What Revision 2 of GVP Module V changed
Revision 2 of Good Pharmacovigilance Practices (GVP) Module V, the EU guidance on risk management systems, answered the problems the first version of the risk management plan (RMP) had run into: after a public consultation it brought a new template, made the plan risk-proportionate and shorter, and required existing plans to be converted to the new format.
The problems before Revision 2
Under the initial guidance, plans in many cases included long lists of safety concerns with the related pharmacovigilance and risk minimisation activities, a significant burden on the risk management system and on marketing authorisation holders. The first version of Module V introduced the plan in a modular structure, with Module SVII devoted exclusively to evaluating the safety concerns. Because the plan and the periodic safety update report (PSUR) listed identical safety concerns, that module transferred easily to section 16 of the PSUR. For many products the list grew over time, often with each PSUR assessment, until some products carried more than 20 safety concerns. One practitioner closely involved in the revision explained that the industry needed more focused plans: before the revision they sometimes carried a high number of safety concerns and ran over 1,000 pages, and the plan had lost its way.
Many of these important risks had been known for years and were well managed: a warning in the product information was enough, the reported case numbers were stable, and there was no plan to investigate them further or to manage them beyond that routine measure. Each still had to be evaluated specifically, with the results presented in both the RMP and the PSUR. Any new information on them, perhaps from post-marketing, meant an update of the plan, which caused a lot of work for both the company and the health authority. Yet when there was no reason to update a plan, it was left with outdated data over the years, because only the PSUR presents periodic, cumulative and up-to-date evaluations of the safety concerns.
Soon after Module V was implemented it became clear that the definitions of important identified risks, important potential risks and missing information needed further clarification and pragmatic guidance. Determining the safety concerns was an intrinsic challenge of RMPs, and the role of the RMP as a planning document was not clearly linked to the life cycle of the medicinal product. Another challenge in preparing plans was how to integrate safety information gathered over time, what to focus on, and how increasing knowledge should support changes in the plan.
The consultation and release of Revision 2
After releasing the GVP guideline in 2012, the European Medicines Agency (EMA) committed to improving its pharmacovigilance guidance continuously on the basis of stakeholder feedback and experience, and in parallel the EMA-Industry stakeholder platform was established for regular dialogue with industry, with regular meetings to give updates and discuss specific topics including RMPs. After publishing an initial revision in 2013, the EMA released drafts of Revision 2 and of the related RMP template for public consultation in February 2016. The public consultation ended in May 2016, and the final revision was then expected in the third quarter of 2016.
The consultation drew a wide variety of feedback from marketing authorisation holders, industry associations, national healthcare system representatives and individuals, among many others. The main topics it raised were the definition and life cycle of the safety concerns (important identified risk, important potential risk and missing information), inconsistencies between the different parts and modules of the plan, and technical issues and questions surrounding duplication of information between the plan and other safety summary documents. The main questions in the stakeholder meetings and consultations between the EMA and industry were these:
- What should be considered relevant for inclusion in the safety specification (Part II) of the plan: what is important, and when is missing information relevant for inclusion?
- How should important risks be defined and characterised: can off-label use in children, for example, be defined as an important potential risk, and should an adverse clinical outcome be defined?
- How should the safety concerns evolve through the life cycle of the medicinal product, and what do the EMA and the national authorities expect?
The final guidance was released at the end of March 2017, accompanied by a revised version of the guidance on the format of the RMP in the EU in integrated format and by the related RMP template update. Revision 2 was a long-awaited and substantial revision of the guidance and of the RMP template. Besides streamlining the guidance text by removing duplications within the RMP modules and with other guidance documents, Revision 2 addresses most of the areas for improvement identified during previous consultations with industry. Two practitioners writing on the revision judged the new RMP template a straightforward, well-structured document that medical writers can easily use to prepare RMPs. The concepts behind risk management have been clarified and adjusted to better reflect the stages of the life cycle of a medicinal product. The revised format became mandatory for all plan submissions from March 2018, and the guidance on the format was updated in October 2018.
A risk-proportionate and shorter plan
Revision 2 brought a new RMP template and updated definitions for safety concerns aimed at reducing the laundry list of safety concerns, and it gave guidance on critically reviewing that list. A couple of years on, the substantially revised definitions of identified and potential risks had left holders clearer about how to categorise risks while keeping them aligned with the adverse drug reactions defined in the product label, and this led to re-evaluated risk management strategies and more appropriate pharmacovigilance plans for each risk.
Revision 2 redefines the purpose of the RMP to strengthen the concept of risk proportionality, and the plan is now a more risk-proportionate document. The amount of information it provides should be proportionate to risk, and it is expected to evolve during the life cycle of the product. The amount of information expected in the safety specification varies with the stage of the product's life cycle and the need for post-authorisation data. The guidance was updated to tailor the plan to different types of initial marketing authorisation application. For an initial marketing authorisation application a full plan needs to be submitted, while for products with an established safety profile and post-marketing knowledge, such as generic drugs, fixed-drug combinations with no new active substance and well-established products, most modules of the safety specification can be omitted.
At its release, Revision 2 was expected to result in shorter plans: concise, scientifically focused and risk-proportionate documents. It applies to all sections of the RMP, especially those that have become overly lengthy over time and often duplicate information presented elsewhere in the dossier or in other documents, such as the PSUR. Most sections on risks not classified as important have been removed, and the section on post-marketing experience has been reduced to the presentation of post-authorisation exposure to avoid redundancy with the PSUR. The EMA significantly cut redundant requirements that added no value or integrated their sections into more relevant plan modules, and it removed information duplicated in other safety documents. The plan's focus is now streamlined to the information relevant to the benefit-risk assessment. The changes to the administrative sections and annexes eased the writer's job considerably, particularly by reducing the time spent keeping modules consistent, while the mapping of plan sections to the other dossier modules and the periodic benefit-risk evaluation report (PBRER) stayed the same. The real breakthrough of the revision can come if it leads to plans that do not overwhelm their reader with information and data on risks already supplied in many other documents, but instead focus on their original intent: identifying or characterising the safety profile of the medicine, indicating how to characterise it further, and documenting the measures to prevent or minimise the risks, including an assessment of whether those measures are effective.
Converting existing plans
Two practitioners presenting on the revision advised that converting a plan to the Revision 2 format is not a simple matter of condensing and copying across: the critical review of the product's safety profile that the revision requires is an opportunity to remove safety concerns where appropriate. The impact of changes to the list of safety concerns has to be discussed carefully within the authoring team. A deep understanding of the principles and requirements of Revision 2 is essential to refocus the plan and to plan risk minimisation measures effectively. Understanding those principles and the expectations of the revised guidance is crucial to prepare and manage RMPs that effectively identify the risks of a medicinal product and lead to appropriate safety decisions. Pharmacovigilance writers should properly train the plan's authors at its kick-off meeting. One of those presenters advised that, when converting a plan, writers should tell their teams to use common sense, for example not generating new data for a product that has been on the market for a long time only for the sake of the revised template. Writers should also give transparent justifications for empty sections and cross-refer to previous procedures, to help the assessor understand how each section was populated.
Revision 2's changes required additional effort and resources to submit all revised plans within the regulatory deadline before the second quarter of 2018, and they had a direct impact on the existing PBRERs for most marketed products. Besides meeting the deadline, holders had to update their internal standard operating procedures and working guidance for regulatory compliance, and to meet the administrative requirement of a tracked-changes version of existing plans. Because the new template changed so much, a tracked-changes version was impossible to produce, and it could be waived for some updates by agreement with the health authority. Collaboration among the project teams and constant interactions with health authorities were vital in dealing with the changes and meeting the submission deadlines for plan updates.
In 2019, most health authorities outside the EU, with or without their own RMP requirements, were still accepting plans in the older format, but they were expected to adopt the new one soon. Holders hoped to implement a global risk management approach with minimal variation across countries, to ensure efficient monitoring of patient safety. At the revision's release, further clarifications and adjustments of the guidance were expected, based on increasing experience with Revision 2 and continuing dialogue between the EMA and industry stakeholders.