Periodic Benefit-Risk Evaluation Reports (PBRER)

Introduction

The Periodic Benefit-Risk Evaluation Report (PBRER) is one of the most comprehensive scientific documents prepared during the post-authorisation lifecycle of a medicinal product. Unlike individual safety case reports, which describe isolated adverse events, or Risk Management Plans, which describe prospective strategies for monitoring and minimising important risks, the PBRER provides a periodic, integrated assessment of whether the overall benefit-risk balance of a medicinal product remains favourable in light of all available evidence.

Preparation of a PBRER requires considerably more than assembling information from different pharmacovigilance activities. It is a process of scientific evaluation in which clinical data, spontaneous adverse event reports, epidemiological evidence, published literature, regulatory actions, non-clinical findings and product utilisation data are interpreted together to determine whether the medicinal product continues to provide benefits that outweigh its known and potential risks.

For this reason, experienced aggregate report authors rarely view the PBRER as simply another regulatory submission. Instead, they consider it to be a periodic scientific review of the evolving safety profile of a medicinal product. Every section of the report contributes to an overarching assessment that culminates in the integrated benefit-risk evaluation. Individual observations are therefore not interpreted in isolation but in the context of cumulative knowledge accumulated since the product first entered clinical development and throughout its post-marketing lifecycle.

The PBRER also serves an important regulatory purpose. Health authorities cannot continuously review every individual adverse event received worldwide for every authorised medicinal product. Instead, they rely upon periodic aggregate reports to provide a structured, balanced and evidence-based assessment prepared by the marketing authorisation holder. The report therefore becomes an important mechanism through which regulators evaluate whether new risks have emerged, whether known risks remain adequately characterised, whether existing risk minimisation measures continue to be appropriate and whether the overall benefit-risk balance remains favourable.

Producing a high-quality PBRER requires expertise that extends beyond pharmacovigilance operations. Medical judgement, epidemiology, clinical pharmacology, regulatory science and scientific writing all contribute to preparation of the final document. Experienced reviewers recognise that the value of a PBRER lies not in the quantity of data presented but in the quality of the interpretation and the strength of the scientific arguments supporting the conclusions.

This guide explains not only the regulatory framework governing PBRERs but also the scientific principles, practical workflows and medical reasoning that underpin their preparation. Subsequent articles within this section examine individual components of the report in greater depth and provide practical guidance for authors, reviewers, quality control specialists and QPPVs.

Why Periodic Benefit-Risk Evaluation Reports Exist

Modern pharmacovigilance recognises that the safety profile of a medicinal product continues to evolve throughout its commercial lifecycle. At the time of marketing authorisation, knowledge regarding product safety is necessarily incomplete. Clinical development programmes are designed primarily to demonstrate efficacy and establish an acceptable safety profile under controlled conditions. They cannot identify every adverse reaction, quantify every potential risk or fully evaluate safety across every population likely to receive the product in routine clinical practice.

Following marketing authorisation, medicinal products are exposed to substantially larger and more diverse patient populations. Individuals with multiple comorbidities, concomitant medications, advanced age, pregnancy, organ impairment or prolonged treatment durations may receive the product despite limited representation during clinical trials. As cumulative exposure increases, uncommon adverse reactions, delayed toxicities and population-specific risks may become apparent.

The objective of periodic aggregate reporting is therefore not merely to summarise new adverse events received during the reporting interval. Rather, it is to evaluate whether new information changes the current understanding of the medicinal product's safety profile and whether that new knowledge alters the overall benefit-risk balance.

This distinction is fundamental. A well-written PBRER does not simply answer the question, "What happened during this reporting period?" Instead, it addresses the more important regulatory question, "What have we learned during this reporting period, and does that new knowledge change how the medicinal product should be used?"

Accordingly, the report integrates information generated by numerous pharmacovigilance activities. Signal management may identify emerging safety concerns. Medical literature may provide new evidence regarding established risks. Post-authorisation safety studies may characterise specific adverse reactions more precisely. Regulatory authorities may request changes to product information or implementation of additional risk minimisation measures. Clinical studies may generate new efficacy data that influence the interpretation of product benefits. The PBRER provides the framework within which these diverse sources of information are evaluated collectively rather than independently.

The emphasis on benefit-risk evaluation also distinguishes the PBRER from earlier approaches to periodic safety reporting. Rather than concentrating exclusively on adverse reactions, modern aggregate reports seek to determine whether the overall therapeutic value of the medicinal product remains favourable when both benefits and risks are considered together. This reflects the fundamental regulatory principle that medicines should not be evaluated solely according to their risks but according to the balance between expected therapeutic benefit and potential harm.

Historical Development of Periodic Safety Reporting

Periodic safety reporting has evolved considerably over the past three decades. Early periodic reports were largely descriptive documents intended to summarise adverse drug reactions received during defined reporting intervals. Although these reports provided valuable surveillance information, they frequently focused on the accumulation of safety data rather than interpretation of its clinical significance.

As pharmacovigilance systems matured and regulatory expectations evolved, it became increasingly apparent that periodic reports should support decision making rather than simply provide summaries of available information. Regulators required reports that integrated multiple sources of evidence, critically evaluated emerging safety concerns and explained whether new information affected the overall benefit-risk profile of the medicinal product.

These developments culminated in the adoption of the ICH E2C(R2) guideline, which introduced the concept of the Periodic Benefit-Risk Evaluation Report. The revised guideline shifted emphasis away from periodic safety summaries towards periodic scientific evaluation. The report was redesigned to encourage integration of efficacy information where relevant, structured assessment of important safety concerns and explicit discussion of the product's overall benefit-risk balance.

Within the European Union, the concepts described in ICH E2C(R2) were incorporated into Good Pharmacovigilance Practices (GVP) Module VII. Although the European regulatory framework retains the legal term Periodic Safety Update Report (PSUR), reports prepared in accordance with GVP Module VII follow the scientific principles and structure described within the ICH PBRER guideline. Consequently, the terms PSUR and PBRER are frequently encountered together in European pharmacovigilance practice. Understanding the relationship between these terms is important for anyone involved in aggregate report preparation, as the legal terminology and the scientific reporting framework have evolved from different regulatory traditions while ultimately serving the same objective of periodic benefit-risk evaluation.

The Regulatory Framework for PBRERs

Preparation of Periodic Benefit-Risk Evaluation Reports is governed by a combination of international guidelines, European Union legislation and detailed pharmacovigilance guidance. Understanding how these documents interact is important because each serves a different purpose. The legal obligations requiring periodic reporting are established through legislation, while the scientific principles governing report preparation are described within international guidelines and Good Pharmacovigilance Practices (GVP).

For organisations marketing medicinal products globally, the PBRER represents one of the most internationally harmonised pharmacovigilance activities. Most major regulatory authorities recognise the value of preparing a single scientific assessment that can be adapted to satisfy regional regulatory requirements. Nevertheless, regional differences remain regarding submission schedules, procedural requirements and administrative processes. Aggregate report authors therefore need to distinguish between the globally harmonised scientific content of a PBRER and the region-specific regulatory requirements governing its submission.

Within the European Union, this distinction is particularly important. Although the legal framework continues to use the term Periodic Safety Update Report (PSUR), the expected scientific content is based largely upon the ICH E2C(R2) guideline for the Periodic Benefit-Risk Evaluation Report. Consequently, an EU PSUR is effectively prepared using the PBRER structure and scientific philosophy described by ICH, while simultaneously complying with European procedural requirements described within GVP Module VII.

This combination of international harmonisation and regional implementation has enabled pharmaceutical companies to prepare scientifically consistent reports for multiple regulatory authorities while allowing individual jurisdictions to maintain their own submission procedures and assessment processes.

ICH E2C(R2): The Scientific Foundation of the PBRER

The International Council for Harmonisation (ICH) developed Guideline E2C to promote a consistent approach to periodic post-authorisation safety reporting across major regulatory regions. Earlier versions of the guideline focused primarily on periodic summaries of safety information. However, increasing recognition that regulatory decision-making depends upon balanced evaluation rather than simple data accumulation led to substantial revision of the guideline.

The revised ICH E2C(R2) guideline introduced the concept of the Periodic Benefit-Risk Evaluation Report. The emphasis shifted from producing a periodic catalogue of adverse reactions to performing an integrated scientific assessment of the medicinal product's evolving benefit-risk profile.

This conceptual change had important implications for aggregate report preparation. Rather than presenting isolated safety findings, authors were expected to evaluate evidence from multiple sources, consider the clinical significance of emerging information and explain how new knowledge influenced the overall understanding of the product.

The guideline also encouraged greater integration between pharmacovigilance activities. Information generated through signal management, post-authorisation safety studies, epidemiological investigations, literature surveillance, clinical trials and regulatory interactions should not be discussed independently. Instead, these activities contribute collectively to understanding the current benefit-risk profile of the medicinal product.

Although the ICH guideline provides the scientific framework, it deliberately avoids prescribing every procedural detail. Individual regulatory authorities remain responsible for defining submission schedules, assessment procedures and administrative requirements appropriate for their jurisdictions.

GVP Module VII

Within the European Union, Good Pharmacovigilance Practices Module VII provides detailed guidance regarding the preparation, submission and assessment of periodic safety reports. While the legal terminology refers to Periodic Safety Update Reports, the scientific content expected by GVP Module VII reflects the principles established by ICH E2C(R2).

Module VII describes considerably more than the structure of the report itself. It explains the objectives of periodic reporting, the responsibilities of marketing authorisation holders, the interaction between periodic reports and other pharmacovigilance activities, submission procedures, assessment processes and regulatory expectations throughout the product lifecycle.

One of the strengths of GVP Module VII is its emphasis on scientific evaluation rather than administrative compliance. Authors are encouraged to interpret available evidence critically rather than simply compiling data from multiple sources. Throughout the guidance, emphasis is placed upon medical judgement, balanced discussion and clear justification of conclusions.

GVP Module VII also reinforces an important principle that is frequently overlooked by inexperienced report authors. The objective of a periodic report is not to repeat information already available elsewhere within the pharmacovigilance system. Instead, it should explain how newly available evidence contributes to the current understanding of the medicinal product and whether that information changes the benefit-risk balance or the need for regulatory action.

European Union Legal Basis

The obligation to prepare periodic safety reports is established through European pharmaceutical legislation rather than through GVP itself.

Directive 2001/83/EC, Regulation (EC) No 726/2004 and Commission Implementing Regulation (EU) No 520/2012 collectively establish the legal framework governing pharmacovigilance activities within the European Union. These legislative instruments define the responsibilities of marketing authorisation holders, specify reporting obligations and provide the legal authority for the preparation, submission and assessment of periodic safety reports.

Good Pharmacovigilance Practices should therefore be viewed as detailed implementation guidance supporting the legislative framework rather than replacing it. During inspections, organisations are expected not only to prepare reports that comply scientifically with GVP Module VII but also to demonstrate compliance with the underlying legal obligations established through European legislation.

Understanding this relationship assists aggregate report authors in distinguishing mandatory legal requirements from guidance describing acceptable methods of compliance.

PSUR Versus PBRER

Few topics generate more confusion among new aggregate report authors than the distinction between the terms PSUR and PBRER. Although they are often used interchangeably in everyday pharmacovigilance practice, they originate from different regulatory contexts.

Historically, the Periodic Safety Update Report represented the standard format for periodic post-authorisation reporting within many regulatory jurisdictions, including the European Union. Earlier PSURs concentrated primarily on summarising cumulative safety experience and describing adverse drug reactions reported during defined reporting periods.

The introduction of ICH E2C(R2) expanded the scope of periodic reporting considerably. The revised guideline recognised that meaningful regulatory decision-making requires integrated evaluation of both benefits and risks rather than consideration of safety data alone. Consequently, the Periodic Benefit-Risk Evaluation Report was developed as a broader scientific assessment incorporating safety information, efficacy data where relevant and explicit evaluation of the overall benefit-risk balance.

Within the European Union, however, existing pharmaceutical legislation continued to use the legally established term Periodic Safety Update Report. Rather than creating an entirely new legal reporting category, European regulators incorporated the scientific principles of the PBRER into the existing PSUR framework through GVP Module VII.

As a result, reports submitted within the European Union are legally referred to as PSURs but are scientifically prepared according to the PBRER principles described within ICH E2C(R2). In practical terms, most pharmacovigilance professionals preparing European periodic reports follow the PBRER structure while complying with EU PSUR submission procedures.

Understanding this distinction helps explain why European guidance frequently uses both terms within the same regulatory context and why international discussions often refer simply to PBRERs when describing the scientific methodology underlying modern periodic reporting.

When is a PBRER Required?

Periodic benefit-risk evaluation is not performed simply because a predefined amount of time has elapsed since the previous report. Rather, it forms part of the lifecycle surveillance of authorised medicinal products and is intended to provide regulators with periodic opportunities to reassess the overall benefit-risk balance using cumulative worldwide experience.

Within the European Union, the legal requirement to submit a periodic report depends upon several factors, including the type of marketing authorisation, the age of the product, applicable legislation and, most importantly, the European Union Reference Date (EURD) List. Consequently, preparation of a PBRER is no longer determined solely by fixed reporting frequencies established at the time of authorisation. Instead, reporting schedules are increasingly harmonised across products containing the same active substance.

The frequency of reporting may therefore change during the lifecycle of a medicinal product. Newly authorised products often require more frequent periodic evaluation because clinical experience remains limited and uncertainties regarding the safety profile are greater. As cumulative exposure increases and the product becomes better characterised, reporting intervals may be extended where appropriate. Conversely, emerging safety concerns or specific regulatory decisions may require more frequent reporting for particular products or active substances.

Marketing Authorisation Holders should therefore regard periodic reporting as a dynamic regulatory obligation rather than a static administrative requirement. Effective aggregate reporting systems include processes for monitoring changes to reporting schedules, tracking regulatory decisions and ensuring that preparation activities begin sufficiently in advance of each Data Lock Point.

The European Union Reference Date (EURD) List

One of the most important developments in European pharmacovigilance has been the introduction of the European Union Reference Date List, commonly referred to as the EURD List.

Before implementation of the EURD system, different Marketing Authorisation Holders frequently submitted periodic reports for the same active substance on different dates. This fragmented approach resulted in multiple independent assessments of similar safety information and placed considerable demands on both regulators and industry.

The EURD List was introduced to harmonise reporting across the European Union. For each active substance or combination of active substances, the list specifies the European Union Reference Date together with the frequency of periodic reporting and the applicable Data Lock Points. As a result, all Marketing Authorisation Holders responsible for medicinal products containing the same active substance generally prepare reports using the same reporting schedule.

This harmonisation offers important scientific advantages. When multiple products containing the same active substance are assessed simultaneously, regulators can evaluate the cumulative worldwide safety experience more comprehensively than would be possible through isolated product-specific reviews. Emerging safety concerns, class effects and changes to the benefit-risk profile can therefore be considered consistently across all relevant products.

For Marketing Authorisation Holders, however, the EURD List introduces operational challenges. Companies must maintain procedures for monitoring updates to the list, evaluating their impact on reporting schedules and implementing any necessary changes to planning activities. Aggregate reporting teams therefore work closely with regulatory affairs functions to ensure that reporting obligations remain current throughout the product lifecycle.

Data Lock Points

Every periodic report is prepared using information available up to a defined cut-off date known as the Data Lock Point (DLP).

The Data Lock Point represents one of the most important operational concepts in aggregate reporting because it establishes the boundary between data included within the current report and information deferred until the next reporting cycle. Consistent application of the Data Lock Point ensures that all analyses, cumulative summaries and benefit-risk evaluations are based upon the same dataset.

Although simple in principle, management of the Data Lock Point requires careful coordination across multiple pharmacovigilance activities. Individual Case Safety Reports, literature surveillance, signal management activities, clinical studies, post-authorisation safety studies, regulatory actions and product information updates must all be reconciled against the same reporting period. Aggregate report teams therefore spend considerable effort confirming that data extraction, database reconciliation and quality control activities have been completed before preparation of the scientific assessment begins.

An important practical consideration is that the Data Lock Point does not represent the report submission date. Considerable work remains after the reporting period closes, including data validation, medical review, scientific writing, quality control, regulatory review and final approval. Large multinational organisations frequently begin planning several months before the Data Lock Point to ensure that sufficient resources are available once the reporting interval closes.

The PSUR Single Assessment (PSUSA)

The introduction of the PSUR Single Assessment procedure represents one of the most significant regulatory developments affecting periodic reporting within the European Union.

Where multiple Marketing Authorisation Holders market products containing the same active substance, it would be inefficient for each periodic report to undergo separate independent scientific assessment by different Member States. The PSUR Single Assessment procedure addresses this problem by providing a coordinated scientific evaluation for all relevant products covered by the same reporting cycle.

During the PSUSA procedure, a designated Rapporteur performs the primary scientific assessment on behalf of the European regulatory network. The assessment considers cumulative evidence relating to all products containing the active substance and may result in recommendations affecting product information, pharmacovigilance activities, risk minimisation measures or future reporting requirements.

The PSUSA procedure therefore extends beyond review of an individual company's report. It represents a coordinated assessment of the active substance itself, taking into account the totality of available evidence from all relevant Marketing Authorisation Holders. Authors preparing European periodic reports should recognise that their scientific conclusions contribute to a broader regulatory evaluation rather than existing in isolation.

The EMA PSUR Repository

To support harmonised submission and assessment of periodic reports, the European Medicines Agency operates the PSUR Repository.

The repository functions as the central electronic submission platform for Periodic Safety Update Reports within the European Union. Marketing Authorisation Holders submit reports electronically through the repository, allowing the same report to be accessed by all competent authorities participating in the assessment procedure.

The introduction of the repository has substantially reduced administrative duplication and improved consistency in regulatory review. Rather than submitting separate reports to multiple national authorities, companies prepare a single electronic submission that becomes available to the relevant assessors through the central repository.

Although the repository simplifies submission logistics, it does not reduce the scientific expectations placed upon the report itself. Authors remain responsible for ensuring that the submitted document presents a balanced, scientifically justified and regulatorily compliant evaluation of the product's benefit-risk profile.

Responsibilities of the Marketing Authorisation Holder

Preparation of a PBRER is a multidisciplinary activity requiring coordination across numerous functional areas. Although responsibility for medical writing frequently rests with dedicated aggregate report teams, successful preparation depends upon contributions from pharmacovigilance operations, signal management specialists, epidemiologists, biostatisticians, regulatory affairs professionals, clinical development teams and product experts.

The Marketing Authorisation Holder is responsible for establishing governance processes that ensure periodic reports are prepared according to applicable regulatory requirements, submitted within the required timelines and supported by robust quality management procedures. This responsibility extends beyond preparation of the report itself and includes maintenance of planning systems, document management, version control, review workflows and regulatory submission processes.

Because periodic reports frequently integrate information generated throughout the pharmacovigilance system, organisations should ensure that communication pathways exist between aggregate reporting teams and other safety functions. Signal assessments, Risk Management Plan updates, post-authorisation studies and regulatory actions should all be evaluated for their potential impact on the current reporting cycle.

The Role of the QPPV

Although the Qualified Person Responsible for Pharmacovigilance is not necessarily the primary author of a PBRER, the QPPV occupies an important oversight role within the aggregate reporting process.

The QPPV should maintain awareness of the organisation's periodic reporting programme, including reporting schedules, significant safety issues, major scientific conclusions and important regulatory commitments arising from completed assessments. During inspections, regulators frequently expect the QPPV to demonstrate familiarity with significant findings described within recent periodic reports and to explain how those findings have influenced wider pharmacovigilance activities.

The PBRER should therefore not be viewed as an isolated regulatory submission. It forms an integral component of the overall pharmacovigilance system and should be considered alongside signal management, risk management planning, benefit-risk evaluation, regulatory intelligence and ongoing safety surveillance. Effective QPPV oversight helps ensure that conclusions arising from periodic reports are translated into appropriate pharmacovigilance actions and organisational decision-making where necessary.

The Philosophy of Aggregate Medical Review

The preparation of a Periodic Benefit-Risk Evaluation Report is fundamentally different from the processing of Individual Case Safety Reports or the assessment of individual safety signals. Whereas individual case review focuses on understanding a single clinical event, aggregate report writing requires the reviewer to examine the entire body of evidence accumulated for a medicinal product and determine whether that evidence changes the current understanding of its safety profile or overall therapeutic value.

This distinction cannot be overemphasised. A PBRER is not a collection of adverse event summaries assembled into a regulatory template. It is a scientific review document in which evidence from multiple pharmacovigilance activities is critically evaluated, interpreted and integrated into a coherent medical assessment. The quality of a PBRER therefore depends less upon the quantity of information presented than upon the quality of the medical judgement applied throughout the report.

Experienced aggregate report physicians often describe their role as one of scientific synthesis. Every reporting period generates information from numerous independent sources, including spontaneous reports, signal evaluations, post-authorisation safety studies, medical literature, regulatory interactions, product information updates and clinical investigations. Each source provides only a partial view of the medicinal product's evolving safety profile. The responsibility of the aggregate report author is to integrate these separate observations into a balanced assessment that explains what has changed, why it matters and whether any action is required.

This process requires considerably more than technical knowledge of pharmacovigilance regulations. It demands clinical reasoning, familiarity with epidemiological principles, understanding of disease natural history, appreciation of therapeutic context and the ability to distinguish clinically meaningful observations from random variation. Consequently, preparation of high-quality PBRERs is generally regarded as one of the most intellectually demanding activities performed within pharmacovigilance.

Moving Beyond Data Compilation

One of the most common misconceptions among inexperienced aggregate report authors is that completeness alone determines report quality. This often results in lengthy documents containing extensive tables, numerous case summaries and detailed descriptions of individual observations without providing meaningful interpretation.

Regulators rarely require additional pages of descriptive information. Instead, they seek answers to scientific questions. Does the newly available evidence alter the understanding of an identified risk? Has uncertainty surrounding a potential risk been reduced? Does cumulative experience suggest that current risk minimisation measures remain appropriate? Has new efficacy information influenced the overall benefit-risk balance? These questions cannot be answered simply by presenting data. They require thoughtful interpretation supported by scientific evidence.

An experienced reviewer therefore approaches each section of the report by asking what decision the available information supports rather than what information is available to describe. This subtle difference profoundly influences the style and structure of the final document. Tables become supporting evidence rather than the principal message. Individual case descriptions illustrate scientific conclusions rather than replace them. Throughout the report, interpretation takes precedence over description.

For this reason, many organisations encourage authors to write the discussion before finalising the supporting tables. The scientific argument should drive presentation of the evidence rather than allowing the evidence to become a disconnected catalogue of observations.

Medical Judgement in Aggregate Reporting

Medical judgement is the defining characteristic of a high-quality PBRER. While statistical analyses, cumulative tabulations and signal assessments provide important information, none of these activities independently determines whether the benefit-risk balance of a medicinal product has changed. That responsibility ultimately rests upon clinical interpretation.

Medical judgement begins with an understanding of the disease being treated. The significance of an adverse reaction cannot be assessed without considering the severity of the underlying condition, the availability of alternative therapies, the characteristics of the treated population and the expected therapeutic benefits. A serious adverse reaction occurring during treatment of a self-limiting condition may have very different implications from the same reaction occurring during treatment of an aggressive malignancy.

Similarly, aggregate report authors must recognise that medicines are not evaluated in isolation. The benefit-risk balance always reflects comparison between therapeutic benefit and potential harm. A medicinal product associated with serious adverse reactions may nevertheless maintain a highly favourable benefit-risk profile if it provides substantial clinical benefit in a life-threatening disease. Conversely, relatively minor safety concerns may assume greater importance when equally effective and safer therapeutic alternatives are available.

Medical judgement therefore requires continuous consideration of clinical context rather than isolated interpretation of adverse event data.

Understanding the Totality of Evidence

No single source of pharmacovigilance information provides a complete understanding of a medicinal product's safety profile. Individual Case Safety Reports provide early warning of potential adverse reactions but often contain incomplete information and cannot establish incidence. Clinical trials provide carefully documented observations but usually involve selected patient populations and relatively limited exposure. Medical literature may offer detailed analyses but frequently reflects unusual cases or specialised clinical settings. Epidemiological studies provide population-level evidence but may be influenced by confounding factors and limitations in data quality.

The aggregate report author must therefore evaluate the totality of evidence rather than relying excessively upon any individual source.

This principle is reflected throughout modern pharmacovigilance practice. Signal management, Risk Management Plans, Post-Authorisation Safety Studies and periodic reports all seek to integrate information obtained from multiple complementary activities. The PBRER represents the point at which these diverse sources converge into a single scientific assessment.

When different sources produce consistent findings, confidence in the conclusions generally increases. Conversely, conflicting observations require careful exploration. Differences may arise because of study design, patient populations, exposure duration, reporting behaviour or underlying disease characteristics. The objective of the aggregate report is not to eliminate uncertainty but to explain it transparently and evaluate its impact on the overall benefit-risk balance.

Distinguishing Signal Detection from Benefit-Risk Evaluation

Another common misunderstanding is the assumption that periodic reports exist primarily to identify new safety signals. In reality, signal detection and periodic benefit-risk evaluation are closely related but distinct pharmacovigilance activities.

Signal management focuses on identifying and evaluating new or changing safety concerns. The objective is to determine whether available evidence supports a previously unrecognised association between a medicinal product and an adverse event or whether existing knowledge regarding a recognised risk should be modified.

The PBRER, by contrast, adopts a much broader perspective. It considers not only emerging signals but also established risks, completed signal assessments, regulatory actions, risk minimisation activities, new efficacy information, post-authorisation studies and cumulative clinical experience. Rather than asking whether a new signal exists, the aggregate report asks whether all available evidence collectively alters the current understanding of the product's benefit-risk profile.

This broader perspective explains why a reporting period containing no major safety signals may nevertheless result in important benefit-risk conclusions. Conversely, identification of several new signals does not necessarily imply deterioration of the overall benefit-risk balance if subsequent evaluation demonstrates that the concerns are adequately characterised or have limited clinical significance.

Experienced aggregate report authors therefore resist the temptation to equate the number of safety issues discussed with the importance of the report itself. The objective is balanced scientific assessment rather than enumeration of safety observations.

Thinking Like an Aggregate Report Author

The transition from case processing or signal assessment to aggregate report writing represents a significant change in professional perspective. Individuals entering aggregate report teams often discover that the analytical approach required for periodic benefit-risk evaluation differs fundamentally from that used during routine pharmacovigilance operations. Rather than determining whether an individual adverse event is reportable or whether a particular safety signal warrants further investigation, the aggregate report author must evaluate the medicinal product as a whole.

This broader perspective requires deliberate changes in clinical reasoning. Individual observations become components of a larger scientific narrative rather than isolated events requiring independent discussion. Every piece of information included within the report should contribute towards answering a central regulatory question: based upon all currently available evidence, does the medicinal product continue to demonstrate a favourable benefit-risk balance?

This principle should guide every stage of report preparation. Before analysing individual sections, experienced authors first consider the overall scientific story of the reporting interval. They seek to understand what genuinely changed during the period under review, which developments have regulatory significance and whether any of those developments modify existing understanding of the product's benefits or risks.

Only after establishing this overarching perspective do they begin writing individual sections. Consequently, experienced authors rarely view the report as sixteen independent sections completed sequentially. Instead, they regard it as a single scientific assessment divided into logical chapters.

Building a Scientific Narrative

Every PBRER tells a scientific story.

The term "story" should not be interpreted as creative writing or persuasive argument. Rather, it refers to the logical progression of evidence that enables the reviewer to understand how the available data support the final conclusions.

The narrative begins with the current understanding of the medicinal product at the end of the previous reporting period. It then examines what new information has become available, evaluates the reliability and clinical significance of that information, integrates findings from different sources and finally determines whether the accumulated evidence changes the overall benefit-risk profile.

This logical progression is important because regulators rarely review individual sections independently. Instead, assessors continually compare conclusions presented in different parts of the report. A new safety concern discussed within the signal evaluation section should be reflected appropriately in later discussions of identified risks, benefit-risk evaluation and conclusions where relevant. Conversely, if an issue is described extensively in one section but disappears without explanation in subsequent discussions, reviewers may question whether the report has been prepared systematically.

Maintaining this continuity requires careful planning before writing begins. Experienced authors frequently develop an outline of the principal scientific messages before drafting the report itself. Supporting evidence is then organised around these key messages rather than allowing the report to become a chronological collection of unrelated observations.

Developing a Regulatory Argument

One of the distinguishing characteristics of experienced aggregate report authors is their ability to construct a balanced regulatory argument.

A regulatory argument differs from an academic discussion or a scientific publication. Its objective is neither to advocate for the medicinal product nor to emphasise potential safety concerns. Instead, it should present a transparent assessment explaining how the available evidence supports the conclusions reached by the Marketing Authorisation Holder.

Every important conclusion within a PBRER should therefore be supported by evidence that is clearly identifiable within the report. If the author concludes that a risk remains adequately characterised, the supporting evidence should be apparent. If additional pharmacovigilance activities are considered unnecessary, the report should explain why existing knowledge is considered sufficient. Similarly, recommendations regarding product information or risk minimisation measures should arise naturally from the preceding scientific discussion rather than appearing as isolated statements within the conclusions.

This approach allows regulators to evaluate not only the conclusions themselves but also the reasoning process that produced them. Transparent reasoning increases confidence in the scientific assessment even where regulators ultimately reach different conclusions.

Balancing Confidence and Uncertainty

An important characteristic of scientific writing is the ability to distinguish established knowledge from remaining uncertainty.

Medicinal products are rarely associated with complete certainty regarding every aspect of their safety profile. Even after many years of post-marketing experience, questions may remain concerning rare adverse reactions, use in special populations or long-term outcomes. The objective of the aggregate report is not to eliminate uncertainty artificially but to describe it accurately and place it within an appropriate clinical context.

Experienced authors therefore avoid presenting speculative conclusions as established facts. Equally, they avoid exaggerating uncertainty where substantial evidence already exists. Throughout the report, the strength of the language used should reflect the strength of the underlying evidence.

This balanced approach is particularly important when discussing potential risks, ongoing signal evaluations or emerging observations from limited datasets. Regulators generally recognise that uncertainty is an inherent feature of pharmacovigilance. What they expect is that uncertainty should be identified clearly, evaluated objectively and managed appropriately.

Reconciling Conflicting Evidence

Conflicting evidence is common during aggregate review. Clinical trials may suggest one conclusion while observational studies suggest another. Spontaneous reporting trends may differ from epidemiological findings. Published literature may describe serious adverse reactions that are not reflected within cumulative company safety data.

These situations require careful scientific evaluation rather than selection of the evidence supporting a preferred conclusion.

The first step is to examine the quality of each evidence source. Differences may arise because of study design, patient selection, exposure duration, comparator groups, reporting practices or statistical methodology. Understanding these methodological differences frequently explains apparently conflicting findings.

Where uncertainty remains, the report should acknowledge the limitations openly rather than attempting to force a definitive conclusion. In many cases, the appropriate outcome is recognition that further pharmacovigilance activities are required to clarify the issue. This approach demonstrates scientific integrity and reflects the iterative nature of pharmacovigilance, where knowledge evolves progressively rather than appearing fully formed.

Avoiding Confirmation Bias

One of the greatest risks during aggregate medical review is confirmation bias. Once a particular view of a medicinal product's safety profile becomes established, there is a natural tendency to interpret new information in a manner consistent with existing beliefs. Such bias may delay recognition of emerging safety concerns or, conversely, perpetuate historical concerns long after the available evidence has changed.

Experienced aggregate report authors consciously challenge their own assumptions. They ask whether the current reporting period contains evidence that contradicts previous conclusions, whether alternative explanations should be considered and whether established risk assessments remain appropriate in light of newly available information.

This approach mirrors the scientific method. Conclusions should emerge from evaluation of the evidence rather than directing interpretation of that evidence. Although complete elimination of cognitive bias is impossible, awareness of its potential influence represents an important component of high-quality aggregate review.

Maintaining Scientific Objectivity

Objectivity is a fundamental expectation of regulatory writing. The purpose of a PBRER is neither to defend the medicinal product nor to emphasise its risks unnecessarily. Instead, it should provide a balanced assessment based upon the available evidence.

Scientific objectivity is demonstrated through careful selection of language, transparent presentation of supporting data and willingness to acknowledge both strengths and limitations of the available evidence. Alternative explanations should be considered where appropriate, uncertainties should be identified explicitly and conclusions should remain proportionate to the quality of supporting information.

Regulators frequently recognise attempts to minimise important safety findings or to overstate reassuring evidence. Equally, reports that exaggerate isolated observations without appropriate context may undermine confidence in the overall scientific assessment. The most persuasive reports are often those that present balanced discussions acknowledging uncertainty while explaining clearly why the available evidence supports the proposed conclusions.

Planning and Preparing a PBRER

Preparation of a high-quality PBRER begins long before the Data Lock Point is reached. Although the report itself evaluates information accumulated during a defined reporting interval, the activities required to produce that report extend across several months and involve multiple functional areas within the organisation.

Neither ICH E2C(R2) nor GVP Module VII prescribes a specific project management methodology for preparing periodic reports. The regulatory expectation is that Marketing Authorisation Holders submit scientifically robust reports within the applicable timelines. How an organisation achieves this objective is therefore largely determined by its quality system, operating procedures and available resources.

Large pharmaceutical companies typically establish formal aggregate reporting programmes involving defined timelines, document ownership, review workflows and quality control procedures. Smaller organisations may operate with considerably leaner teams, but the underlying principles remain the same. Sufficient planning should ensure that all relevant data are available for review, appropriate subject matter experts contribute where necessary, quality review is completed before submission and the scientific conclusions remain consistent throughout the report.

Planning activities should therefore focus not only on report production but also on scientific preparedness. Aggregate report authors should understand what major pharmacovigilance activities have occurred during the reporting interval, whether important signal evaluations are expected to conclude before the Data Lock Point, whether major regulatory procedures are ongoing and whether any significant changes to product information or risk management activities are anticipated. Early awareness of these developments allows sufficient time for scientific discussion before drafting begins.

Aggregate Reporting as a Multidisciplinary Process

Although the completed PBRER is usually presented as a single document, it represents the combined work of numerous specialists.

Pharmacovigilance operations provide cumulative case information and ensure that the safety database accurately reflects all reportable cases available at the Data Lock Point. Signal management teams contribute information regarding completed and ongoing signal evaluations. Epidemiologists and pharmacoepidemiologists may provide analyses from post-authorisation safety studies or observational research. Clinical development teams contribute relevant information from ongoing or completed clinical studies where appropriate. Regulatory affairs personnel advise on current regulatory procedures, product information updates and health authority interactions. Medical writers and aggregate physicians integrate these diverse sources into a coherent scientific assessment.

This multidisciplinary approach reflects the broad objectives of the PBRER. No single function possesses all of the information required to evaluate the evolving benefit-risk profile of a medicinal product. Effective communication between functional areas therefore becomes an important determinant of report quality.

From a governance perspective, organisations should define responsibilities clearly for data generation, medical review, quality control, document approval and regulatory submission. Although organisational structures differ considerably between companies, uncertainty regarding ownership frequently results in inconsistent scientific messages, duplicated effort or delays during report preparation.

Preparing for the Data Lock Point

The Data Lock Point represents the transition between ongoing pharmacovigilance activities and formal aggregate evaluation. Preparation for this milestone should therefore begin well in advance of the reporting period closing.

Before the Data Lock Point, organisations commonly review the status of ongoing pharmacovigilance activities that may influence the report. These include signal evaluations approaching completion, post-authorisation safety studies expected to generate new findings, regulatory procedures likely to conclude during the reporting interval and important updates to reference safety information. Identifying these activities early reduces the likelihood that significant scientific developments are recognised only after drafting has begun.

Another important objective during this period is verification of data readiness. Aggregate reports rely upon multiple information sources, each of which may have its own quality control processes and reporting timelines. Medical review cannot begin effectively unless these underlying datasets have been finalised and reconciled appropriately.

Although regulatory guidance does not prescribe how organisations should perform these preparatory activities, mature pharmacovigilance systems generally establish internal milestones that ensure scientific review can commence promptly following the Data Lock Point.

Sources of Information Used in a PBRER

One of the defining characteristics of a PBRER is the integration of information from multiple complementary sources. Aggregate review should not rely exclusively upon spontaneous adverse event reports, nor should individual evidence sources be considered independently of one another.

Depending upon the medicinal product and reporting period, information may be obtained from Individual Case Safety Reports, signal management activities, cumulative safety analyses, post-authorisation safety studies, medical literature, clinical trials, epidemiological investigations, regulatory authority communications, product information updates, Risk Management Plans and other pharmacovigilance activities.

The relative contribution of each information source varies considerably between products and reporting periods. For some products, spontaneous reporting remains the principal source of new safety information. For others, long-term extension studies, disease registries or observational database studies provide the most important evidence regarding evolving benefit-risk. The aggregate report author should therefore evaluate all relevant evidence proportionately rather than applying a predetermined hierarchy to available information.

Subsequent articles within this section examine each major information source in detail. At this stage, it is sufficient to recognise that preparation of a PBRER depends upon integration of evidence rather than sequential review of independent datasets.

Maintaining Consistency Across the Report

One of the most challenging aspects of aggregate report preparation is maintaining consistency throughout a document that may exceed several hundred pages and involve contributions from multiple reviewers.

Scientific consistency extends beyond simple agreement between sections. The rationale supporting a conclusion reached in one chapter should remain evident throughout the remainder of the report. Safety concerns discussed during signal evaluation should be reflected appropriately within later discussions of identified risks and benefit-risk evaluation. Important regulatory actions should be considered when discussing changes to product information. Findings from post-authorisation safety studies should contribute to the interpretation of established safety concerns where relevant.

Inconsistent reports frequently arise when individual sections are prepared independently without adequate integration during medical review. Readers may therefore encounter contradictory interpretations, unnecessary repetition or conclusions that appear unsupported by the preceding discussion.

Experienced aggregate report authors often perform one or more complete scientific reviews of the assembled document before final approval. The objective of these reviews is not merely correction of language or formatting but confirmation that the report presents a coherent, balanced and internally consistent scientific assessment.

The Structure of a PBRER

The structure of a PBRER reflects the sequence of scientific reasoning rather than an arbitrary regulatory template. Each major section contributes information that progressively builds the final assessment of the medicinal product's benefit-risk balance. Earlier sections establish the regulatory and clinical context, middle sections evaluate newly available evidence, while the concluding sections integrate all available information into a balanced medical assessment.

Authors should therefore resist the temptation to treat individual sections as independent writing exercises. Information presented in one part of the report frequently influences discussions elsewhere. For example, important safety actions taken during the reporting interval may influence interpretation of emerging risks, while new efficacy information may alter the overall benefit-risk assessment. The report should therefore be viewed as a single scientific document rather than a collection of unrelated chapters.

Although every section serves a distinct purpose, all ultimately contribute towards answering the same regulatory question: based on all available cumulative evidence, does the medicinal product continue to demonstrate a favourable benefit-risk balance?

Subsequent articles within this series examine each section of the PBRER individually, explaining its purpose, regulatory expectations, scientific objectives, common deficiencies and practical approaches to writing.

Integration with the Pharmacovigilance System

The PBRER occupies a unique position within the pharmacovigilance system because it brings together information generated by almost every major pharmacovigilance activity.

Signal management contributes evaluations of new or changing safety concerns. Risk Management Plans describe important identified risks, important potential risks and missing information that require continued monitoring throughout the product lifecycle. Post-authorisation safety studies generate additional evidence regarding specific risks or populations. Medical literature monitoring identifies published evidence that may influence understanding of product safety. Regulatory procedures, product information updates and safety communications provide insight into actions already taken in response to emerging information.

The aggregate report does not replace these activities. Instead, it periodically evaluates their collective impact on the current understanding of the medicinal product.

This integration is one of the principal strengths of the PBRER. Rather than requiring regulators to review multiple independent pharmacovigilance outputs separately, the report provides a single scientifically reasoned assessment that considers all important developments during the reporting interval. Consequently, conclusions presented within the PBRER should remain consistent with information described elsewhere within the pharmacovigilance system.

How Regulators Assess a PBRER

Although the PBRER follows a structured format, regulatory assessors rarely read the document sequentially from beginning to end. Instead, experienced assessors examine the consistency of the scientific argument across multiple sections of the report.

For example, an important safety concern discussed during signal evaluation should be reflected appropriately within the evaluation of risks, benefit-risk assessment and final conclusions where relevant. Likewise, changes to product information should be supported by the preceding scientific discussion. Conclusions that appear inconsistent with the evidence presented elsewhere in the report frequently generate requests for clarification during regulatory assessment.

Assessors also consider the completeness of the evaluation. They expect significant findings arising from clinical studies, published literature, post-authorisation safety studies and regulatory procedures to be integrated appropriately into the overall assessment. Omission of important evidence or failure to discuss conflicting information may reduce confidence in the scientific conclusions presented by the Marketing Authorisation Holder.

Ultimately, regulators evaluate not only the conclusions reached within the report but also the quality of the reasoning supporting those conclusions. Transparent discussion of uncertainties, balanced interpretation of evidence and logical progression from data to conclusion are therefore essential characteristics of a high-quality PBRER.

Common Deficiencies Observed During PBRER Preparation

Many deficiencies identified during quality review or regulatory assessment arise not because important data are missing but because the scientific interpretation is incomplete or inconsistent.

One common problem is excessive emphasis on description at the expense of interpretation. Reports may contain extensive tables, case summaries and literature reviews without adequately explaining the clinical significance of the information presented. In such situations, regulators are left to determine the implications of the evidence themselves rather than being guided through a structured medical assessment.

Another recurring deficiency is inconsistency between different sections of the report. Emerging safety concerns may be described during signal evaluation but not considered during the integrated benefit-risk discussion. Conversely, conclusions may recommend no regulatory action despite earlier discussions suggesting substantial changes in the understanding of product safety.

Poor integration between pharmacovigilance activities represents another frequent weakness. Findings from Risk Management Plans, post-authorisation studies, regulatory commitments or signal evaluations should contribute to the overall scientific assessment where relevant. Treating these activities as independent workstreams rather than components of a single pharmacovigilance system reduces the value of the aggregate report.

Finally, inexperienced authors sometimes attempt to eliminate uncertainty by presenting overly definitive conclusions. Scientific uncertainty is an expected feature of pharmacovigilance. The objective of the PBRER is not to remove uncertainty but to describe it honestly, evaluate its significance and explain how it influences the current benefit-risk assessment.

The Future of Aggregate Reporting

Periodic benefit-risk evaluation continues to evolve alongside advances in pharmacovigilance science, regulatory practice and digital technologies.

Increasing use of structured safety databases, real-world evidence, advanced pharmacoepidemiological methods and electronic regulatory submissions has already transformed many aspects of aggregate reporting. Artificial intelligence and large language models are expected to support activities such as literature review, drafting of descriptive sections, identification of inconsistencies and quality control of completed reports.

Despite these technological advances, the central purpose of the PBRER is unlikely to change. Regulatory decision-making depends upon balanced scientific judgement, transparent interpretation of evidence and careful evaluation of the overall benefit-risk balance. These responsibilities require clinical expertise and remain the responsibility of appropriately qualified pharmacovigilance professionals.

Technology should therefore be viewed as an aid to aggregate report preparation rather than a substitute for medical judgement. The future aggregate report author is likely to spend less time compiling information and more time evaluating its scientific significance.

Key Takeaways

The Periodic Benefit-Risk Evaluation Report represents one of the most important scientific assessments performed during the post-authorisation lifecycle of a medicinal product. It integrates information generated throughout the pharmacovigilance system and provides regulators with a cumulative evaluation of whether the medicinal product continues to demonstrate a favourable benefit-risk balance.

Preparation of a high-quality PBRER requires considerably more than knowledge of the reporting template. Authors must understand pharmacovigilance principles, clinical medicine, epidemiology, regulatory science and scientific writing. Equally important is the ability to interpret evidence objectively, reconcile conflicting information and communicate balanced conclusions supported by transparent scientific reasoning.

This article has introduced the principles underlying modern aggregate reporting. The remainder of this section examines each component of the PBRER in greater depth, beginning with the overall process of planning and writing a scientifically robust report before progressing to detailed discussion of every major section of the document.

References

Primary Regulatory References

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

2. EMA Good Pharmacovigilance Practices (GVP) Module VII – Periodic Safety Update Report.

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

4. Directive 2001/83/EC, as amended.

5. Regulation (EC) No 726/2004, as amended.

EMA Guidance

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

2. EMA PSUR Repository Guidance.

3. EMA European Union Reference Dates (EURD) List.

4. EMA Procedural Guidance for PSUR Single Assessment (PSUSA).

Supporting References

1. CIOMS Working Group Reports relevant to aggregate safety evaluation.

2. ENCePP Guide on Methodological Standards in Pharmacoepidemiology.

Where the PBRER Fits Within the Pharmacovigilance System

The PBRER should not be viewed as an isolated regulatory document. It occupies a central position within the pharmacovigilance system because it periodically integrates information generated by multiple pharmacovigilance activities into a single scientific assessment.

Rather than creating new safety information, the report evaluates evidence that has already been generated through routine pharmacovigilance processes and determines whether that evidence changes the overall understanding of the medicinal product.

Information Flow into a PBRER

Diagram: Information Flow into a PBRER

Signal Management

↓

Individual Case Safety Reports

↓

Medical Literature Monitoring

↓

Post-Authorisation Safety Studies

↓

Clinical Trial Safety Data

↓

Risk Management Plan Activities

↓

Regulatory Actions

↓

Integrated Benefit-Risk Evaluation

↓

Periodic Benefit-Risk Evaluation Report (PBRER)

The value of the PBRER lies in the integration of these diverse information sources rather than consideration of each source independently. The report therefore represents the periodic scientific interpretation of the entire pharmacovigilance system rather than the output of a single pharmacovigilance activity.

Inspection Insight

During inspections, regulators frequently compare important conclusions described within recent PBRERs against corresponding Risk Management Plans, product information, signal assessments and other pharmacovigilance activities. Scientific conclusions should remain consistent across the pharmacovigilance system.

What a PBRER Is Not

Understanding what a PBRER is intended to achieve becomes easier when common misconceptions are recognised.

A PBRER is not a compilation of Individual Case Safety Reports.

It is not an expanded line listing.

It is not a literature review.

It is not a Signal Assessment Report.

It is not a Risk Management Plan.

It is not simply a regulatory submission prepared to satisfy a reporting obligation.

Instead, the PBRER is a structured scientific assessment that integrates all relevant evidence accumulated during the reporting interval and evaluates whether the medicinal product continues to demonstrate a favourable benefit-risk balance.

Writing Tip

Every section of the report should contribute towards answering a single scientific question:

Does the cumulative evidence change the current understanding of the product's benefit-risk balance?

Fundamental Principles of Good Aggregate Reporting

Regardless of therapeutic area, company procedures or report complexity, several principles underpin every well-prepared PBRER.

Scientific interpretation should always take precedence over description.

Discussions should remain cumulative rather than focusing exclusively on events occurring during the current reporting interval.

Evidence from multiple pharmacovigilance activities should be integrated into a coherent medical assessment rather than discussed independently.

Scientific uncertainty should be acknowledged openly where appropriate.

Conclusions should be proportionate to the strength of the available evidence.

Internal consistency should be maintained throughout the report.

Benefit-risk evaluation should remain the central theme of the document.

Common Mistake

A frequent weakness of inexperienced authors is producing a report that describes large amounts of data without explaining why those data are medically important.

Who Should Read This Guide?

This article provides an overview of Periodic Benefit-Risk Evaluation Reports and is intended for:

• Aggregate report authors
• Pharmacovigilance physicians
• Medical reviewers
• Medical writers
• QPPVs
• Pharmacovigilance managers
• Regulatory affairs professionals
• Pharmacovigilance auditors
• Pharmacovigilance inspectors
• Healthcare professionals wishing to understand aggregate safety reporting

Readers seeking detailed guidance on individual sections of the report should continue with the articles contained within the PBRER series.

Continue Reading

This article introduces the principles underlying Periodic Benefit-Risk Evaluation Reports. The following articles examine individual topics in substantially greater depth.

Recommended reading:

• [[how-to-write-a-pbrer]]
• [[pbrer-workflow]]
• [[planning-a-pbrer]]
• [[pbrer-medical-review]]
• [[pbrer-quality-review]]
• [[data-sources-for-pbrer]]
• [[writing-the-executive-summary-in-a-pbrer]]
• [[writing-the-estimated-exposure-section]]
• [[writing-the-signal-evaluation-section]]
• [[writing-the-integrated-benefit-risk-analysis]]

Glossary

Benefit-Risk Balance

The overall evaluation of whether the therapeutic benefits of a medicinal product continue to outweigh its risks within the authorised conditions of use.

Data Lock Point (DLP)

The cut-off date for inclusion of data within a periodic report.

European Union Reference Date (EURD)

The reference date used to harmonise periodic reporting schedules across the European Union.

Individual Case Safety Report (ICSR)

A structured report describing one or more suspected adverse reactions occurring in an individual patient.

Periodic Benefit-Risk Evaluation Report (PBRER)

The internationally harmonised format described by ICH E2C(R2) for periodic evaluation of the benefit-risk balance of authorised medicinal products.

Periodic Safety Update Report (PSUR)

The legal term used within European Union legislation for periodic reports prepared according to GVP Module VII and the scientific principles of ICH E2C(R2).

Pharmacovigilance Risk Assessment Committee (PRAC)

The EMA scientific committee responsible for assessing and monitoring safety issues relating to human medicines.

PSUR Single Assessment (PSUSA)

The coordinated European procedure for assessment of PSURs relating to the same active substance or combination of active substances.

Reference Safety Information (RSI)

The agreed reference against which expectedness of adverse reactions is evaluated for clinical trial safety reporting.