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

The Evaluation of Risks and New Information section asks a cumulative scientific question: what does the evidence now tell us about the medicinal product's important risks and safety-related uncertainty? It is not a second signal log and not a repetition of the RMP safety specification. Its purpose is to explain whether the understanding of each important safety concern has changed during the reporting interval and why.

Purpose and Regulatory Framework

The PBRER format is defined by ICH E2C(R2) and implemented in the EU PSUR framework through Commission Implementing Regulation (EU) No 520/2012 and GVP Module VII — Periodic safety update report (Rev. 1).

The section draws on evidence generated throughout the reporting interval and cumulatively. Its role is synthesis. Earlier parts of the PBRER present source information and completed signal evaluations; the risk-evaluation section integrates that information into an updated understanding of recognised and potential risks and relevant missing information.

Risk Evaluation Is Different From Signal Evaluation

Signal evaluation and risk evaluation are related but answer different questions.

Signal evaluation asks whether information supports a new potentially causal association or a new aspect of a known association and what conclusion follows.

Risk evaluation asks how the totality of evidence changes the current understanding of an important safety concern.

A completed signal may therefore become one piece of evidence in a broader risk discussion. Conversely, a risk may evolve gradually across several reporting intervals without any single signal dominating the assessment.

Begin With the Current Safety Concern

Each discussion should begin from the current scientific status of the concern, not from the historical narrative of every previous PBRER.

For an important identified risk, the central question is usually whether new evidence changes its frequency, severity, clinical pattern, risk factors, preventability, reversibility or affected population.

For an important potential risk, the question is whether cumulative evidence strengthens, weakens or leaves unchanged the causal hypothesis and whether the concern remains important for benefit-risk management.

For missing information, the question is whether the relevant safety uncertainty has been reduced, remains materially important or no longer meets the criteria for inclusion.

The Evidence Set

Risk evaluation may draw on:

• spontaneous and solicited ICSRs;
• completed signal evaluations;
• clinical trials and extension studies;
• observational studies and PASS;
• epidemiology and real-world data;
• scientific literature;
• non-clinical or mechanistic evidence where relevant;
• regulatory assessments and actions;
• risk-minimisation effectiveness data; and
• exposure information.

The section should integrate these sources rather than present them as a sequence of disconnected summaries.

What Has Changed?

For every important safety concern, the author should determine whether new evidence changes one or more dimensions of the current understanding.

Relevant dimensions can include:

• causal confidence;
• frequency or incidence where reliable data exist;
• seriousness or clinical severity;
• reversibility and outcome;
• time to onset;
• dose or duration relationship;
• susceptible populations;
• modifiable risk factors;
• detectability or preventability;
• effectiveness of risk minimisation; and
• remaining uncertainty.

A reporting interval can also produce a legitimate conclusion of no material change. That conclusion should be supported by the evidence rather than stated mechanically.

Evaluating Important Identified Risks

An important identified risk already has sufficient evidence supporting an association. The author therefore should not repeatedly re-prove causality unless materially new evidence changes that conclusion. The emphasis should be on characterisation.

Questions may include:

• Has the clinical phenotype changed?
• Is frequency better estimated from new controlled or observational data?
• Are new risk factors apparent?
• Is the risk confined to, or more important in, a particular population?
• Has management or reversibility changed?
• Are existing warnings or risk-minimisation measures adequate?

When new evidence does not change the risk, a concise statement may be more useful than repeating historical case summaries.

Evaluating Important Potential Risks

Potential risks require careful treatment of uncertainty. The author should weigh both supportive and contradictory evidence.

The discussion may consider:

• strength and consistency of case evidence;
• epidemiological findings;
• trial data;
• biological or pharmacological plausibility;
• class effects;
• evidence against the association;
• limitations of the available datasets; and
• whether additional data collection remains justified.

The conclusion should explain whether confidence in the hypothesis has increased, decreased or remained materially unchanged.

Reclassification to an identified risk should follow the evidence; it should not occur merely because the issue has been monitored for a long time. Likewise, removal of a potential risk should be justified by the totality of evidence and its relevance to risk management.

Evaluating Missing Information

Missing information is not synonymous with absent data. It represents a safety-relevant knowledge gap that matters to risk management.

The author should therefore ask:

• Has exposure in the previously under-studied population increased?
• Have new trial, registry or observational data reduced uncertainty?
• Has the safety profile in that population become sufficiently characterised?
• Does a scientific reason remain to expect a different safety profile?
• Would the remaining uncertainty still influence pharmacovigilance or risk minimisation?

Exposure counts alone do not provide universal thresholds for removing missing information. The decision should be scientific and product-specific.

Conflicting Evidence

Conflicting evidence is common and should be handled explicitly rather than averaged into a vague conclusion.

For example, spontaneous reports may suggest an association while a well-designed observational study does not. The author should compare the strengths and limitations of each source, considering selection, exposure ascertainment, outcome definition, confounding, reporting bias and statistical precision.

The goal is not to choose the source that supports the preferred conclusion. It is to explain why the totality of evidence leads to the current judgement.

Integrating Risk-Minimisation Evidence

Evidence about risk-minimisation effectiveness can change the practical clinical impact of a risk without changing its biological causality.

The author should distinguish:

• whether the risk itself has changed;
• whether understanding of risk factors has improved; and
• whether the measures used to reduce harm are effective.

This distinction is important because an unchanged intrinsic risk can become more manageable when patients at highest risk are identified or preventive measures work reliably.

Reclassification and Removal

Changes in safety-concern classification should be explained as scientific conclusions, not administrative updates.

Where a potential risk becomes identified, the report should state what new evidence crossed the evidentiary threshold. Where a concern is removed, the report should explain why continued classification no longer contributes meaningfully to risk management.

Where the RMP has not yet been formally updated at the DLP, the PBRER should distinguish the MAH's scientific conclusion from the current regulatory status of the RMP.

Structuring Each Risk Discussion

A consistent structure helps the assessor follow the reasoning:

1. Current understanding — brief context, not a full history.
2. Important new evidence — only information material to the question.
3. Integrated interpretation — what supportive and contradictory findings mean together.
4. Change in characterisation — what is now understood differently, if anything.
5. Consequence — whether product information, RMP, pharmacovigilance or risk minimisation changes are proposed or already implemented.

This structure should be adapted to the scientific problem rather than applied as a rigid template.

Illustrative Example

Consider an important potential risk of severe arrhythmia. During the interval, additional spontaneous cases appear, but most have major confounders; a mechanistic study supports plausibility; and a large observational study shows no clear increase in risk but has limited power for the rare outcome.

A weak discussion would list each source and conclude that the risk is “unchanged.”

A stronger discussion would explain that mechanistic plausibility and additional cases modestly support the hypothesis, while the observational study provides important but not definitive negative evidence because of limited precision. The conclusion could therefore be that the potential risk remains unresolved, with no sufficient basis yet for reclassification. The key is showing why the evidence changes—or does not change—the scientific position.

Potential Writing Failure Modes

The following are illustrative writing failures, not inspection findings.

Cross-Section Reconciliation

The risk-evaluation section should be consistent with:

• the applicable reference safety information;
• completed signal evaluations;
• the RMP safety specification where relevant;
• risk-minimisation measures and their effectiveness evidence;
• the benefit evaluation; and
• the integrated benefit-risk conclusion.

A safety concern should not appear as an important potential risk in one section, an established adverse reaction in another and unresolved signal in a third without an explanation of timing or regulatory status.

Practical Review Checklist

1. Is each safety concern classified correctly?
2. Does the discussion focus on what changed rather than repeat history?
3. Are supporting and contradictory data integrated?
4. Are reliable quantitative estimates distinguished from spontaneous-report counts?
5. Are important limitations explicit?
6. Is missing information evaluated as a safety-relevant knowledge gap rather than a simple exposure count?
7. Are reclassification decisions scientifically justified?
8. Are RMP regulatory status and MAH scientific position distinguished?
9. Are risk-minimisation consequences addressed where relevant?
10. Does each discussion end with a clear statement of the current understanding?
11. Is the conclusion consistent with the signal section and RSI?
12. Does the integrated benefit-risk section reflect the updated risk characterisation?

Relationship With Other QPPV.com Articles

Foundational concepts are covered in [[important-identified-risks]], [[important-potential-risks]] and [[missing-information]]. For signal science see [[signal-assessment]]. For the report as a whole see [[understanding-the-structure-of-a-pbrer]], [[pbrer-guide]] and [[how-to-write-a-pbrer]].

Key Takeaways

The risk-evaluation section explains how cumulative evidence changes the current understanding of important safety concerns.

Identified risks require updated characterisation; potential risks require balanced evaluation of the causal hypothesis; missing information requires assessment of whether safety-relevant uncertainty remains.

The strongest writing integrates evidence rather than cataloguing it and states explicitly what changed, what did not change and why.

Reclassification, removal and resulting actions should follow scientific reasoning and be distinguished from the formal regulatory status of the RMP or product information.

References

1. International Council for Harmonisation. ICH E2C(R2): Periodic Benefit-Risk Evaluation Report (PBRER). Step 4, 15 November 2012.
2. International Council for Harmonisation. ICH E2C(R2) Questions and Answers. Last update 31 March 2014.
3. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module VII — Periodic safety update report (Rev. 1). EMA/816292/2011 Rev. 1.
4. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module V — Risk management systems (Rev. 2). EMA/838713/2011 Rev. 2.
5. European Medicines Agency. Periodic safety update reports (PSURs). Current procedural guidance.
6. European Union. Commission Implementing Regulation (EU) No 520/2012, as amended.
7. European Union. Directive 2001/83/EC, as amended.
8. European Union. Regulation (EC) No 726/2004, as amended.

Regulatory Note

This article explains scientific authoring of the PBRER/PSUR risk-evaluation section. It does not create numerical exposure thresholds or automatic rules for classification of identified risks, potential risks or missing information. As of 9 September 2026, GVP Module VII Rev. 1 and GVP Module V Rev. 2 remain the published EMA modules; current procedural guidance should be checked for live submissions.