The DSUR, the RMP and the PSUR across the lifecycle
Three documents carry a medicine's aggregate safety assessment across its life: the development safety update report while trials run, the risk management plan from the marketing application onward, and the periodic safety update report after approval. An aggregate report follows a common workflow from a data lock point and draws its inputs from many functions. Post-marketing safety writing follows guidance and practices of its own, the three documents sit among other regulatory documents that also carry safety, and they keep changing as knowledge of the product grows.
The three documents across the lifecycle
A medicine is not only effective against a disease but also brings side effects, so there must be a positive balance between benefits and risks, and the benefits must outweigh the risks by the greatest margin achievable. That holds throughout the lifecycle of the product, from the pre-authorisation phase during clinical development into the post-marketing phase, when the medicine is marketed and taken by a very large portion of the population. The main pharmacovigilance documents in the lifecycle are the Development Safety Update Report, the Periodic Safety Update Report and the Risk Management Plan.
The DSUR, the RMP and the PSUR can be seen as three chapters in the lifecycle of a medicinal product. The first chapter opens once the first investigational clinical trial of a clinical development programme is approved anywhere in the world, which obliges the sponsor to write an annual DSUR. The second chapter is the RMP, a mandatory part of the application for marketing authorisation in the EU, and the third, which begins after successful registration in the EU, is the PSUR. The preparation of pharmacovigilance documents is related to ongoing activities during the lifecycle and encompasses crucial processes beyond writing: strategic planning and interdisciplinary work in the context of submissions, definition of the product's safety concerns, alignment with the key messages in the marketing authorisation application dossiers, and interactions with health authorities during assessment.
A product's lifecycle is divided into pre-authorisation, submission and post-authorisation phases, and each phase has its own legislative requirements for the pharmacovigilance documents to be written and submitted. The development safety update report belongs to the pre-authorisation phase, the risk management plan and its updates to submission and authorisation, and the risk management plan with its updates and the periodic safety update report to the post-authorisation phase.
The aggregate report and its workflow
Individual case reporting looks at adverse events from the individual patient's point of view, whereas an aggregate report takes the opposite stance and profiles the product from the drug's perspective, collating data from diverse sources such as individual case safety reports and the literature. Aggregate reports are the part of pharmacovigilance that runs parallel with the medical-writing scope of work, and one of the biggest medical-writing portfolios within it, in one practitioner's view the biggest. An aggregate report is written to the health authority's guidance but from the product's perspective: it covers the safety of the product, what kinds of adverse events are being reported, their frequency, the correlation between side effect and adverse event, and their categorisation, such as whether an event is very severe, rare, common or abnormal.
Aggregate reports fall into two categories by the stage at which they are written: before approval, the annual reports in Europe, the IND reports in the US and development safety update reports; after approval, reports including risk management plans. The basic workflow of an aggregate report is common across the types. It opens with a kick-off meeting and a planning phase that defines the data lock point. At the data lock point the safety system is locked for the reporting period: the data for the period ending there are captured retrospectively, nothing after it is taken in, and the line listings and other outputs are created from those data. Drafting starts from those outputs, followed by internal reviews, quality control and comments, then final reviews that are quality-checked, then possibly review and approval by the qualified person responsible for pharmacovigilance, the global safety lead or the safety leads, then finalisation, formatting, publishing and submission.
The inputs for an aggregate report come from many stakeholders together. The clinical team supplies the clinical data, the preclinical team the data from animal studies, and in vitro and in vivo data relevant to the product come in; the safety, regulatory, literature, statistics and finance teams and the licence partners contribute too. Finance supplies the sales data, how many units were sold, the volumes and how they compare with previous years, so that the adverse events can be correlated with the volumes sold. The writer adds those inputs, compiles the data, drafts the report section by section, analyses it and sends it for review and publication.
Post-marketing safety writing and its guidance
Post-marketing safety writing plays a vital role in the ongoing evaluation of drug products after marketing authorisation and is fundamental to maintaining the benefit-risk balance of medicinal products. It is crucial in post-marketing safety writing to communicate evolving safety information to stakeholders, including regulators, healthcare professionals and patients. Under GVP Module XV, such communications should actively consider and address the perspectives of patients and healthcare professionals. The EUPATI toolbox describes safety communications, such as those in the summary of product characteristics and the package leaflet, as aiming to prevent patients from experiencing adverse effects and to give timely, evidence-based information on the safe and effective use of medicines and the appropriate clinical management of adverse reactions. In the US, FDA guidance highlights the importance of timely dissemination of drug safety updates to professionals, patients and interested members of the public. These objectives are fulfilled through a variety of structured documents designed to meet global regulatory requirements.
Post-marketing safety writing is governed by a range of international and regional guidelines and guidance documents that establish the format, content and timing of safety reports. Among them, ICH E2E gives guidance on proactive planning of pharmacovigilance activities throughout the product lifecycle, ICH E2C(R2) outlines the structure and objectives of aggregate post-marketing safety reports, the EU GVP modules detail the requirements for safety data collection, risk management and communication, the FDA's risk evaluation and mitigation strategies are there to ensure that the benefits of certain medicines outweigh their risks, and the PADER provides a consolidated overview of a drug's safety and benefit information over a specific reporting interval. Each jurisdiction may impose specific requirements in addition to these international frameworks, so safety writers must be familiar with both global harmonisation initiatives and regional variations.
The PBRER, formerly known as the PSUR, provides a comprehensive analysis of a medicinal product's benefit-risk profile over a defined reporting period, including analysis of cumulative and interval safety data, summaries of new safety findings, and conclusions on whether changes to the product information or the risk management plan are warranted. For the PBRER, medical writers are responsible for coordinating multidisciplinary inputs from teams such as the clinical trials, epidemiology and signal detection teams, and draft scientifically sound narratives based on individual case safety reports that meet regulatory requirements. The RMP is a dynamic document that identifies known and potential safety concerns and outlines strategies for their management, and it contains safety specifications, planned pharmacovigilance activities and risk minimisation measures. In line with GVP Module V, the RMP must be regularly updated to reflect the current safety profile and to anticipate regulatory queries. Medical writers ensure that the RMP remains scientifically accurate, aligned with the safety data and presented in accordance with regulatory standards.
Medical writers should begin by thoroughly understanding the applicable international and regional guidelines. Reports should use standardised medical terminology, such as MedDRA coding, and keep style, tone and structure consistent across sections and reporting periods. Accuracy of data presentation is paramount and requires close collaboration with the pharmacovigilance, biostatistics and regulatory teams to verify data sources and resolve discrepancies before submission. Balanced benefit-risk assessment is a hallmark of effective safety writing: writers should objectively present both safety concerns and therapeutic benefits, integrating cumulative data from spontaneous reporting, literature, post-authorisation safety studies and real-world evidence. That information must be synthesised into coherent narratives that align with regulatory expectations while remaining accessible to stakeholders. Late submissions can delay regulatory assessment and affect public health, so writers should establish robust internal timelines and document management processes to meet regulatory deadlines. Communicating evolving safety information effectively involves translating complex pharmacovigilance findings into clear, actionable messages, in line with GVP Module XV.
Post-marketing safety writing is adapting to a rapidly changing regulatory and technological landscape. Regulatory agencies such as the EMA and FDA increasingly encourage the use of real-world evidence from electronic health records, patient registries and insurance claims data to complement spontaneous reporting and clinical trial data, which enables more comprehensive safety evaluations and supports timely regulatory decision-making. Natural language processing, machine learning and automated literature screening are being applied to accelerate signal detection, case processing and the drafting of routine safety documents, and while they can improve efficiency, they require careful human oversight to ensure narrative quality and regulatory compliance. Evaluating the effectiveness of risk minimisation is receiving growing emphasis. Global harmonisation of safety reporting formats continues through ICH guidelines such as E2C(R2) and E2D, but regional variations persist, and writers must navigate these differences, often producing multiple versions of the same report to meet region-specific requirements. The focus on transparent communication of safety information to regulators, healthcare professionals and patients is increasing, reflecting a broader shift towards patient engagement and public trust in the regulatory process.
Post-marketing safety writing serves as a critical bridge between pharmacovigilance data and regulatory decision-making, enabling the continued evaluation of a product's benefit-risk profile in real-world settings. As the limitations of pre-approval clinical trials become increasingly acknowledged, the importance of structured, evidence-based post-marketing documentation grows. Through documents such as PBRERs, RMPs, PADERs and DSURs, medical writers help translate complex safety data into clear, actionable insights for regulators, healthcare professionals and patients.
Their place among other regulatory documents
Plenty of documents need to be written, especially in clinical medical writing during clinical development, and some of them also have safety sections, while dedicated safety documents such as the DSUR, the RMP and the PSUR are required at specific phases of the lifecycle. Other documents are involved as well, such as the addendum to the clinical overview, prepared at marketing renewal, and safety summaries and the clinical overview, normally submitted along with RMPs when, for example, the label changes or a new indication is applied for. The picture can get even more complex, and there are interfaces and overlaps with other documents and other clinical writing activities.
At the time of a marketing authorisation application, pharmacovigilance documents represent a significant proportion of the documents in the dossier, including CTD Module 2.5.5, the overview of safety; CTD Module 2.7.4, the summary of clinical safety; the integrated summary of safety; the 120-day safety update report; the RMP; and the benefit-risk evaluation report. The two CTD modules and the integrated summary of safety are integrated analyses of all the safety data collected in the product's clinical development and form the basis for its labelling and for the totality of safety information made available to prescribers and other healthcare professionals once it is authorised. The benefit-risk evaluation report assesses the benefit of the product against its risks for a particular patient population and treated indication, to determine whether the product has a favourable benefit-risk profile. After successful application, other pharmacovigilance documents come into effect, including PSURs, or PADERs for the US; PSUR addenda; summary bridging reports; RMPs and benefit-risk evaluation reports; and ad hoc safety reviews. By region, clinical development pairs the clinical trial application with the DSUR in the EU and the IND submission with an IND annual report or a DSUR in the US; the marketing application carries the overview of safety, the summary of clinical safety, an RMP and a risk-benefit analysis in the EU, and the same with the integrated summary of safety and the 120-day safety update for a US new drug application; and the post-marketing set is the same in both regions, with the PADER as the US alternative to the PSUR.
Addenda to clinical overviews are required in the EU under certain circumstances, such as the emergence of significant new post-marketing safety information, to update the Module 2.5 section of the common technical document. They summarise and critically appraise post-marketing safety data that could affect the product's benefit-risk balance, and the writer interprets data from diverse sources, including periodic safety reports, post-authorisation studies and signal detection activities, and integrates them into a structured, evidence-based narrative for regulatory submission. In one practitioner's answer, the safety concerns an addendum to the clinical overview should carry are those presented in the PSUR, rather than just those described in the RMP.
Asked at a September 2019 EMWA webinar whether pharmacovigilance writing and clinical medical writing interact, 58% of attendees answered that there are common data and key messages across submission documents, 34% something in between, and 8% that pharmacovigilance and clinical documents have a different focus.
When one regulatory writer started in the field, over a decade before 2016, the documents they typically worked on were clinical study reports, investigator's brochures, maybe protocols, and later clinical summaries and overviews; advertisements for regulatory writers usually mentioned these, and they were the focus of EMWA's training programme. In one regulatory writer's impression, pharmaceutical companies then gave drug safety documents less importance than other types, and those documents seemed more like compilations of notifications of adverse drug reactions than documents that attempted to synthesise and analyse information. A greater focus on drug safety, both during development and after approval, has since changed how these documents are perceived and increased documentation requirements, and by 2016 drug safety documents were becoming increasingly important to companies and regulators. By 2016 EMWA's Professional Development Programme offered workshops on the three main types, periodic benefit-risk evaluation reports, development safety update reports and risk management plans.
Drug safety documents differ from other regulatory documents in their general processes. Periodic benefit-risk evaluation reports and development safety update reports are updated periodically, whereas other regulatory documents are usually written as needed, investigator's brochures and protocols perhaps excepted, so resource planning for them is more predictable, although the timetables for submitting drug safety documents can be quite complex. Risk management plans are not needed on a periodic schedule but are still living documents that are frequently updated, and to assist with updating, drug safety documents generally have a very modular structure. Drug safety documents often attempt to integrate information from multiple real-world sources, such as spontaneous reports of adverse drug reactions from health care providers and literature reports, to a greater extent than other regulatory documents, which generally use clean data collected with well-controlled procedures such as a case report form. The large number of sources coupled with their greater heterogeneity can be a challenge when writing and compiling drug safety documents.
Updates across the lifecycle
The preparation of the DSUR, the RMP and the PSUR does not end with their submission, and the RMP in particular may be updated during the lifecycle. A submitted PSUR, RMP, DSUR or addendum to the clinical overview is subject to evaluation and will likely draw health authority questions or requests for supplementary information, so the pharmacovigilance writer's tasks do not end with the submission of the document but can continue during the lifecycle and within the assessment procedure.
Risks and benefits may evolve during the lifecycle: the benefit-risk profile evolves as knowledge of a product's risk profile grows through the evaluation of risks, safety findings and signals, and new evidence from studies or from post-marketing settings may show a higher or lower benefit. A typical consequence is a change to the label and planning for new or different risk minimisation measures where those in place were not effective, and a risk that had no risk minimisation measures at the outset may need some in the post-marketing phase. The whole process is dynamic, changing and evolving during the lifecycle.
Three main aspects are subject to change during the lifecycle. The definition of an important risk, made at the very beginning of the lifecycle, is itself subject to change: an important risk could be no longer important after some time, or when its risk minimisation measures are very well applied. The categorisation of pharmacovigilance activities changes because they come to an end, studies especially, and once completed they should be removed from the plan. Risk minimisation activities need to be proportional to the risk and could evolve over time; even additional measures could be integrated into clinical practice and considered routine measures after some time. All these changes are reflected in changes to the pharmacovigilance documents.
Data are evaluated on an ongoing basis, at defined points such as the PSUR and at an application to renew the marketing authorisation, and the documents need updating as soon as major safety concerns or new risks arise, when milestones of the pharmacovigilance plan are reached, such as the closure of a safety study and its report, and as soon as risk minimisation measures prove not to be effective. An application for a new indication or a new formulation requires re-evaluating all the safety knowledge of the product and assessing whether it also applies to the new indication or formulation, or whether anything additional relates to it. This never-ending safety story is translated into documents, processes and procedures that a pharmaceutical company has to apply.
Although RMPs and benefit-risk evaluation reports are an integral part of the documents submitted for marketing authorisation, they continue to be amended and updated throughout the product's post-marketing life, in scenarios including licence renewals, the identification of new safety concerns, the registration of new and clinically dissimilar indications, and the registration of treatment in a special population such as paediatrics or the elderly.
As of 2016, the increasing focus on pharmacovigilance and drug safety was generating a greater need for drug safety documentation. The documents need to be updated regularly, periodically for PBRERs and DSURs, while an RMP update may be needed at short notice. As drug safety does not stop as soon as approval is obtained, PBRERs are still required even when the clinical development of a product has finished. In some cases the documents may be complex, and their interrelationship may need careful management. The result was a high documentation burden for pharmaceutical companies and potentially a good source of work for regulatory writers.
There will be a period, often extending for many years, in which a drug has been approved for one indication but is still under development for another, or while studies in a paediatric investigation plan are being conducted, and during it both DSURs and PBRERs are required. As there is much overlap between the two, and their modular nature means some sections may be identical, it makes sense to develop and submit them in parallel, which also eases the burden on the health authority reviewers. Working out the schedule to make this work is not always easy: submission dates for PBRERs are generally gated on the first approval of the drug, its international birth date, whereas DSURs are gated on the first authorisation to conduct a clinical trial, its development international birth date, and different regions may require different submission frequencies.