Writing the Evaluation of Risks and New Information Section in a PBRER

Introduction

The Evaluation of Risks section represents the point at which the individual components of pharmacovigilance assessment are brought together into an integrated scientific discussion. Earlier sections of the PBRER describe new safety information, signal evaluations, changes to the Reference Safety Information, patient exposure and summary tabulations. This section asks a different question:

How has the current understanding of the medicinal product's risks changed during the reporting interval?

The emphasis is no longer on describing individual observations but on evaluating the cumulative body of evidence relating to recognised and potential risks.

For each important identified risk, important potential risk and relevant area of missing information, the reviewer should determine whether the available evidence has altered the current understanding of the frequency, severity, clinical consequences, affected populations or preventability of the risk.

Consequently, this section forms the scientific foundation for the integrated benefit-risk evaluation presented later in the report.

Regulatory Basis

ICH E2C(R2) requires a critical evaluation of important identified risks, important potential risks and relevant missing information using cumulative safety data available at the Data Lock Point.

Within the European Union, these requirements are reflected in Good Pharmacovigilance Practices (GVP) Module VII.

The purpose is not to repeat information presented elsewhere in the PBRER but to provide an updated scientific assessment of the medicinal product's established and emerging safety profile.

Accordingly, discussions should integrate all relevant evidence available during the reporting interval while remaining focused on changes in scientific understanding.

Relationship to Earlier Sections

This section should not be read in isolation.

It draws upon information presented throughout the earlier sections of the PBRER, including:

• Reference Safety Information;
• estimated patient exposure;
• summary tabulations;
• completed signal evaluations;
• clinical trial safety findings;
• post-authorisation safety studies;
• scientific literature;
• regulatory actions;
• additional pharmacovigilance activities.

Rather than repeating those discussions, the reviewer should integrate their findings into an updated assessment of each important risk.

The objective is synthesis rather than repetition.

The Purpose of Risk Evaluation

Risk evaluation differs fundamentally from signal evaluation.

Signal evaluation asks:

"Does the available evidence support a causal association?"

Risk evaluation asks:

"Given the available evidence, how has our understanding of this recognised or potential risk changed?"

A signal may therefore be fully evaluated without altering the discussion of an important identified risk.

Conversely, several completed signal evaluations may collectively justify substantial revision of the assessment of a recognised risk.

The focus should therefore remain on the evolving scientific understanding of the medicinal product rather than on individual signal management activities.

Writing Tip

Think of signal evaluation as examining individual pieces of evidence. Risk evaluation explains what the complete body of evidence now tells us about the medicinal product.

Principles of Risk Evaluation

The objective of this section is not to restate the recognised safety profile of the medicinal product. Instead, it should explain whether the cumulative evidence available at the Data Lock Point has altered the current understanding of each important risk.

Every discussion should therefore compare current knowledge with the understanding reflected in previous PBRERs rather than describing the risk in isolation.

Readers should finish each subsection with a clear understanding of whether the scientific interpretation of the risk has changed and, if so, why.

Evaluating Evidence Evolution

The most useful way to structure each risk evaluation is to ask how the evidence has evolved during the reporting interval.

For every important identified risk, important potential risk and relevant area of missing information, the reviewer should consider whether new evidence has changed any aspect of the existing scientific understanding.

Examples include:

• changes in frequency;

• changes in clinical severity;

• newly recognised clinical manifestations;

• changes in reversibility;

• changes in patient outcomes;

• identification of new risk factors;

• identification of susceptible patient populations;

• changes in time to onset;

• evidence relating to dose dependency;

• evidence relating to duration of treatment;

• effectiveness of existing risk minimisation measures;

• important negative evidence reducing uncertainty.

Not every reporting interval results in changes.

Where cumulative evidence confirms the existing understanding without materially altering it, this should also be stated clearly.

Integrating Multiple Sources of Evidence

High-quality risk evaluations integrate all relevant evidence rather than discussing each source independently.

The reviewer should consider information obtained from:

• completed signal evaluations;

• interval and cumulative case review;

• summary tabulations;

• clinical trials;

• post-authorisation safety studies (PASS);

• non-interventional studies;

• published scientific literature;

• regulatory authority assessments;

• class-wide safety information;

• mechanistic and pharmacological evidence where relevant.

The discussion should explain how these evidence sources collectively influence the current understanding of the risk.

Simply listing studies or summarising publications without integrating their findings does not constitute an effective risk evaluation.

Evaluating Important Identified Risks

Important identified risks represent adverse reactions for which sufficient evidence supports a causal association with the medicinal product.

Accordingly, the discussion should focus upon whether cumulative evidence has modified current understanding of the recognised risk.

Examples of questions that should be considered include:

• Has the frequency changed?

• Has the severity changed?

• Are different patient populations affected?

• Have additional risk factors been identified?

• Have new clinical presentations emerged?

• Has management of the adverse reaction improved?

• Have outcomes changed following implementation of risk minimisation measures?

• Does the new evidence influence the overall benefit-risk balance?

The emphasis should remain on changes in scientific understanding rather than repeating established knowledge presented in previous reports.

Evaluating Important Potential Risks

Evaluation of important potential risks requires particular scientific balance because uncertainty remains regarding causality.

The objective is to determine whether cumulative evidence strengthens, weakens or leaves unchanged the current hypothesis.

Important considerations include:

• new supportive evidence;

• contradictory findings;

• biological plausibility;

• epidemiological evidence;

• signal evaluations completed during the reporting interval;

• findings from PASS;

• regulatory assessments;

• remaining uncertainties.

Where the available evidence supports reclassification of an important potential risk to an important identified risk, the discussion should explain the scientific basis for that change.

Conversely, if accumulating evidence no longer supports the potential risk, the rationale for removing or reclassifying it should be described transparently.

Medical Review Consideration

Avoid describing every new publication or case individually. Instead, explain how the totality of new evidence has altered—or confirmed—the current understanding of the risk.

Evaluating Missing Information

Unlike important identified and important potential risks, missing information does not represent an adverse reaction. Instead, it represents areas where available knowledge remains insufficient to adequately characterise the benefit-risk profile of the medicinal product.

Accordingly, the objective of this section is not to determine whether a safety concern exists but to evaluate whether uncertainty has been reduced during the reporting interval.

The reviewer should therefore focus on the evolution of knowledge rather than the occurrence of adverse events.

Questions that should be considered include:

• Have additional patients within the missing population been exposed?

• Have new clinical trial data become available?

• Have post-authorisation studies addressed the uncertainty?

• Have registry data reduced knowledge gaps?

• Has real-world clinical experience expanded?

• Have additional published data become available?

• Have regulatory authorities requested further investigations?

• Does important uncertainty remain?

The discussion should explain how the cumulative evidence has influenced the current level of uncertainty.

Structuring Individual Risk Discussions

Each important risk should be discussed using a consistent scientific framework.

Although the level of detail should reflect the importance of the risk, a logical structure improves readability and facilitates regulatory review.

An effective discussion usually addresses:

Background

Briefly remind the reader why the risk is important.

Avoid repeating the complete historical discussion from previous PBRERs.

Only sufficient context should be provided to understand the current evaluation.

New Evidence During the Reporting Interval

Summarise the important new evidence relevant to the risk.

This may include:

• completed signal evaluations;

• important Individual Case Safety Reports;

• cumulative review;

• clinical trial findings;

• PASS;

• observational studies;

• published literature;

• regulatory decisions;

• important product information changes.

Only evidence that materially contributes to the evaluation should be discussed.

Interpretation of the Evidence

This is the scientific core of the discussion.

Rather than listing findings, explain what they mean.

Examples include:

• increased confidence in causality;

• reduced uncertainty;

• improved understanding of risk factors;

• better definition of susceptible populations;

• clarification of clinical outcomes;

• identification of preventive measures;

• evidence suggesting that previous concerns were unfounded.

The discussion should integrate all available evidence into a coherent medical interpretation.

Impact on the Current Understanding of the Risk

Every subsection should explicitly answer the following question:

Has our understanding of this risk changed?

Possible conclusions include:

• no meaningful change;

• improved characterisation;

• increased clinical importance;

• reduced uncertainty;

• strengthened evidence for causality;

• weakened evidence supporting the association;

• need for additional evaluation.

Readers should never have to infer how the evidence has influenced the current understanding.

Regulatory and Pharmacovigilance Consequences

Finally, explain whether the updated evaluation has resulted in any action.

Examples include:

• revision of the Company Core Safety Information;

• revision of the Reference Safety Information;

• updates to product information;

• implementation of additional risk minimisation measures;

• initiation of additional PASS;

• continuation of routine pharmacovigilance activities;

• no action required.

The consequences should arise naturally from the preceding scientific discussion rather than appearing as isolated regulatory decisions.

Determining the Appropriate Depth of Discussion

Not every important risk requires the same level of detail.

The amount of discussion should reflect:

• the clinical importance of the risk;

• the amount of new evidence available;

• whether understanding has changed;

• regulatory significance;

• impact upon the benefit-risk balance.

For example, an important identified risk for which substantial new evidence has emerged may require several pages of discussion.

Conversely, where extensive review confirms that no meaningful new information has become available, a concise but scientifically justified update may be entirely appropriate.

Proportionate reporting improves readability and allows regulatory reviewers to focus their attention on areas where the scientific understanding has genuinely evolved.

Writing Tip

Avoid rewriting previous PBRERs.

Every subsection should answer one question:

"If the previous PBRER did not exist, what does the reader now need to know about the current understanding of this risk?"

This approach naturally removes repetition while ensuring that genuinely new scientific knowledge receives appropriate emphasis.

Complex Risk Evaluation Scenarios

Risk evaluation rarely follows a simple linear pathway. As products mature and cumulative evidence grows, reviewers frequently encounter situations where different evidence sources appear inconsistent, uncertainties remain unresolved or scientific understanding evolves gradually over several reporting intervals.

The purpose of this section is not to provide prescriptive answers for every situation. Instead, it illustrates how experienced aggregate physicians approach complex scientific questions while remaining objective, transparent and consistent with the totality of available evidence.

A Signal Is Closed but the Important Potential Risk Remains

Closure of a signal evaluation does not automatically justify removal of an important potential risk.

For example, a specific signal may be closed because the available evidence does not currently support a causal association. However, important uncertainty may remain because exposure is limited, long-term follow-up is unavailable or ongoing studies have not yet reported their results.

In these circumstances, the signal evaluation and the Risk Management Plan serve different purposes.

The signal evaluation answers whether the available evidence supports the specific safety concern that prompted formal review.

The important potential risk reflects whether sufficient uncertainty remains to justify continued pharmacovigilance activities or further data collection.

Authors should therefore explain why the signal was closed while also describing why continued monitoring of the potential risk remains appropriate.

An Important Potential Risk Becomes an Important Identified Risk

As evidence accumulates, a potential risk may become sufficiently characterised to support a causal association.

This transition should not simply be documented as a change in terminology.

Instead, the evaluation should explain:

• what new evidence became available;

• why the cumulative evidence now supports causality;

• how uncertainty has been reduced;

• whether the clinical consequences of the risk are now better understood;

• whether additional risk minimisation measures have become necessary.

The discussion should clearly describe the scientific evolution that justified the reclassification.

An Important Identified Risk Is Re-evaluated

Although uncommon, cumulative evidence may substantially alter understanding of an established important identified risk.

For example, additional studies may demonstrate that the risk is confined to a specific patient population, occurs only under particular treatment conditions or is considerably less frequent than originally believed.

The objective is not to minimise previously recognised risks but to refine scientific understanding as better evidence becomes available.

Where the evaluation results in modification of the recognised safety profile, the rationale should be explained transparently together with any resulting regulatory consequences.

Multiple Signals Affect a Single Risk

Several apparently independent signal evaluations may ultimately contribute to improved understanding of one recognised risk.

For example, separate evaluations concerning hepatic enzyme elevations, drug-induced liver injury and hepatic failure may collectively improve characterisation of hepatotoxicity.

Rather than discussing each signal independently within the risk evaluation, authors should integrate the findings into a single coherent assessment explaining how cumulative evidence has refined current understanding of the recognised risk.

The emphasis should remain on the risk itself rather than the individual signal evaluations.

One Signal Influences Several Risks

Conversely, one signal may have implications for several recognised risks.

For example, evidence relating to immune-mediated toxicity may influence understanding of hepatotoxicity, dermatological reactions and endocrine disorders.

In these situations, authors should ensure that related risk discussions remain internally consistent while avoiding unnecessary duplication.

Cross-references between sections may be helpful where appropriate, but each risk discussion should remain sufficiently complete to be understood independently.

Different Evidence Sources Reach Different Conclusions

Conflicting evidence is common in pharmacovigilance.

Examples include:

• spontaneous reports suggesting an association while epidemiological studies do not;

• clinical trials demonstrating no increased risk but accumulating real-world evidence suggesting otherwise;

• published literature reaching inconsistent conclusions;

• regulatory authorities adopting different scientific positions.

Such situations should not be resolved by selecting the preferred evidence source.

Instead, the reviewer should evaluate the strengths and limitations of each dataset, discuss possible reasons for the differences and explain how the overall conclusion was reached.

Acknowledging uncertainty generally strengthens scientific credibility.

PASS and Real-World Evidence Differ from Clinical Trials

Differences between clinical trial findings and post-authorisation data are not unusual.

Clinical trials typically involve carefully selected patient populations, standardised treatment protocols and relatively limited follow-up.

By contrast, post-marketing experience reflects routine clinical practice, broader patient populations, concomitant therapies and longer treatment durations.

Where findings differ, the evaluation should consider whether these differences are explained by study design, patient characteristics, exposure duration or other methodological factors before concluding that the underlying safety profile has changed.

Risk Characterisation Differs Between Populations

Some risks may differ substantially according to:

• indication;

• age group;

• renal function;

• hepatic function;

• pregnancy status;

• genetic factors;

• route of administration;

• formulation.

Authors should avoid presenting such risks as though they apply uniformly to every patient population.

Instead, the evaluation should explain which populations are affected, the evidence supporting these observations and the implications for clinical use.

This is particularly important for products with multiple therapeutic indications or specialised patient populations.

Rare Risks with Slowly Accumulating Evidence

Some clinically important adverse reactions require many years of pharmacovigilance before sufficient evidence becomes available.

Very rare events, delayed toxicities and events occurring only after prolonged treatment may evolve gradually over successive PBRERs.

In these situations, reviewers should avoid drawing strong conclusions from small incremental changes observed during a single reporting interval.

Instead, the discussion should place new findings within the context of the cumulative evidence accumulated throughout the product lifecycle.

Medical Review Consideration

Complex evaluations should focus on explaining how scientific understanding has evolved rather than attempting to force every situation into predefined categories. Regulators are generally interested in the quality of the reasoning process as much as the final conclusion.

Multi-Company and Global Risk Evaluation Scenarios

Many medicinal products are marketed through complex commercial arrangements involving global Marketing Authorisation Holders (Global MAHs), local Marketing Authorisation Holders (Local MAHs), licensing partners, distributors and co-marketing agreements.

These commercial arrangements influence how safety information is collected, shared and evaluated. However, they should not change the scientific principles applied when evaluating risks within the PBRER.

The objective remains to present the most complete and scientifically justified evaluation of the medicinal product's benefit-risk profile using all relevant safety information available to the Marketing Authorisation Holder responsible for preparing the report.

Global MAH with Regional Affiliates

Many multinational organisations maintain a single global pharmacovigilance system while regional affiliates hold individual marketing authorisations.

In these situations, the Global MAH generally prepares a single scientific evaluation using worldwide cumulative safety data, while regional affiliates implement resulting regulatory actions according to local regulatory requirements.

The scientific discussion should therefore be based upon the global evidence base rather than individual country experience unless important regional differences materially influence the evaluation.

Examples include:

• differences in approved indications;
• differences in patient populations;
• different dosage recommendations;
• region-specific risk minimisation measures;
• region-specific product information.

Where these differences affect interpretation of a recognised risk, they should be described explicitly.

Independent Local Marketing Authorisation Holders

Some medicinal products are licensed to independent companies that hold marketing authorisations within specific territories.

Each Marketing Authorisation Holder remains responsible for evaluating the safety profile of the products for which it holds regulatory responsibility.

Consequently, the PBRER should evaluate all safety information available to that Marketing Authorisation Holder, including information received through pharmacovigilance agreements from licensing partners.

Where important information is unavailable because of contractual limitations or timing of data exchange, this should be managed according to the applicable pharmacovigilance agreement and regulatory requirements. The scientific discussion should accurately reflect the evidence available at the Data Lock Point.

Licensing and Development Partners

Licensing partners frequently exchange Individual Case Safety Reports (ICSRs), aggregate safety information, signal evaluations and risk assessments under Safety Data Exchange Agreements (SDEAs).

Although different partners may perform independent medical reviews, significant differences in scientific conclusions should be uncommon and should normally be explainable by:

• differences in available datasets;
• different Data Lock Points;
• territory-specific product use;
• indication-specific evidence;
• timing of ongoing studies;
• regulatory status.

Where meaningful differences exist, the evaluation should explain the scientific basis rather than simply documenting that another company reached a different conclusion.

Distributor Arrangements

A distributor is generally not the Marketing Authorisation Holder and therefore is usually not responsible for preparing a PBRER.

However, distributor activities may contribute important safety information.

For example, distributors may:

• receive spontaneous adverse event reports;
• provide product utilisation information;
• support local literature surveillance where contractually agreed;
• contribute exposure information;
• notify local regulatory actions.

Where distributor-derived information materially influences evaluation of an important risk, it should be incorporated into the scientific assessment in the same manner as any other relevant pharmacovigilance information.

The emphasis should remain on the evidence itself rather than its commercial source.

Co-marketing and Co-promotion Arrangements

Under co-marketing or co-promotion agreements, more than one organisation may participate in pharmacovigilance activities.

Responsibilities should be determined by the applicable contractual agreements and local regulatory requirements.

Where aggregate evaluations are prepared jointly or where safety information is exchanged between companies, authors should ensure that:

• all relevant safety data have been considered;
• duplicate cases have been reconciled where appropriate;
• conclusions remain scientifically consistent across organisations;
• differences in interpretation are explained where relevant.

Commercial arrangements should never compromise scientific objectivity.

Global and Local Risk Characterisation

Occasionally, the overall global evaluation may differ from the assessment required within a specific region because of differences in authorised indications, formulations, routes of administration or patient populations.

In such situations, the global scientific evaluation should remain evidence-based while clearly identifying circumstances in which local regulatory implementation or local product information differs.

The objective is not to produce different scientific truths but to explain how regional regulatory or clinical factors influence the application of the global safety evaluation.

Practical Perspective

The responsibility for preparing a PBRER generally rests with the Marketing Authorisation Holder responsible for the product. However, the scientific evaluation should consider all relevant safety information available through the organisation's pharmacovigilance system, including information received from affiliates, licensing partners and other contractual partners, in accordance with applicable agreements and regulatory requirements.

Evaluating the Complete Evidence Base

High-quality risk evaluation depends upon consideration of the complete body of available scientific evidence. Focusing exclusively on evidence supporting a particular conclusion may distort interpretation of the medicinal product's evolving safety profile.

Accordingly, reviewers should actively seek evidence that both strengthens and challenges the current understanding of each important identified risk, important potential risk and area of missing information.

The objective is not to collect every available publication or case report but to ensure that the evaluation reflects the totality of relevant evidence available at the Data Lock Point.

Evidence Supporting Stability of the Risk Profile

An absence of important new safety findings is itself an important scientific observation.

Examples include:

• large cumulative exposure without new safety concerns;

• completion of PASS showing no increased risk;

• epidemiological studies demonstrating no clinically meaningful association;

• long-term extension studies confirming previous safety findings;

• consistent findings across successive PBRERs;

• stable reporting patterns after adjustment for patient exposure.

Where new evidence reinforces the existing understanding of a recognised risk, this should be discussed explicitly rather than omitted because "nothing changed."

Confirmatory evidence strengthens confidence in the current benefit-risk assessment.

Negative Studies

Studies that fail to demonstrate an association deserve careful consideration.

Negative findings should not be dismissed simply because they do not support a suspected safety concern.

Instead, reviewers should evaluate:

• study design;

• statistical power;

• patient population;

• duration of follow-up;

• exposure assessment;

• endpoint definitions;

• important methodological limitations.

Well-conducted negative studies may substantially reduce uncertainty surrounding an important potential risk.

Conversely, poorly designed negative studies should be interpreted cautiously.

Evidence That Challenges Previous Assumptions

Scientific understanding evolves continuously.

New evidence may indicate that previously accepted assumptions require modification.

Examples include:

• lower-than-expected frequency of a recognised adverse reaction;

• restriction of risk to particular patient populations;

• absence of previously suspected dose dependency;

• improved understanding of underlying mechanisms;

• identification of protective factors;

• clarification of reversible versus irreversible outcomes.

Risk evaluation should describe these developments transparently, even when they reduce the perceived importance of a recognised safety concern.

Product Quality and Manufacturing Information

Occasionally, product quality issues contribute to safety evaluation.

Examples include:

• manufacturing changes affecting immunogenicity;

• contamination events;

• formulation changes;

• device-related issues;

• stability concerns;

• packaging or labelling defects resulting in medication errors.

Where these issues influence the interpretation of an important identified or potential risk, they should be integrated into the scientific discussion rather than treated as isolated quality events.

Cross-reference should be made to relevant sections of the PBRER where appropriate.

Medication Errors, Misuse and Off-label Use

Medication errors, intentional misuse, abuse, overdose and off-label use may influence the observed safety profile.

Reviewers should consider whether these patterns:

• explain apparent increases in adverse event reporting;

• identify new risk factors;

• reveal deficiencies in existing risk minimisation measures;

• indicate the need for additional educational activities;

• alter interpretation of recognised risks.

The objective is to distinguish adverse reactions attributable to the medicinal product from events resulting primarily from patterns of product use.

Regulatory Assessments

Evaluations performed by regulatory authorities provide important scientific context.

Examples include:

• PRAC recommendations;

• CHMP opinions;

• European Commission decisions;

• FDA safety communications;

• MHRA Drug Safety Updates;

• PMDA safety measures;

• Health Canada advisories;

• TGA safety communications.

Where regulatory conclusions differ, the discussion should explain the scientific reasons where known.

Differences may arise from:

• different datasets;

• different Data Lock Points;

• different approved indications;

• regional utilisation patterns;

• differing regulatory questions under consideration.

The objective is not to reconcile every difference but to demonstrate awareness of the wider regulatory environment.

Evidence from Special Populations

Evidence relating to special populations frequently modifies understanding of recognised risks.

Examples include:

• paediatric patients;

• older adults;

• pregnant or breastfeeding women;

• patients with renal impairment;

• patients with hepatic impairment;

• patients with significant comorbidities;

• transplant recipients;

• immunocompromised patients.

Where sufficient evidence becomes available, the evaluation should explain how these findings influence overall risk characterisation and whether additional risk minimisation measures should be considered.

Registry and Real-World Evidence

For orphan medicinal products, advanced therapy medicinal products (ATMPs), vaccines and medicines requiring long-term follow-up, registry data and other real-world evidence may contribute substantially to risk evaluation.

Reviewers should consider:

• completeness of follow-up;

• duration of observation;

• representativeness of enrolled patients;

• consistency with spontaneous reporting;

• comparison with clinical trial findings.

Registry data frequently provide valuable information regarding delayed adverse reactions, durability of safety outcomes and use in patient populations underrepresented during clinical development.

Medical Review Consideration

Scientific credibility is strengthened when the evaluation discusses evidence that confirms, challenges and refines current understanding of a risk. Regulators expect balanced scientific assessment rather than selective presentation of supportive findings.

Common Mistakes

Deficiencies within the Evaluation of Risks section generally arise from one of three causes: weaknesses in scientific interpretation, weaknesses in medical writing or weaknesses in pharmacovigilance governance. Recognising these deficiencies helps authors prepare evaluations that are scientifically robust, internally consistent and readily understandable by regulatory assessors.

Scientific Mistakes

The most frequent scientific deficiency is treating the section as a summary of new information rather than an evaluation of how cumulative evidence has changed the understanding of a risk.

Other common scientific deficiencies include:

• discussing individual studies without integrating their findings;

• relying excessively on spontaneous reports while ignoring higher levels of evidence;

• failing to consider contradictory evidence;

• confusing statistical association with causal interpretation;

• drawing conclusions without considering patient exposure;

• failing to distinguish recognised risks from potential risks;

• overinterpreting small numerical changes;

• failing to explain why the current understanding has—or has not—changed.

The discussion should always focus on scientific interpretation rather than description alone.

Writing Mistakes

Many Evaluation of Risks sections become unnecessarily long because previous PBRER text is reproduced with only minor additions.

Examples of poor writing practice include:

• repeating historical information that has not changed;

• reproducing case narratives already discussed elsewhere;

• summarising every published paper individually;

• presenting conclusions before explaining the evidence;

• inconsistent terminology for the same risk;

• failure to distinguish observations from conclusions;

• inconsistent discussions across different risks.

Each subsection should tell one coherent scientific story explaining how understanding of the risk has evolved during the reporting interval.

Governance Mistakes

Scientific evaluations may also be weakened by governance deficiencies.

Examples include:

• inconsistent conclusions between the PBRER and the Risk Management Plan;

• failure to incorporate completed signal evaluations;

• inconsistencies between the Company Core Safety Information (CCSI), Reference Safety Information (RSI) and risk evaluation;

• omission of important partner safety information available before the Data Lock Point;

• inadequate reconciliation of affiliate safety data;

• lack of documentation supporting major scientific conclusions.

Strong governance improves both scientific quality and regulatory confidence.

Inspection and Regulatory Assessment Considerations

Regulatory assessors expect this section to demonstrate how the Marketing Authorisation Holder has interpreted the cumulative evidence relating to the medicinal product's recognised and potential risks.

During assessment, reviewers may evaluate whether:

• every important identified risk has been reviewed;

• important potential risks have been assessed objectively;

• relevant missing information has been re-evaluated;

• cumulative evidence has been integrated appropriately;

• completed signal evaluations are reflected consistently;

• conclusions are supported by the available evidence;

• changes to product information are scientifically justified;

• benefit-risk implications are discussed consistently throughout the PBRER.

During pharmacovigilance inspections, inspectors may additionally review:

• traceability between signal management and risk evaluation;

• governance of aggregate medical review;

• consistency between the PBRER, Risk Management Plan and product information;

• documentation supporting important scientific decisions;

• multidisciplinary review and approval processes;

• implementation of pharmacovigilance commitments arising from previous evaluations.

Inspectors are often interested in the decision-making process as much as the scientific conclusion itself. Organisations should therefore be able to demonstrate how evidence was reviewed, discussed and translated into the final aggregate assessment.

Inspection Insight

A high-quality Evaluation of Risks section demonstrates continuity of scientific thinking across successive PBRERs. Assessors should be able to understand not only the current interpretation of each important risk but also how that interpretation has evolved over time.

Key Takeaways

The Evaluation of Risks and New Information section is the point at which diverse pharmacovigilance evidence is transformed into an updated understanding of the medicinal product's safety profile.

Rather than describing individual studies or case reports, authors should integrate cumulative evidence to explain whether current knowledge of each important identified risk, important potential risk and area of missing information has changed during the reporting interval.

High-quality evaluations remain balanced, proportionate and evidence-based. They acknowledge uncertainty where appropriate, discuss contradictory findings openly and distinguish clearly between observations, scientific interpretation and resulting regulatory actions.

Ultimately, this section provides the scientific foundation for the Integrated Benefit-Risk Evaluation that follows.

How a Senior Aggregate Physician Thinks

Experienced aggregate physicians rarely ask:

"What new cases were received?"

Instead, they ask:

"What do these new data teach us that we did not know at the previous Data Lock Point?"

They recognise that every new case, study, signal evaluation or regulatory action is valuable only insofar as it changes—or confirms—the current understanding of a recognised risk.

They deliberately seek evidence that challenges their existing interpretation, integrate findings from multiple independent sources and resist changing conclusions unless the cumulative evidence justifies doing so.

This approach ensures that the Evaluation of Risks section reflects scientific progress rather than simply documenting pharmacovigilance activities.

Continue Reading

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• [[important-potential-risks]]
• [[missing-information-in-risk-management-plans]]
• [[signal-evaluation-methodology]]
• [[benefit-risk-evaluation]]
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• [[risk-management-plans]]

References

Primary Regulatory References

1. ICH E2C(R2): Periodic Benefit-Risk Evaluation Report.

2. European Medicines Agency. Good Pharmacovigilance Practices (GVP) Module VII – Periodic Safety Update Report.

3. European Medicines Agency. Good Pharmacovigilance Practices (GVP) Module V – Risk Management Systems.

4. Commission Implementing Regulation (EU) No 520/2012.

5. Directive 2001/83/EC.

6. Regulation (EC) No 726/2004.

Supporting Regulatory Guidance

1. EMA Questions and Answers on Periodic Safety Update Reports (PSURs).

2. EMA Procedural Guidance for EU Single Assessment of PSURs (PSUSA).

3. EMA guidance relating to Risk Management Plans and post-authorisation safety evaluation.

Scientific References

1. CIOMS Working Group reports on benefit-risk assessment, signal management and aggregate safety reporting.

2. ENCePP Guide on Methodological Standards in Pharmacoepidemiology.

3. ISPE Good Pharmacoepidemiology Practices.

4. Selected peer-reviewed publications relating to benefit-risk evaluation, causal inference and lifecycle pharmacovigilance.