A PBRER is not simply a periodic collection of case reports, signals, and literature findings. When preparing a PBRER for medicinal products, the most challenging aspect is transforming heterogeneous sources into a coherent, clinically sound, and defensible benefit-risk evaluation. A complete but uninterpreted table, or a conclusion that is not supported by the underlying data, can compromise the quality of the entire document.
For Marketing Authorization Holders (MAHs) and companies managing complex portfolios, the PBRER also serves as evidence of the maturity of the pharmacovigilance system. It demonstrates the ability to identify new information, assess its impact, and, when necessary, translate it into concrete risk minimization measures or updates to product documentation.
Writing PBRERs for medicinal products: starting with the correct scope
The PBRER (Periodic Benefit-Risk Evaluation Report) follows the principles of ICH E2C(R2) and, within the European framework, is governed by the Good Pharmacovigilance Practices (GVP), particularly Module VII. Its objective is not to confirm that a medicinal product is absolutely safe, but to periodically reassess its benefit-risk profile in light of all evidence available during the reporting interval.
The first operational priority is to clearly define the scope of the report: the Data Lock Point, reporting interval, medicinal products and active substances covered, authorized indications, relevant populations, and regulatory status across different countries. Errors at this stage can propagate throughout the document, creating inconsistencies between exposure data, safety information, regulatory actions, and conclusions.
It is also important to distinguish the PBRER from other documents with different purposes. The DSUR relates to clinical development and follows a specific approach for investigational medicinal products; the Risk Management Plan describes and plans risk management activities; the PSUR is the term historically used in Europe for the periodic report and is now generally structured according to the PBRER format. While some overlap exists, their objectives, content, and timelines are not interchangeable.
The 1uality of a PBRER depends on the data before it depends on the writing
Effective report preparation begins long before medical writing activities. The final document can only be clear and well structured if the underlying sources have been collected, verified, and reconciled through a documented process.
Key sources include individual safety data from spontaneous reports and support programs, scientific literature, clinical and non-interventional studies, registries, utilization or exposure data, Medical Information data, quality complaints potentially relevant to safety, and regulatory decisions taken in other markets. These sources are complemented by signal management activities, efficacy data emerging during the reporting period, and updates to labeling or the safety profile.
The challenge is not simply collecting all available information. It is ensuring that the different sources speak the same language. Discrepancies between pharmacovigilance databases, commercial systems, clinical reports, regulatory documentation, and Safety Data Exchange Agreements are common. These differences may involve MedDRA coding, dates, case counts, follow-up status, estimated exposure, or risk classification.
For this reason, it is useful to formalize a data reconciliation process before writing begins. This includes cross-checking sources, versions used, inclusion criteria, and approval responsibilities. Traceability is not merely an administrative exercise. It is what makes it possible to explain where each data point originated and why a particular clinical assessment was made.
From case presentation to medical evaluation
One of the most common mistakes is confusing description with analysis. Reporting the number of ICSRs, serious adverse events, or reporting frequencies does not constitute an evaluation of the safety profile.
Medical assessment requires context. For each important identified risk, potential risk, and missing information, consideration should be given to trends over time, severity and reversibility of the event, biological plausibility, temporal relationship, possible dechallenge or rechallenge, confounding factors, exposed populations, and the effect of measures already implemented. Even the absence of new findings should be discussed proportionately and supported by an actual review of the available data, rather than by generic statements.
Quantitative analysis can strengthen interpretation, but it cannot replace clinical judgment. For example, an increase in the absolute number of reports may result from increased exposure, a change in the reporting channel, media attention surrounding an event, or a shift in the treated population. Conversely, a low number of reports does not exclude a clinically significant risk in vulnerable subgroups.
The same principle applies to efficacy. Within a PBRER, efficacy data become relevant when they have the potential to modify the overall benefit assessment, such as new real-world evidence, loss of efficacy, emergence of resistance, changes in the therapeutic landscape, or findings that redefine benefits within specific populations. Including irrelevant efficacy data unnecessarily burdens the report; omitting data that alter the clinical context weakens the benefit-risk evaluation.
A structure that makes the reasoning verifiable
The structure defined by the ICH guidelines should not be viewed as a checklist to complete. Each section supports the next, moving from product information and regulatory status, through exposure data, safety-related actions, information from studies and literature, and finally to the integrated evaluation of benefits and risks.
Narrative sections should remain consistent with the Company Core Data Sheet, Summary of Product Characteristics (SmPC), package leaflet, and applicable Risk Management Plan. If the PBRER describes an event as a potential risk while the RMP classifies it as an identified risk, or if it describes an action that is not reflected in product documentation, the discrepancy requires explanation and often formal alignment.
Particular attention should be paid to the conclusions section. It should not merely state that the benefit-risk balance remains favorable. It should answer specific questions: What new data emerged? Did these data change the nature, frequency, severity, or preventability of a risk? Did they affect the exposed population or the expected benefit? Are additional pharmacovigilance activities, further risk minimization measures, labeling changes, or additional analyses required?
When the answer is negative, the rationale should be explicit. When the answer is positive, the action plan should be proportionate, assigned, and verifiable.
Governance, roles, and version control
A PBRER typically involves Pharmacovigilance, Medical Affairs, Regulatory Affairs, Quality Assurance, Clinical functions, Epidemiology or Biostatistics teams, and, in some cases, local affiliates and external partners. Without clear governance, a last-minute rush before submission becomes almost inevitable.
An effective project plan defines deliverables, sources, data owners, internal deadlines, review workflows, and approval criteria from the beginning. Reviews should focus on distinct aspects: data accuracy, medical and scientific robustness, regulatory consistency, editorial quality, and compliance with the applicable template. Relying on a single generic review increases the likelihood that significant issues will be overlooked.
Version control is equally important. Comments, changes to tables, late updates to case line listings, or new regulatory decisions must be managed transparently. The objective is not to eliminate all changes, but to ensure that no unevaluated modification alters conclusions that have already been approved.
When to seek specialist support
Outsourcing the preparation of a PBRER can be particularly valuable when internal teams face workload peaks, have limited resources for mature products, manage multiple international procedures, or require integrated expertise across pharmacovigilance, literature research, medical writing, and regulatory affairs. This is not about delegating the MAH’s responsibility, but about building a controlled operational capability.
The value of a specialized partner lies in the ability to work with traceable sources, understand the clinical rationale behind safety data, and coordinate with company functions without disrupting existing workflows. For organizations with variable needs, a scalable support model can reduce internal workload while maintaining methodological consistency and document quality.
Eureka InfoMed supports these activities through integrated expertise in pharmacovigilance, literature research, and medical writing, acting as a qualified extension of company teams during data collection, evaluation, and document finalization.
A well-constructed PBRER makes a complex decision understandable. It shows not only what data were available, but also how those data were evaluated and which operational consequences resulted from that evaluation. It is through this clarity, maintained from the initial reconciliation process to final approval, that compliance becomes a reliable process rather than a last-minute verification exercise.
Sources
- International Council for Harmonisation (ICH). ICH E2C(R2) Periodic Benefit-Risk Evaluation Report (PBRER).
- European Medicines Agency (EMA). Good Pharmacovigilance Practices (GVP), Module VII – Periodic Safety Update Report.
- International Council for Harmonisation (ICH). ICH E2D Post-Approval Safety Data: Definitions and Standards for Expedited Reporting.
- European Medicines Agency (EMA). Guideline on Good Pharmacovigilance Practices (GVP), Module IX – Signal Management.