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How to Write a PBRER or PSUR for a Biological Medicinal Product

This article teaches every formal PBRER section from title page through appendices and explains how biological identity, batch, manufacturing change, immunogenicity, formulation, device, route, biosimilar switching and class effects alter the analysis. A continuing monoclonal-antibody example shows how interval data become an integrated benefit-risk conclusion.

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How to Write a PBRER or PSUR for a Biological Medicinal Product

A Periodic Benefit–Risk Evaluation Report (PBRER) is the ICH format for periodically reassessing a medicine’s benefits and risks using interval information in the context of cumulative knowledge. In the European Union, the corresponding regulatory submission is commonly called the Periodic Safety Update Report (PSUR). The names are not perfectly interchangeable in every jurisdiction, but the EU PSUR follows the ICH E2C(R2) content model with EU-specific requirements.

A PBRER is not a warehouse into which every new case and study is deposited. It is closer to a periodically reconstructed evidence model: the writer defines the product and reporting boundary, assembles evidence from multiple systems, tests whether the known safety profile has changed, re-examines benefits, and explains whether the balance remains favourable and what action follows. The analogy has limits—the report is a regulated document with prescribed content—but it helps distinguish critical evaluation from data accumulation.

Biological medicines add nested levels of identity. “Eculizumab” may identify an active substance; a brand identifies a particular authorised product; a batch links the administered medicine to a manufacturing unit; and a device or formulation may create another exposure pathway. These levels resemble nested addresses. A country name is insufficient when the question concerns one building; a batch number is unnecessarily narrow when evidence shows a target-mediated class effect. The writer must choose the level that matches the safety question.

Table of Contents

Regulatory framework and essential terms

ICH E2C(R2) describes the PBRER content and structure. EU GVP Module VII explains the EU PSUR system, including submission and assessment. EMA’s explanatory note supplements Module VII for PSUR single assessment. GVP Product- or Population-Specific Considerations II explains pharmacovigilance issues distinctive to biological medicines. The applicable EU reference-date list and product-specific conditions determine whether and when a PSUR is required; the existence of this article does not create a submission obligation.

The data lock point (DLP) is the date through which interval data are included. It is a controlled boundary on the main reporting dataset, not the date on which scientific awareness stops. Important information arising after the DLP may belong in late-breaking information. The reporting interval runs from the previous DLP to the current DLP. Cumulative information extends from the international birth date or another justified origin through the current DLP.

The reference safety information (RSI) used for the report provides the baseline against which new safety information is evaluated. In a PBRER this is commonly the company core data sheet or another specified reference document. EU product information is addressed through the EU regional appendix and assessment context. The writer must state the reference version and date rather than silently changing the comparator during drafting.

The continuing worked example

The article uses a hypothetical authorised monoclonal antibody, mAb-X, for two immune-mediated indications. It is available as an intravenous reference product and a subcutaneous formulation with an injector. Biosimilars are marketed in some territories. The interval contains:

The example is illustrative. It is not a real product or regulatory conclusion.

Evidence model for a biological PBRER

Figure 1. A biological PBRER integrates clinical safety, exposure, benefit, quality, immunogenicity and product-identity evidence. Each source retains its limitations before conclusions are integrated.

Before writing: build the evidence map

Before prose is drafted, create a section-to-source matrix. Assign data owners, extraction dates, cumulative and interval boundaries, product hierarchy and medical reviewers. Map safety database cases, clinical trials, non-interventional studies, literature, quality complaints, manufacturing changes, immunogenicity assays, device data, exposure, regulatory actions, risk-management activities and benefit evidence.

For a biological, decide in advance which analyses require active-substance aggregation and which require stratification by brand, batch, formulation, device, route or manufacturing period. Aggregating everything can hide a batch cluster; fragmenting everything can hide a target-mediated class risk.

Title page

The title page identifies the active substance, proprietary products included, reporting interval, DLP, report number and marketing-authorisation holder. For biologicals, scope must be explicit where several brands, formulations, devices or biosimilars exist. Do not imply that a company’s biosimilar and reference product share one authorisation history.

mAb-X example: list the intravenous and subcutaneous company products and state whether partner territories are included. A biosimilar marketed by another holder is external evidence, not automatically part of the submitting holder’s exposure denominator.

Executive summary

Write the executive summary last. It should state product/indication scope, interval, exposure, important regulatory actions, new and ongoing signals, important risks, benefit findings, integrated benefit–risk conclusion and proposed actions. A biological-specific summary should mention a material immunogenicity, batch, device or manufacturing issue when it changed interpretation—not merely because such data exist.

For mAb-X, the summary would distinguish the delayed-hypersensitivity signal from the injector-lot complaint. The first may concern the biological product or immune response; the second initially points to a presentation-specific delivery problem. Neither should be described as a class-wide risk before assessment.

Section 1: Introduction

Section 1 defines the report rather than introducing the disease generally. State the international birth date, reporting interval, DLP, product scope, indications, routes, formulations and populations. Briefly describe the mechanism where it is needed to interpret later risks.

For a biological, explain relationships among reference product, biosimilars, combination products and devices. Identify major scope exclusions. A common failure is to copy a generic mechanism paragraph while leaving the reader unable to determine which products and presentations the report evaluates.

mAb-X example: state that both routes share the antibody active substance, while only the subcutaneous presentation uses the injector. This distinction will later control exposure and device-event analyses.

Section 2: Worldwide Marketing Approval Status

Present first approval, countries or regions authorised, indications and important status changes. The purpose is to show the regulatory footprint in which exposure and evidence arose.

Biological products may have different brands, strengths, formulations, devices and authorised indications across territories. Biosimilar status and interchangeability are jurisdiction-specific. A compact matrix can prevent the misleading statement that “the product is approved globally” when the actual presentations differ.

Territory Product identity Route/device Indications Interval change
Region A mAb-X IV Infusion Disease 1, 2 None
Region B mAb-X SC Injector Disease 1 New strength
Region C Partner brand Infusion Disease 1 Transfer completed

Reconcile this section with exposure, RSI changes and actions taken. A territory absent here should not appear unexplained in sales exposure.

Section 3: Actions Taken in the Reporting Interval for Safety Reasons

Describe significant safety-related actions by regulators, the holder, investigators, ethics committees and data-monitoring bodies. Examples include study suspension, distribution restriction, urgent safety measure, risk-minimisation change, batch recall, device field action or safety communication.

For biologicals, distinguish a quality action with possible safety relevance from a confirmed adverse-reaction conclusion. A recall for reduced injector delivery does not prove molecular loss of efficacy, although clinical consequences of incomplete dosing must be assessed. Conversely, a manufacturing deviation cannot be dismissed as “quality only” if patient exposure occurred.

For each action state date, territory, product/presentation/batch, trigger, action and current status. Cross-reference the corresponding signal or risk evaluation.

mAb-X example: a field correction for injector lot L17 belongs here. Section 16 later evaluates clinical events linked to L17. Repeating the chronology without evaluation would be inadequate.

Section 4: Changes to Reference Safety Information

List significant interval changes to the RSI and explain the safety basis. The writer must preserve version history: what wording applied at the start, what changed, when it became effective and whether regional labels remain different.

Biological-specific changes may concern immunogenicity, infusion or injection reactions, traceability, storage, preparation, device use, vaccination, infection screening or formulation excipients. A manufacturing change is not automatically an RSI change, but new clinical safety implications may require one.

mAb-X example: delayed hypersensitivity was not added during the interval because assessment remained ongoing. The report should say so transparently; absence of a label change is not absence of a signal.

Section 5: Estimated Exposure and Use Patterns

Exposure is the denominator context for interpreting events. It does not turn spontaneous reports into incidence rates unless numerator and denominator arise from a valid common population.

5.1 Cumulative subject exposure in clinical trials

Summarise cumulative trial exposure by indication, age, sex and relevant dose or duration. For a biological, add route, formulation, treatment duration, repeat courses and immunogenicity sampling where material. Long pharmacodynamic effects may require exposure categories that extend beyond the last dose.

5.2 Cumulative and interval patient exposure from marketing experience

Explain the calculation method and limitations. Sales units may be converted into doses, treatment courses or patient-years only with justified assumptions. State whether estimates include free goods, wastage, loading regimens and dose variation.

Stratify mAb-X exposure by IV versus injector presentation and by indication. Without this, an apparent increase in injection-site or incomplete-dose reports after launch of the subcutaneous product would be uninterpretable.

Biosimilar switching adds another problem: prescriptions, dispensing and administration records may identify different products at different reliability levels. Do not count external biosimilar exposure in the holder’s denominator while including only the holder’s reports in the numerator.

Biological exposure hierarchy

Figure 2. Exposure should be estimated at the level needed for the safety question. Active-substance totals support class interpretation; product, route, device and manufacturing-period strata support specific investigations.

Section 6: Data in Summary Tabulations

Summary tabulations provide structured case counts; they do not replace medical evaluation. State the Medical Dictionary for Regulatory Activities (MedDRA) version and the RSI used for expectedness or listedness as applicable.

6.1 Reference information

Identify the coding dictionary and reference document. If product information changed during the interval, explain how historical cases were classified and avoid retrospectively rewriting the original reporting decision.

6.2 Cumulative serious adverse events from clinical trials

Tabulate serious trial events cumulatively. Preserve blinded data where required. Biological-specific stratification may include route, formulation, indication, dose and antidrug-antibody status, but only where study design and sample size make the comparison interpretable.

6.3 Cumulative and interval post-marketing tabulations

Provide cumulative and interval adverse-reaction summary tabulations as required by the format. Product identity may be incomplete in spontaneous cases. State the proportion with confirmed brand and batch rather than creating false precision.

For mAb-X, provide active-substance totals, then a focused presentation-specific analysis of incomplete-dose cases elsewhere. A table containing 18 injector complaints does not establish 18 adverse reactions; complaints without clinical consequence and clinical cases must remain linkable but conceptually distinct.

Section 7: Summaries of Significant Findings from Clinical Trials

Summarise safety-relevant findings, not every study result.

7.1 Completed clinical trials

Explain new findings and their relationship to known risks. For biologicals, include immunogenicity methods, sampling schedule, assay sensitivity, drug tolerance and clinical correlates when antibody data affect interpretation.

7.2 Ongoing clinical trials

Describe important emerging information without compromising trial integrity. An imbalance may remain uncertain while blinded.

7.3 Long-term follow-up

Long follow-up is especially relevant for persistent immune modulation, gene or cell therapies, delayed malignancy, immune deficiency or neonatal effects after pregnancy exposure.

7.4 Other therapeutic use

Include structured programmes such as expanded access where relevant, clearly describing data limitations.

Address combination products when applicable. Do not attribute a combination event automatically to the biological constituent.

mAb-X example: the new-indication trial shows similar infection frequency but shorter exposure and healthier patients. “No increase” is premature unless these differences are acknowledged.

Section 8: Findings from Non-Interventional Studies

A non-interventional study observes treatment under routine practice without assigning therapy according to a trial protocol. Registries, database studies and post-authorisation safety studies may provide larger or more representative populations, but confounding and exposure misclassification remain important.

For biologicals, assess whether data distinguish brands, batches and switching. A database that records only the active substance cannot reliably compare reference and biosimilar products. An immunogenicity registry must link assay results to product sequence, sampling time, concentration and clinical outcome.

In mAb-X, an observational cohort reports more antidrug-antibody positivity after switching. The report should examine assay platform, sampling intensity, baseline antibodies, multiple switching and loss-of-effect outcomes before interpreting a switch effect.

Section 9: Information from Other Clinical Trials and Sources

Include relevant pooled analyses, investigator-sponsored studies, meta-analyses and development-partner information not already presented. Explain overlap so the same patients are not counted as independent evidence.

Biological class data can be useful when target or immune mechanism is shared, but molecular architecture matters. A receptor-fusion protein, monoclonal antibody and antibody–drug conjugate aimed at related biology may not share all risks.

Section 10: Non-Clinical Data

Summarise new non-clinical findings with potential clinical safety relevance. These may include tissue cross-reactivity, cytokine release, reproductive toxicity, juvenile-animal findings, impurity or aggregate studies, device extractables and leachables, or comparability investigations.

A manufacturing-site transfer supported by comparability is not described as a new clinical risk merely because analytical differences are measurable. Explain which quality attributes changed, why they remain within an acceptable range and whether enhanced clinical surveillance was instituted.

mAb-X example: the site transfer shows a small glycan-distribution shift within the justified comparability range and unchanged Fc-function assays. The PBRER records the evidence and surveillance; it does not manufacture an immunogenicity signal.

Section 11: Literature

Describe the search period, databases, strategy and medically important findings. Literature is evaluated, not listed. Biological searches should include INN, brand names, biosimilar suffixes where applicable, target/class terms, immunogenicity, formulation/device and relevant manufacturing or quality concepts.

Single case reports may supply rich timelines but cannot estimate frequency. Mechanistic studies may strengthen plausibility without proving clinical causation. Reviews can orient the assessment, while primary sources should support decisive claims.

Section 12: Other Periodic Reports

Summarise relevant conclusions from periodic reports prepared by another holder, partner, combination-product owner or regional entity, and explain differences in DLP, scope, RSI and conclusions.

For co-developed biologicals, reconciliation is essential. Two reports can reach apparently different conclusions because one includes a subcutaneous formulation or a different indication. The writer should resolve the scope difference rather than merely quote both conclusions.

Section 13: Lack of Efficacy in Controlled Clinical Trials

Lack of efficacy becomes especially important where treatment failure can cause serious or life-threatening outcomes. In biological therapy, apparent failure may reflect target biology, neutralising antibodies, underexposure, device malfunction, storage error, switching gaps or disease heterogeneity.

For mAb-X, separate failure of the molecule to control disease from incomplete injector delivery. In a controlled trial, analyse endpoint definition, rescue treatment, pharmacokinetics, pharmacodynamics and antidrug antibodies. Do not use “drug ineffective” case counts as a surrogate for trial efficacy.

Section 14: Late-Breaking Information

Late-breaking information is important evidence arising after the DLP but before finalisation. The DLP closes the main interval dataset, not scientific responsibility.

State why the information is material, what is known, what remains preliminary and whether immediate action occurred. Avoid silently adding post-DLP cases to interval tables, which breaks reproducibility.

mAb-X example: two serious delayed-hypersensitivity cases arrive after the DLP. They are discussed here and considered in the conclusion, while the Section 6 interval counts remain locked.

Section 15: Overview of Signals

A safety signal is information suggesting a new potentially causal association, or a new aspect of a known association, that warrants further investigation. It is a hypothesis, not proof.

Provide a table of new, ongoing and closed signals with dates, source, status and concise rationale. “Closed” means the signal evaluation process reached a documented conclusion; it does not necessarily mean that no risk exists.

Signal Status at DLP Evidence level Product scope Next step
Delayed hypersensitivity Ongoing Cases + mechanism Both routes Integrated assessment
Incomplete injector dose Closed as device issue Complaint investigation SC lot L17 Field action/effectiveness
Serious infection increase Refuted for interval Registry + trial Active substance Routine monitoring

Biological signal tables should show whether the hypothesis concerns a class/target, active substance, product, batch, formulation or device. This one column prevents many later analytical errors.

Signal attribution levels for biological medicines

Figure 3. The signal question determines the level of attribution. Evidence should be tested across class, active substance, product, batch, formulation and device rather than being forced prematurely into one level.

Section 16: Signal and Risk Evaluation

Section 16 is the main safety reasoning section. It moves from signal inventory to evaluation of signals, known risks and risk-minimisation effectiveness.

16.1 Summary of safety concerns

Present important identified risks, important potential risks and important missing information as applicable to the report and region. Reconcile with the current risk-management plan. A difference requires explanation; copy-forward is not reconciliation.

16.2 Signal evaluation

For each completed signal evaluation, define the question and evidence. Examine case quality, chronology, dechallenge/rechallenge, alternative causes, biological plausibility, dose/exposure, trial and observational data, literature, class evidence, quality complaints and manufacturing periods.

For delayed hypersensitivity with mAb-X, stratify by route and formulation; examine antidrug antibodies, excipients and time to onset. Absence of a batch cluster weakens a batch hypothesis but does not refute an active-substance immune mechanism.

16.3 Evaluation of risks and new information

Evaluate new information for known risks even when no new signal was opened. Has severity, frequency, preventability, risk group or outcome changed? For biologicals, ask whether new presentation or switching changes exposure to the risk.

16.4 Characterisation of risks

Describe frequency where estimable, seriousness, severity, reversibility, preventability, risk factors, mechanism and public-health impact. Separate what is established from what remains uncertain. Spontaneous reporting proportions are not incidence.

16.5 Effectiveness of risk minimisation

Evaluate whether risk-minimisation measures work. Distribution of an educational guide is a process measure; improved vaccination, screening or correct device use is closer to an outcome. Biologicals may require measures for infection screening, infusion monitoring, traceability, pregnancy prevention or device training.

For mAb-X, complaint rates after the injector field correction and observed completion of dosing are more informative than the number of letters distributed.

Section 17: Benefit Evaluation

Benefit evaluation prevents the PSUR from becoming an isolated safety report.

17.1 Important baseline efficacy and effectiveness information

Summarise established benefits by indication and population. Do not reproduce the full clinical overview. State the outcomes that matter for the integrated analysis.

17.2 Newly identified information on efficacy and effectiveness

Discuss new trials, observational effectiveness, durability, resistance, treatment persistence and relevant comparative evidence. Biosimilar comparative studies usually address similarity rather than rediscovering all reference-product benefits.

17.3 Characterisation of benefits

Describe magnitude, durability, affected populations, uncertainty and clinical importance. A statistically significant change may have limited clinical importance; a modest average benefit may be important in a severe disease with few alternatives.

For mAb-X, the new indication has lower baseline severity. Absolute benefit is smaller even if relative effect is similar. This matters when the same serious risk is evaluated across indications.

Section 18: Integrated Benefit–Risk Analysis

18.1 Benefit–risk context: medical need and important alternatives

Set the clinical context by indication. Consider disease seriousness, natural history, untreated outcomes, alternatives and affected populations. The same biological can have different benefit–risk balances across indications.

18.2 Benefit–risk analysis evaluation

Integrate—not merely repeat—Sections 16 and 17. Explain which benefits and risks drive the conclusion, how uncertainty affects confidence, and whether subgroups, routes or presentations differ. A numerical score is not required unless a justified method is used.

The writer can use a structured matrix:

Dimension Disease 1 Disease 2 Biological-specific interpretation
Benefit magnitude Large Moderate Different baseline severity
Serious infection Stable Limited exposure Class/target risk remains
Delayed hypersensitivity Emerging Emerging Possible product-wide immune risk
Injector failure Not applicable Lot-specific Presentation risk, not molecule failure
Uncertainty Moderate High New indication and short follow-up

The conclusion might remain favourable for both indications while supporting label evaluation for delayed hypersensitivity and continued effectiveness monitoring of the device action. “Favourable” does not mean risk-free; it means that benefits outweigh risks under the authorised conditions with stated uncertainties and controls.

From evidence to action in a biological PBRER

Figure 4. The final conclusion emerges by integrating risk, benefit, uncertainty, product scope and risk-minimisation effectiveness. It should lead to explicit actions rather than a generic favourable statement.

Section 19: Conclusions and Actions

State whether the benefit–risk balance changed and specify actions. Possible actions include RSI or regional-label change, RMP update, additional pharmacovigilance, additional risk minimisation, quality/device action, study amendment, targeted follow-up or routine monitoring.

Separate proposal from completed action. Assign owner and expected route of implementation outside the report where company governance requires it.

For mAb-X:

Section 20: Appendices

Include the appendices required by ICH and regional rules, such as reference information, signal tabulations and study listings. The EU regional appendix contains EU-specific information required by GVP.

Appendices must reconcile with the body. A signal cannot be “ongoing” in one table and “closed” in the narrative without explaining the date or governance transition. Product names, DLPs and exposure totals should be consistent.

For biologicals, supplementary tables may show brand/batch completeness, formulation and route exposure, switching sequences, immunogenicity assay context or quality-event linkage. Include them only when they clarify the evaluation; do not bury the main conclusion in an appendix.

Authoring, review and governance

Section-to-source planning matrix

PBRER area Principal owner/source Biological-specific check
Approval status/RSI Regulatory affairs Brand, route, device and jurisdiction
Exposure Epidemiology/commercial/clinical Denominator assumptions and product strata
Cases/tabulations Safety database Brand/batch completeness and duplicates
Trials/studies Clinical/epidemiology Immunogenicity assays and switching
Non-clinical/quality Quality/non-clinical Comparability and manufacturing periods
Signals/risks Safety science Correct attribution level
Benefits Clinical/medical Indication and population differences
Actions Governance functions Traceability to evidence and owner

Medical-review questions

The medical reviewer should be able to answer:

  1. What changed during the interval?
  2. Which level of biological identity does each finding concern?
  3. Are numerator and denominator compatible?
  4. Were immunogenicity measurements linked to clinical outcomes?
  5. Were quality, device and safety systems reconciled?
  6. Are class data relevant to this molecular architecture?
  7. Did new evidence alter severity, frequency, preventability or affected population?
  8. Do risk, benefit and action sections reach the same conclusion?

QPPV and governance perspective

The QPPV does not write every section personally. Oversight means ensuring that material safety and benefit evidence reached the report, major disagreements are visible, conclusions are supported, proposed actions enter controlled governance, and late information is handled appropriately.

An inspection-ready evidence trail includes the authoring plan, data requests, source outputs, analyses, medical comments, reconciliation records, review decisions, version history and approval. It should show why a conclusion was reached, not merely who signed it.

Common failure modes

These are illustrative quality failures, not reported inspection findings.

Key Takeaways

References

  1. International Council for Harmonisation. ICH E2C(R2): Periodic Benefit-Risk Evaluation Report. 2012. https://database.ich.org/sites/default/files/E2C_R2_Guideline.pdf.
  2. International Council for Harmonisation. ICH E2C(R2) Questions and Answers. Current implementation material. https://www.ich.org/page/efficacy-guidelines.
  3. European Medicines Agency. Guideline on good pharmacovigilance practices: 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.
  4. European Medicines Agency. Explanatory Note to GVP Module VII (Rev. 4). Updated 22 May 2026. https://www.ema.europa.eu/en/events/psur-roadmap-joint-industry-assessor-training.
  5. European Medicines Agency. GVP Product- or Population-Specific Considerations II: Biological medicinal products. EMA/168402/2014; legally effective 16 August 2016. https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/good-pharmacovigilance-practices-gvp.
  6. European Medicines Agency. Periodic safety update reports: questions and answers and EU reference dates list. Current procedural information. https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/periodic-safety-update-reports-psurs.
  7. European Parliament and Council. Directive 2001/83/EC, as amended, Articles 107b–107g.
  8. European Parliament and Council. Regulation (EC) No 726/2004, as amended, Article 28.
  9. QPPV.com. GVP Module VII: Writing the PSUR Safety Evaluation.
  10. QPPV.com. GVP Product- or Population-Specific Considerations II: Biological Medicinal Products.

Regulatory Note

This article is an educational interpretation of the PBRER/PSUR framework, not a substitute for current legislation, ICH guidance, EU GVP, the applicable EU reference-date list, submission instructions or product-specific regulatory conditions. The fictional mAb-X examples illustrate reasoning and do not represent an authorised product, regulatory precedent or mandatory wording.

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