How to Write a PBRER

A Periodic Benefit-Risk Evaluation Report (PBRER) is a cumulative regulatory assessment of a medicinal product in which new information from a defined reporting interval is interpreted against everything already known about the product. Its central question is not “what safety data were received?” but whether the new evidence changes the current understanding of benefit, risk or the overall benefit-risk balance.

This distinction determines how the report should be written. A PBRER assembled section by section from independent source documents can be technically complete yet scientifically weak. A strong report begins with an understanding of the product's existing benefit-risk profile, identifies what changed during the interval, and then uses the ICH E2C(R2) structure to build a traceable argument from evidence to conclusion.

In the European Union, the corresponding regulatory document is the periodic safety update report (PSUR), whose format and content follow the PBRER model. GVP Module VII provides EU guidance, and EMA also maintains an explanatory note that should be consulted for current EU preparation and PSUSA considerations. The underlying ICH E2C(R2) structure remains the scientific architecture of the report.

Regulatory Framework and Report Purpose

ICH E2C(R2) defines the recommended content and format of the PBRER. In the EU, the PSUR format is legally required under the pharmacovigilance legislation and Commission Implementing Regulation (EU) No 520/2012, with GVP Module VII providing detailed regulatory guidance.

The terms PBRER and PSUR are therefore related but not perfectly interchangeable. PBRER is the ICH harmonised scientific format; PSUR is the EU regulatory report that uses that format and is submitted according to EU-specific requirements such as the EURD list and PSUR single assessment procedure where applicable.

Before drafting, the author should establish:

• whether a report is required in the relevant jurisdiction;
• the applicable data lock point (DLP) and reporting interval;
• the product/substance scope and formulations covered;
• the reference product information and Reference Safety Information (RSI);
• the current RMP where applicable;
• relevant regional requirements; and
• responsibilities where multiple companies or partners contribute data.

These are not administrative preliminaries. They define the scientific population and time boundary of the report.

Data lock point and submission timeline

ICH E2C(R2) defines the DLP as the cut-off date for data included in the PBRER. It recommends submission within 70 calendar days for reports covering intervals of 6 or 12 months and within 90 calendar days for intervals longer than 12 months, subject to regional requirements. In the EU, the applicable submission schedule should be verified against the EURD list and current procedural guidance rather than assumed from the ICH default alone.

Start With the Scientific Story

Before opening the template, the lead author should be able to summarise the reporting interval in a few paragraphs. This preparatory synthesis identifies the developments that should drive emphasis throughout the report.

Useful questions include:

• Were any important signals opened, closed or materially advanced?
• Did the understanding of an identified or potential risk change?
• Were there important changes to product information?
• Did any regulator take action for safety reasons?
• Did new trial, observational, PASS or literature evidence become available?
• Did exposure change substantially or extend into new populations?
• Did efficacy or effectiveness information change the benefit side of the balance?
• Did any risk-minimisation measure prove ineffective or require modification?
• Did the overall benefit-risk conclusion change?

If little changed, the report should say so clearly and proportionately. PBRER quality is not measured by length.

Establish the baseline

The previous report provides the baseline against which current-period developments are interpreted. The author should understand the previous conclusions, safety concerns, ongoing signals, regulatory commitments, outstanding studies and previously proposed actions before evaluating new evidence.

The baseline should also include the current RSI and approved indications. E2C(R2) makes the reference information central because interval changes are judged against previous knowledge and because the benefit evaluation is tied to approved use.

Build a Source and Responsibility Map

PBRER preparation usually involves data from several functions. A controlled source map helps prevent gaps and late surprises.

Typical inputs include:

• worldwide marketing-authorisation status;
• safety-driven regulatory actions;
• reference-information changes;
• clinical-trial exposure and safety findings;
• marketing exposure and utilisation;
• post-marketing ICSR summary tabulations;
• completed and ongoing clinical studies;
• non-interventional studies and PASS;
• literature and other sources;
• non-clinical data;
• efficacy/effectiveness information;
• signal evaluations;
• risk evaluations;
• RMP and risk-minimisation information; and
• late-breaking safety information.

A source map should identify the data owner, cut-off, required format, reviewer and any reconciliation needed between systems. This is recommended project-management practice, not an ICH-required template.

Understanding the PBRER Architecture

The report structure is deliberately cumulative. The earlier sections establish regulatory context and exposure; the middle sections present important interval evidence; the later sections integrate signals, risks, benefits and benefit-risk.

The principal ICH E2C(R2) sections are:

1. Introduction
2. Worldwide Marketing Approval Status
3. Actions Taken in the Reporting Interval for Safety Reasons
4. Changes to Reference Safety Information
5. Estimated Exposure and Use Patterns
6. Data in Summary Tabulations
7. Summaries of Significant Findings from Clinical Trials during the Reporting Period
8. Findings from Non-Interventional Studies
9. Information from Other Clinical Trials and Sources
10. Non-Clinical Data
11. Literature
12. Other Periodic Reports
13. Lack of Efficacy in Controlled Clinical Trials
14. Late-Breaking Information
15. Overview of Signals: New, Ongoing or Closed
16. Signal and Risk Evaluation
17. Benefit Evaluation
18. Integrated Benefit-Risk Analysis for Approved Indications
19. Conclusions and Actions
20. Appendices

The headings are fixed by the reporting framework, but the depth within them should be proportional to the product's important and emerging benefits and risks. ICH E2C(R2) explicitly recognises this principle.

Sections 1–6: Establish the Context Before Interpretation

Sections 1–6 define the frame within which later safety observations are interpreted.

Section 1 — Introduction

The introduction should identify the product, approved indications and populations, reporting interval and other information needed to understand scope. It should orient the assessor, not retell the product's development history.

Section 2 — Worldwide Marketing Approval Status

Present the regulatory footprint accurately and consistently. The purpose is to establish where and under what broad conditions the product is authorised, not to create an encyclopaedic country narrative.

Section 3 — Actions Taken for Safety Reasons

Describe significant safety-related actions taken by regulators or the MAH during the interval. The section should explain the safety reason and resulting action clearly enough that later signal and risk discussions can connect back to it.

Section 4 — Changes to Reference Safety Information

Identify significant changes to the RSI during the interval and explain the safety basis. Changes after the DLP but before submission may need consideration as late-breaking information.

Section 5 — Estimated Exposure and Use Patterns

Exposure provides context for the amount and pattern of product use. Distinguish clinical-trial exposure from post-marketing estimates and explain assumptions and limitations. Sales-derived exposure is an estimate, not direct patient counting.

Section 6 — Data in Summary Tabulations

Summary tabulations provide the quantitative safety background. They are evidence inputs rather than conclusions. Avoid interpreting raw counts as incidence where no valid exposure denominator exists.

Sections 7–14: Identify What the Interval Added

The middle of the PBRER gathers clinically important information that became available during the reporting interval. The objective is selective interpretation, not reproduction of study reports or case databases.

Section 7 — Significant Findings from Clinical Trials

Discuss completed and ongoing trials only to the extent that findings materially inform safety, efficacy/effectiveness or benefit-risk. Relevant topics may include new adverse-event patterns, clinically important laboratory changes, mortality findings, subgroup effects, dose relationships or new information from long-term follow-up.

A negative study finding can also be important when it reduces uncertainty about a previously suspected risk.

Section 8 — Findings from Non-Interventional Studies

Include relevant findings from observational studies, registries, database studies, drug-utilisation work and PASS. The discussion should distinguish the study result from the strength of inference. A large observational association is not automatically causal; study design, confounding, selection, outcome validation and exposure definition determine evidentiary weight.

Section 9 — Other Clinical Trials and Sources

This section captures relevant clinical information not already addressed elsewhere. It should not become a miscellaneous dumping ground. Each item included should contribute to understanding the product's safety or benefit-risk profile.

Section 10 — Non-Clinical Data

New toxicology, pharmacology or mechanistic findings may strengthen or weaken the plausibility of a clinical concern. Translate the non-clinical finding into its potential human relevance and explain uncertainty rather than simply summarising an experiment.

Section 11 — Literature

The literature section should focus on publications that materially contribute to the report's safety, benefit or benefit-risk assessment. Literature already processed as ICSRs may also contribute scientific context, but case collection and aggregate interpretation are distinct tasks.

Section 12 — Other Periodic Reports

Where another periodic report contains information relevant to the PBRER, use it carefully and maintain consistency. Shared content should be current for the PBRER DLP and should not be copied without considering the different regulatory purpose of the receiving report.

Section 13 — Lack of Efficacy in Controlled Clinical Trials

Lack of efficacy can have safety significance, particularly where failure of treatment creates serious clinical consequences. The relevance depends on indication and context; the section is not simply an efficacy summary.

Section 14 — Late-Breaking Information

Important information arising after the DLP but before report finalisation can materially affect interpretation. Late-breaking information should be clearly distinguished from interval data so that the evidence boundary remains transparent.

Section 15: Overview of Signals

Section 15 provides the bridge between interval observations and cumulative risk evaluation. It should give an organised view of signals that were new, ongoing or closed during the reporting interval.

A signal table should be more than an inventory. It should allow the assessor to understand:

• when the signal was identified;
• its status at the DLP;
• the principal evidence considered;
• whether the signal was closed or remained under evaluation; and
• where detailed discussion appears in the report.

Newly identified signals are those first identified during the interval, including previously closed issues that reopen because meaningful new evidence emerges. Ongoing signals remain under evaluation at the DLP. Closed signals are those for which evaluation was completed during the interval.

The signal section should be reconciled with the company's signal tracker. Missing or differently named signals can create inconsistencies later in risk evaluation.

Section 16: Signal and Risk Evaluation

Section 16 is the scientific centre of the PBRER. It converts a set of safety observations into an updated understanding of risk.

16.1 Summary of safety concerns

Where relevant, present the important identified risks, important potential risks and important missing information that provide the baseline for evaluation. In the EU, consistency with the RMP requires careful attention, while recognising that the documents serve related but distinct purposes.

16.2 Signal evaluation

For each important signal closed during the interval, explain the evidence and reasoning that led to the conclusion. The discussion should usually cover the clinical question, relevant case evidence, literature, trial and observational data, exposure context, alternative explanations, biological plausibility and the final conclusion.

Do not reduce signal evaluation to case counts. The task is to explain why the totality of evidence changed—or did not change—the product's known risk profile.

16.3 Evaluation of risks and new information

New information on previously recognised risks should be assessed even when it does not constitute a new signal. Important questions include whether the frequency, severity, outcome, risk factors, preventability or affected population have changed.

16.4 Characterisation of risks

Risk characterisation should answer clinically useful questions: What is the nature of the risk? How serious is it? Who is most susceptible? When does it occur? Is it dose- or duration-related? Is it reversible? Can it be detected early or prevented? What remains uncertain?

This section should not merely restate the label. It should synthesise the cumulative evidence in a way that supports the later benefit-risk evaluation and any proposed risk-management action.

16.5 Effectiveness of risk minimisation

Where risk-minimisation measures are relevant, discuss available evidence on whether they are achieving their intended objective. Distinguish implementation from effectiveness: distributing educational material demonstrates delivery, not necessarily a change in knowledge, behaviour or clinical outcome.

Section 17: Benefit Evaluation

Benefit evaluation is not a decorative preface to the risk discussion. The PBRER is a benefit-risk report, and the strength and durability of benefit influence how a given risk is interpreted.

The section should establish baseline efficacy/effectiveness and then evaluate important new benefit information from the interval. Consider approved indications separately where their benefits, populations or alternatives differ materially.

Relevant dimensions can include:

• magnitude of effect;
• clinically meaningful outcomes;
• durability;
• populations in whom benefit is demonstrated;
• real-world effectiveness where reliable data exist;
• important uncertainty; and
• changes in therapeutic alternatives or clinical practice where relevant to interpretation.

The report does not require a formal mathematical benefit-risk model unless one is otherwise justified. The reasoning should nevertheless be explicit.

Section 18: Integrated Benefit-Risk Analysis

Section 18 should not introduce a new scientific story. By this point, the important evidence should already have been evaluated in Sections 15–17. The integrated analysis explains how the benefits and risks relate to one another for each approved indication and, where relevant, important subgroups.

A useful sequence is:

benefit context → most important risks → important new interval evidence → remaining uncertainty → effect on the balance → need for action.

The author should avoid two extremes. One is a generic statement that benefits continue to outweigh risks without showing why. The other is an exhaustive repetition of every safety section. Integration means selecting the evidence that actually determines the balance.

Writing under uncertainty

Benefit-risk conclusions are often made before every uncertainty has been resolved. The report should identify what is known, what remains uncertain and why the remaining uncertainty does or does not change the current regulatory position.

Transparent uncertainty is scientifically stronger than unjustified precision.

Section 19: Conclusions and Actions

The conclusion should state the implications of new information for the overall benefit-risk evaluation and identify any actions that follow logically from the evidence.

Potential actions can include:

• change to reference product information;
• product-information variation;
• new or revised pharmacovigilance activity;
• RMP update;
• modification of risk minimisation;
• further study or analysis; or
• continued monitoring with no immediate regulatory change.

A conclusion that proposes action not supported by the preceding assessment indicates a break in the report's reasoning chain.

Section 20: Appendices

ICH E2C(R2) identifies appendices that may include reference information, summary tabulations, a signal table, relevant study listings and, where desired, sources used to prepare the report. Regional appendices may be needed for jurisdiction-specific requirements.

Appendices should support the report without hiding conclusions that belong in the main assessment.

Writing as One Scientific Document

PBRERs are usually produced by multidisciplinary teams, but the submitted report should not read like a bundle of function-specific contributions. The lead author or medical reviewer should actively reconcile terminology, data cut-offs and conclusions across sections.

Particular interfaces deserve deliberate review:

• Section 3 safety actions versus Section 15 signals;
• Section 4 RSI changes versus Section 16 risk conclusions;
• Section 5 exposure versus reporting-rate interpretations;
• study findings in Sections 7–9 versus signal and risk evaluation;
• Section 16 safety concerns versus the current RMP;
• Section 17 benefit evidence versus Section 18 integrated analysis; and
• Section 19 actions versus all preceding conclusions.

A contradiction at one of these interfaces often indicates that the report was assembled rather than integrated.

Shared content with other regulatory documents

ICH E2C(R2) deliberately supports modularity. Some content can be shared with the DSUR or RMP when timing and scope permit. ICH's E2C(R2) Q&A maps several shared PBRER/DSUR sections, and GVP Module VII identifies common PSUR/RMP content.

Re-use should reduce duplication, not bypass review. Content imported from another document must be current for the PBRER DLP, appropriate to the PBRER's regulatory purpose and consistent with the rest of the report.

Review Strategy

A mature review process uses different passes for different purposes.

Scientific review

The first pass asks whether the evidence has been interpreted correctly. Reviewers should challenge causality reasoning, epidemiological inference, exposure assumptions, signal conclusions, risk characterisation and benefit-risk integration.

Cross-document consistency review

The next pass compares the report with controlling and related documents, including the RSI, current product information, RMP, signal records, key regulatory correspondence and relevant study conclusions.

Data and traceability review

Confirm that tabulations, numbers, dates, DLPs, exposure estimates and signal statuses can be traced to controlled sources and that apparently different numbers are reconciled or explained.

Editorial and submission review

Only after the scientific content is stable should the team focus on formatting, internal references, headings, appendices, hyperlinking and technical submission requirements.

Separating these passes prevents editorial perfection from masking scientific inconsistency.

Potential Failure Modes

The following are illustrative failure modes rather than reported inspection findings.

The previous PBRER is copied forward mechanically

Re-use can preserve continuity, but it can also preserve obsolete assumptions and bury interval developments. Every carried-forward conclusion should remain supported by the current cumulative evidence.

The report is descriptive rather than evaluative

Large case tables and study summaries do not substitute for medical interpretation. The assessor needs to understand what the evidence means for risk and benefit-risk.

Section 16 and Section 18 tell different stories

If risk evaluation identifies a meaningful change but the benefit-risk section remains generic, the integration has failed. Conversely, Section 18 should not introduce a major risk that was never evaluated in Section 16.

Exposure is treated as exact

Post-marketing exposure is often estimated from sales, dispensing or healthcare data. The method and limitations should be clear, and spontaneous reporting rates should not be presented as incidence unless the underlying data justify incidence estimation.

Closed signals disappear from the narrative

A closed signal may be scientifically important because its evaluation changed product information or clarified a risk. Section 15 and the relevant Section 16 discussion should preserve the reasoning.

The report hides uncertainty

Qualifying uncertainty is not weakness. Failure to describe missing data, confounding or imprecision can make conclusions appear more certain than the evidence supports.

Actions are disconnected from conclusions

A proposed RMP change, label variation or new study should arise from the evidence evaluated in the report. Unsupported actions suggest a break in traceability.

Inspection and Assessment Considerations

Regulatory assessors evaluate the submitted report; pharmacovigilance inspectors may also examine the system by which reports are produced and whether conclusions are supported by underlying evidence.

Illustrative questions include:

• How were the DLP and reporting interval established?
• What controlled sources fed each major section?
• How were safety actions, signals and RSI changes reconciled?
• Can exposure calculations and assumptions be reproduced?
• Why was a particular signal closed or carried forward?
• How does risk characterisation correspond with the current RMP and product information?
• How were important disagreements between contributors resolved?
• Can the final benefit-risk conclusion be traced to the underlying evidence?
• How were late-breaking data handled?
• Were actions proposed in Section 19 implemented and tracked?

These questions are illustrative. The actual scope depends on the regulatory procedure and inspection objective.

Practical Final Checklist

Before approval, the lead reviewer should be able to confirm that:

• the reporting obligation, DLP, interval and product scope are correct;
• the current applicable RSI and approved indications are identified;
• important interval developments are clear from the report's emphasis;
• exposure methods and limitations are transparent;
• safety tabulations reconcile with controlled sources;
• important trial, observational, literature and non-clinical findings have been interpreted rather than merely listed;
• all new, ongoing and closed signals are correctly represented;
• Section 16 explains the reasoning behind important signal and risk conclusions;
• risk characterisation is clinically useful and cumulative;
• benefit evaluation is sufficient for the approved indications;
• Section 18 integrates rather than repeats the preceding evidence;
• Section 19 actions follow logically from the assessment;
• conclusions are consistent with the RSI, product information, RMP and relevant regulatory decisions;
• late-breaking information has been handled transparently;
• uncertainty is stated at the appropriate level; and
• the submitted report can be reconstructed from its controlled evidence sources.

Key Takeaways

A high-quality PBRER is a cumulative scientific argument structured by ICH E2C(R2). The report begins with regulatory and exposure context, identifies the important evidence that became available during the interval, evaluates signals and risks, evaluates benefit, integrates the two sides of the balance and then derives actions from that assessment.

The template provides the architecture, but it does not create the reasoning. The author must decide which evidence matters, how strongly it supports a conclusion and what uncertainty remains.

In the EU, the PBRER format is used within the legally required PSUR framework, with GVP Module VII, the EURD list, current EMA explanatory material and procedural guidance determining the regional implementation.

The final quality test is straightforward: could an independent assessor follow the evidence from interval development to cumulative interpretation to benefit-risk conclusion without having to infer the missing reasoning?

References

1. International Council for Harmonisation. ICH E2C(R2): Periodic Benefit-Risk Evaluation Report (PBRER). https://database.ich.org/sites/default/files/E2C_R2_Guideline.pdf
2. International Council for Harmonisation. ICH E2C(R2) Questions and Answers, last update 31 March 2014. https://database.ich.org/sites/default/files/E2CR2_Q%26As_Q%26As.pdf
3. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module VII – Periodic safety update report (Rev. 1). EMA/816292/2011 Rev. 1. Available from: https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/periodic-safety-update-reports-psurs
4. European Medicines Agency. GVP Module VII – Periodic safety update report: Explanatory note, EMA/670256/2017 Rev. 4, updated 22 May 2026. Available from the EMA PSUR page.
5. European Medicines Agency. Periodic safety update reports (PSURs) — preparation, EURD list, repository and PSUSA information. https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/periodic-safety-update-reports-psurs
6. European Commission. Commission Implementing Regulation (EU) No 520/2012, consolidated version. https://eur-lex.europa.eu/eli/reg_impl/2012/520/2026-02-12/eng
7. U.S. Food and Drug Administration. Providing Postmarket Periodic Safety Reports in the ICH E2C(R2) Format (Periodic Benefit-Risk Evaluation Report). November 2016. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-postmarket-periodic-safety-reports-ich-e2cr2-format-periodic-benefit-risk-evaluation

Regulatory Note

ICH E2C(R2) is an internationally harmonised guideline defining the recommended PBRER format. In the EU, PSUR format and content are legally governed by applicable EU pharmacovigilance legislation and Commission Implementing Regulation (EU) No 520/2012, with GVP Module VII and EMA procedural guidance explaining implementation. The EURD list and current product-specific obligations should be checked when determining EU submission requirements and frequency. Project plans, source maps, review meetings, checklists and other workflow controls described in this article are recommended operational practices unless an authoritative requirement is specifically identified.