and version Maintain version chronology
Signal evaluation Totality of evidence A listed/expected reaction can still generate a signal
Local label change Applicable regulatory procedure Core and local implementation dates may differ

This table should be converted into controlled organisational procedures rather than left as tacit expert knowledge.

The Date of the Reference Matters as Much as the Document

A classification can be correct under one version and wrong under another.

For every expectedness or listedness assessment, the organisation should be able to reconstruct:

This becomes particularly important during:

The next section translates these principles into an operational control system and shows what evidence an inspector should expect to see.

Practical Implementation

A reliable listedness and expectedness process requires more than a label repository.

The organisation needs a controlled mapping between regulatory decision, product, jurisdiction or trial, reference document and effective version.

A practical architecture contains six connected controls.

Reference Inventory

For each product, maintain a controlled inventory of applicable reference sources.

This may include:

The inventory should identify ownership and effective dates rather than merely storing files.

Decision-to-Reference Matrix

Procedures should state explicitly which reference applies to which decision.

For example:

Process Reference
Local post-authorisation expectedness Applicable regional/local label
Global listedness Current controlled CCSI
PBRER reference safety evaluation Defined PBRER RSI/reference product information
Trial SUSAR expectedness Approved clinical-trial RSI
DSUR expectedness presentation Defined development RSI/version

This prevents case processors from choosing whichever document is easiest to access.

Version Control

Every reference should have:

The safety database should either store the relevant reference version directly or retain enough metadata to reconstruct it reliably.

A binary expected/unexpected field without reference metadata is weak evidence.

Change Control

Safety-reference changes should connect scientific evaluation to regulatory implementation.

A controlled change record should show:

New safety evidence
      ↓
Medical / signal evaluation
      ↓
Decision to revise core or trial safety information
      ↓
Approval of revised reference
      ↓
Regional submissions / trial modifications
      ↓
Effective dates
      ↓
Updated case and aggregate assessment rules

The process should define when a new version becomes operational for each use.

Global-Local Implementation Tracking

When the CCSI changes, local labels may update at different times.

A global regulatory tracker should make those differences visible.

Useful fields include:

This tracker is not merely a regulatory-affairs tool. It directly supports correct expectedness classification.

Case-Level Traceability

For a sampled case, a reviewer should be able to see:

Where multiple reactions are present, classification should remain reaction specific when the framework requires it.

Roles and Responsibilities

The process normally crosses several functions, and the interfaces between them matter as much as the individual tasks. Case processing applies the controlled reference to individual cases; medical review resolves clinically ambiguous matches; signal management determines whether new evidence changes the known risk; aggregate reporting controls the reference used in PBRERs and DSURs; global labelling and regulatory affairs translate safety decisions into core and local product information; and clinical safety governs trial RSI.

Function Principal responsibility in this framework
Pharmacovigilance case processing Apply the correct jurisdiction-specific or process-specific reference and record the reaction-level classification
Safety physicians / medical reviewers Determine whether the reported clinical concept, severity and outcome are adequately represented when textual matching is insufficient
Signal management Evaluate whether new evidence represents a new risk or a new aspect of a known risk, regardless of whether the reaction is already listed or expected
Aggregate reporting Identify the applicable PBRER or DSUR reference and version, describe important changes and maintain consistency with signal and benefit-risk evaluation
Global labelling / regulatory affairs Govern CCSI/CCDS changes, local label submissions and the implementation chronology needed for expectedness assessment
Clinical safety Control trial RSI and its use in SUSAR and DSUR processes
QPPV / PV governance Oversee whether the end-to-end system for reference maintenance, classification, interfaces and quality control remains effective

For marketed products that remain under clinical development, the clinical and post-authorisation safety interfaces require particular attention because their reference documents may legitimately differ.

QPPV oversight does not mean personal approval of every expectedness decision. It means having sufficient visibility of material weaknesses in reference maintenance, global-local implementation, case classification, clinical/post-marketing interfaces and recurring discrepancies identified through quality review, and ensuring that those weaknesses are governed and corrected.

Quality Controls

Quality review should test the classification logic, not only whether a field is populated.

Useful checks include:

Metrics can identify systematic problems.

Examples include:

Metric What it can reveal
Cases with missing reference-version metadata Weak traceability
QC changes from expected to unexpected Over-matching to label wording
QC changes from unexpected to expected Under-recognition of equivalent clinical concepts
Country-specific mismatch rate Local label configuration problems
Cases assessed using superseded CCSI Core reference maintenance failure
Trial cases assessed against wrong IB version Clinical safety version-control failure
Repeated manual overrides Reference data or rules engine not reflecting operational reality

A high override rate should prompt investigation of the process, not simply normalisation of manual correction.

Inspection Perspective

An inspector evaluating listedness and expectedness is likely to test whether the organisation can reconstruct why a classification was made.

Potential questions include:

The strongest evidence is a coherent chain from controlled reference to case-level result, supported by contemporaneous version records.

Illustrative Failure Modes

The following are hypothetical failure modes, not actual inspection findings. They illustrate how the same conceptual error can propagate into case processing, aggregate reporting or clinical safety.

Failure mode Why the control is weak
One global expectedness flag for every reaction Post-authorisation expectedness can differ by jurisdiction because local authorised labels differ
CCSI used for every post-marketing case ICH E2D(R1) uses regional or local product labelling for post-authorisation unexpectedness, whereas the CCSI supports listed/unlisted periodic-reporting classification
Whichever local label is easiest to access is used for PBRER listedness The PBRER reference should be explicitly selected and controlled; a local label can be appropriate in some circumstances, but not by convenience
MedDRA term presence is the only matching rule Nature, severity, specificity and outcome can make the reported reaction inconsistent with the reference even when a similar term appears
A class warning automatically makes the reaction expected for every product in the class E2D(R1) states that class ADRs should not automatically be treated as expected for an individual medicinal product
A new label version is applied retrospectively to earlier cases without preserving the original assessment The chronology of when the risk became recognised is lost and historical compliance or aggregate analyses can be distorted
Trial RSI and marketed CCSI are treated as the same document Trial RSI is a controlled development reference with its own regulatory lifecycle
A serious EU spontaneous case is not submitted because the reaction is expected Current EU post-authorisation law requires serious suspected adverse reactions to be submitted within the applicable 15-day timeframe irrespective of this expectedness filter

Practical Decision Framework

For each classification, ask in order:

  1. What process is this? Post-authorisation case, PBRER, clinical trial, DSUR or signal evaluation?
  2. What jurisdiction or trial applies?
  3. What reference document is specified for that process?
  4. Which version was effective at the relevant date?
  5. Does the reported reaction match the clinical nature of the reference wording?
  6. Are severity, specificity and outcome consistent?
  7. Is the wording only a class effect rather than a product-specific reaction?
  8. Is the conclusion expected/unexpected or listed/unlisted?
  9. What regulatory consequence actually follows in that framework?
  10. Is additional signal or benefit-risk evaluation needed despite the classification?

This sequence keeps classification connected to purpose.

Reference Safety Information Checklist

Before finalising an assessment, verify:

Relationship With Other QPPV.com Articles

The broader post-authorisation case framework is covered in ICH E2D(R1): What Changed in Post-Approval Pharmacovigilance.

The separation of seriousness, expectedness and causality is developed in GVP Module VI: Seriousness, Expectedness and ICSR Case Assessment.

The use of reference information in periodic reporting is covered in GVP Module VII: PSUR Reference Data and International Safety Information.

The practical PBRER writing implications are addressed in Writing the Changes to Reference Safety Information Section in a PBRER.

Clinical-trial case handling is discussed in GVP Module VI: Clinical Trials and ICSR Management, while the present article focuses on the reference framework that determines listedness and expectedness.

Key Takeaways

References

  1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH E2D(R1): Post-Approval Safety Data: Definitions and Standards for Management and Reporting of Individual Case Safety Reports. Final Step 4 guideline, adopted 15 September 2025.
    https://database.ich.org/sites/default/files/ICH_E2D%28R1%29_Step4_FinalGuideline_2025_0819.pdf

  2. European Medicines Agency. ICH E2D(R1) Guideline on post-approval safety data: definitions and standards for management and reporting of individual case safety reports — Step 5. EMA/CHMP/ICH/59123/2024. Legal effective date in the EU: 18 March 2026.
    https://www.ema.europa.eu/en/ich-e2d-post-approval-safety-data-management-scientific-guideline

  3. European Medicines Agency. EU implementation strategy of ICH E2D(R1) Guideline — Post-approval safety data: Definitions and standards for management and reporting of individual case safety reports. EMA/11141/2026.
    https://www.ema.europa.eu/en/documents/scientific-guideline/eu-implementation-strategy-ich-e2dr1-guideline-post-approval-safety-data-definitions-standards-management-reporting-individual-case-safety-reports_en.pdf

  4. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH E2C(R2): Periodic Benefit-Risk Evaluation Report (PBRER).
    https://database.ich.org/sites/default/files/E2C_R2_Guideline.pdf

  5. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module VII — Periodic safety update report (Rev. 1). EMA/816292/2011 Rev. 1.
    https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-vii-periodic-safety-update-report_en.pdf

  6. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module VI — Collection, management and submission of reports of suspected adverse reactions to medicinal products (Rev. 2). EMA/873138/2011 Rev. 2.
    https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-good-pharmacovigilance-practices-gvp-module-vi-collection-management-submission-reports-suspected-adverse-reactions-medicinal-products-rev-2_en.pdf

  7. European Parliament and Council. Directive 2001/83/EC on the Community code relating to medicinal products for human use, as amended, including Article 107 on post-authorisation recording and submission of suspected adverse reactions.
    https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:02001L0083

  8. European Parliament and Council. Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use, including Article 55 and Annex I provisions on the Investigator's Brochure and Reference Safety Information.
    https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32014R0536

  9. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH E2F: Development Safety Update Report.
    https://database.ich.org/sites/default/files/E2F_Guideline.pdf

  10. European Medicines Agency. Good pharmacovigilance practices (GVP): current modules and implementation information. Current EMA GVP webpage, including interim application of ICH E2D(R1) pending relevant GVP revisions.
    https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/good-pharmacovigilance-practices-gvp

Regulatory Note

This article was reviewed on 2 October 2026.

ICH E2D(R1) has been in effect in the EU since 18 March 2026. EMA has stated that GVP modules affected by ICH E2D(R1) will be revised and that the ICH guideline and EU implementation strategy should be applied in the interim as far as they affect current GVP.

The article distinguishes harmonised ICH guidance, EU legal requirements, GVP guidance and recommended operational controls. The company core structures described here, including the CCDS and CCSI, are ICH concepts used for harmonised periodic reporting and global safety management; they should not be represented as national marketing authorisations.

Clinical-trial expectedness is governed by the applicable clinical-trial framework and approved trial documents. Post-authorisation expectedness and trial expectedness should therefore not be conflated even when the same active substance is involved.

Illustrative scenarios and failure modes are examples for teaching and quality-system design. They are not presented as actual inspection findings.

Revision History

Related Articles

GVP Module VI: Clinical Trials and ICSR Management

Explains how clinical-trial safety reporting interfaces with the EU pharmacovigilance system, why the applicable regulatory framework matters, and how sponsors and MAHs should distinguish trial safety reporting from post-authorisation ICSR processing.

GVP Module VI: Seriousness, Expectedness and ICSR Case Assessment

Explains how seriousness and expectedness differ from validity and causality, how cases should be assessed consistently, and where common classification errors create regulatory and data-quality risks.

Writing the Changes to Reference Safety Information Section in a PBRER

Explains how to identify the reference information used for the PBRER, describe clinically meaningful safety changes during the reporting interval, handle multiple versions and regional implementation differences, and connect those changes to later signal, risk and benefit-risk evaluation.

Last reviewed: 2026-10-02

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