What the plan asks of its writer
Writing an EU risk management plan asks for more than drafting: the writer summarises the plan's risks, coordinates the functions that supply its content, keeps it consistent with the other safety and dossier documents, and authors it with the programme team as the expert on its template.
The writer's role
The plan is complex but clearly structured, and it can be mastered by following a step-by-step approach. Writers, with their attention to detail, writing expertise and communication skills, are a valuable part of the authoring team. For someone with experience in regulatory writing, preparing the plan can be a rewarding challenge.
Several of the plan's sections need medical writing expertise to summarise properly the important identified and important potential risks of an investigational product, including its missing information. The writer's role and interaction with the other internal functions are crucial to the plan's quality from both a scientific and a medical content perspective. Throughout the plan's development the writer is a cog in the wheel, and has been gaining importance not only as an active contributor but also as an expert and a collaborator.
Preparing the plan successfully requires interaction and communication, and its writing and review process needs consensus agreements to meet the required deadlines for regulatory submission.
The template expert
The writer is deemed the template expert. Authoring the plan well is not as complex as it may seem, provided the good pharmacovigilance practices (GVP) guidance is applied with a logical and scientific approach in whatever scenario the plan's development presents. Until the guidance's revision, writers read its template as too bureaucratic and somewhat ambiguous, especially where the rationale behind a requirement was unclear or unexplained. The writer has to know the nuances of each module and how the modules depend on each other, so that data flow between them optimally and in chronological order. Regulatory guidance documents are living documents that depend on a regulatory landscape changing with the advent of a wide range of new therapeutics, so writers should invest extra time in understanding the guidance and the template, follow them closely and learn to handle their flaws case by case. Over time, writers learn more about the template's requirements from rapporteurs' comments, the Pharmacovigilance Risk Assessment Committee's assessment reports and the authorities' questions received at points after the common technical document's submission, such as day 120 and day 180.
The template's framework follows a typical risk management cycle of three questions: what is known and unknown about the product's safety profile, which activities are undertaken to collect additional data to fill the gaps in that knowledge, and what measures are implemented to mitigate the risks. Information on the three questions flows in chronological order within the template's modular framework. The safety specification covers every aspect needed to define, categorise and justify the product's safety concerns, including the epidemiology, the preclinical and clinical data on safety, efficacy and pharmacokinetics, the limitations of the clinical programme and, where applicable, post-marketing data. This comprehensive assessment is paramount to planning the plan's remaining elements, the pharmacovigilance plan and the risk minimisation measures, and to justifying the proposed strategy. So the writer should be aware of how the modules depend on each other and keep them consistent with each other, with the other documents in the common technical document and with the other safety reports in the submission's regulatory procedure.
What the writer needs to know
A writer could take a holistic approach to authoring high-quality plans seamlessly, and the concepts of such a 360-degree approach may give basic guidance on it. Such a comprehensive approach eases authoring the plan within the constantly changing regulatory landscape of the GVP legislation.
Knowledge of the disease or therapeutic area is expected of any writer, but a plan also needs extensive knowledge and understanding of pharmacovigilance, which is probably one reason why plan writers are usually titled safety writers rather than regulatory writers. The guidance covers every definition needed for the plan, and the writer should understand their meanings and the differences between them, if any, as well as the categories of pharmacovigilance activity and which category each proposed activity belongs to. Beyond the plan's guidance, the European Medicines Agency's guidance on lay summaries can be applied to the plan's lay summary for the European public assessment report.
Because the plan covers a product's key safety concerns, the writer should understand the product's overall safety profile before beginning to draft. As a starting point, the drug's class gives a clear picture of its pharmacological class effects, from which to understand the product's preliminary safety profile. Safety data are first generated in the preclinical setting and become more in-depth and reliable as the molecule moves through clinical development, so the first comprehensive document to read is the investigator's brochure, followed by the developmental core data sheet or the current approved label, if there is one. Understanding how safety data flow from one document to the next and what each document in the programme is for helps the writer use the right source for each piece of information.
Because a single plan exists for a single product, understanding the overall clinical development plan and drawing on experience of prior submissions eases authoring. Knowing the programme's history, such as its approvals, indications, formulations, the triggers for its updates, regulatory actions taken for safety reasons and the Pharmacovigilance Risk Assessment Committee's assessment reports, helps the writer identify which modules or sections an update touches and how far each needs updating.
The extent of an update depends heavily on its trigger and on the regulatory procedure it falls under, such as Type I or Type II variations, renewals or article referrals, so awareness of these procedures helps the writer understand an update's scope. The writer also needs to understand the disease or therapeutic context of the submission, such as paediatric indications, advanced therapy medicinal products, biosimilars, generics or associated medical devices. The template's requirements depend primarily on the scope of the submission, and not every section of the plan may apply. Understanding the trigger, such as reaching a pharmacovigilance or risk minimisation milestone or downgrading or upgrading a risk, helps identify the sections or modules an update touches, and knowledge of the current regulatory landscape helps in evaluating the impact on updates.
Consistency with other documents
The modular format brings an obligation of consistency with the source documents and the programme's other documents, and the alignment it asks for is message-led rather than verbatim. The sources, depending on the procedure, include the common technical document's Module 2.7, the investigator's brochure, safety reports, labelling documents such as the core data sheet or the summary of product characteristics, clinical study reports, the periodic benefit-risk evaluation report and the development safety update report. The plan is synchronised with other aggregate safety documents and reports that are not necessarily found in the regulatory submission, such as the periodic safety update report, the company core data sheet and the local labels, and the summary of clinical safety. The writer communicates with the other regulatory writers on the submission to keep the plan's key messages consistent with other dossier documents, such as Modules 2.7.4 and 2.5.
The GVP guidance recommends a mapping of the plan to the common technical document's modules and to the periodic benefit-risk evaluation report.
| Plan module | Electronic common technical document module |
|---|---|
| Part I Product(s) overview | Module 2.3 Quality overall summary |
| Module 3 Quality | |
| Module SI Epidemiology of the indication(s) and target population(s) | Module 2.5 Clinical overview |
| Module SII Non-clinical part of the safety specification | Module 2.4 Non-clinical overview |
| Module 2.6 Non-clinical written and tabulated summaries | |
| Module 4 Non-clinical study reports | |
| Module SIII Clinical trial exposure | Module 2.7 Clinical summary |
| Module 5 Clinical study reports | |
| Module IV Populations not studied in clinical trials | Module 2.5 Clinical overview |
| Module SV Post-authorisation experience | Module 2.5 Clinical overview |
| Module SVI Additional EU requirements for the safety specification | Data not presented elsewhere in the electronic common technical document |
| Module SVII Identified and potential risks | Module 2.5 Clinical overview (including benefit-risk conclusion) |
| Module 2.7 Clinical summary (summary of product characteristics) | |
| Module SVIII Summary of safety concerns | Module 2.5 Clinical overview |
| Module 2.7 Clinical summary | |
| Part III Pharmacovigilance plan (including post-authorisation safety studies) | Module 2.5 Clinical overview |
| Module 2.7 Clinical summary | |
| Part IV Plans for post-authorisation efficacy studies | Module 2.5 Clinical overview |
| Module 2.7 Clinical summary | |
| Part V Risk-minimisation measures (including evaluation of the effectiveness of risk-minimisation activities) | Module 2.5 Clinical overview |
| Module 2.7 Clinical summary |
| Plan section | Periodic safety update report section |
|---|---|
| Part II Module SIII Clinical trial exposure | Sub-section 5.1 Cumulative subject exposure in clinical trials |
| Part II Module SV Post-authorisation experience | Sub-section 5.2 Cumulative and interval patient exposure from marketing experience |
| Module SVII Identified and potential risks and Module SVIII Summary of the safety concerns | Sub-sections 16.1 Summaries of safety concerns and 16.2 Characterisation of risks |
| Part V Risk-minimisation measures (including evaluation of the effectiveness of risk-minimisation activities) | Sub-section 16.5 Effectiveness of risk-minimisation (if applicable) |
Working with the programme team
The writer is a collaborator, not the sole author: as with any other regulatory document, safety, clinical, preclinical, epidemiology, regulatory, biostatistics, data management, pharmacokinetics and formulation development, among others, contribute to the plan. The team knows the product's profile and its regulatory lifecycle better than the writer does, so the writer should seek the team's contributions on the product's scientific aspects. In the industry's conventional organisation, the other contributors are often dedicated to specific products while the writer may not be, and the writer gains broader experience of authoring plans for several products than any other contributor does. The writer is therefore deemed a key driver of the process and should lead the team on the template's requirements. In the end it is the team's responsibility to collaborate and integrate its work into a high-quality plan that draws minimal or no questions from the authorities, at least on template compliance.
Authoring a plan goes beyond collating content: it is a strategy in itself that is legally binding, so working with the right members of the programme team at the right time, beyond the regular project meetings, is imperative in implementing the risk management strategy. Opportunities to keep the plan's development moving smoothly include the following:
- Work with the statistician and the statistical programmer during planning to review the requirements for mock statistical outputs for each safety concern.
- Keep in regular contact with the safety lead for updates on any changes to the safety profile, since the safety lead is the plan's official responsible author and answers to the qualified person for pharmacovigilance.
- Work with the regulatory affairs representative during planning and after health authority or labelling review committee meetings, to stay aware of any changes to the scope of the submission's requirements.
- Gather the epidemiologist's and preclinical expert's inputs before the data are available.
The writer should also comment on the statistician's and programmer's mock statistical outputs and identify any discrepancies in the draft outputs, to avoid major rework and potential delays to the submission timelines. Collecting clinical inputs, including administrative information on pharmacovigilance milestones for clinical studies and the benefit-risk information, before and during drafting helps avoid last-minute follow-ups. Throughout the plan's development, the writer should ensure that each contributor's inputs comply with the template's requirements.