Risk Minimisation Measures (RMMs): the new approach in GVP Module XVI Revision 3

Risk Minimisation Measures (RMMs) are at the core of the newly released Revision 3 of GVP Module XVI. This updated guidance redefines strategies, tools, and criteria to enable a more effective and measurable approach to risk management. These significant regulatory updates were presented by Giovanni Diana (AIFA) during the pharmacovigilance session at the 64th AFI Symposium.

Entered into force on 6 August 2024, Revision 3 of the Guideline on Good Pharmacovigilance Practices (GVP) Module XVI – Risk Minimisation Measures aims to enhance the effectiveness of RMMs by reinforcing their integration into the overall benefit–risk management lifecycle of medicinal products. The updated guidance applies to new marketing authorisations (MA), newly proposed risk minimisation measures, and new studies evaluating the effectiveness of existing RMMs. One of the core concepts highlighted is proactivity. The revision calls for a fundamental shift in the approach to RMMs, promoting preventive strategies that incorporate emerging technologies, improve risk communication, and increase patient engagement.

GVP Module XVI Revision 3 clearly states that additional risk minimisation measures (aRMMs) should only be implemented when truly necessary and proportionate. The selection of the most appropriate tool must be based on a structured assessment that considers:

• the severity and nature of the risk, to the actions required of patients and healthcare professionals (HCPs);
• the characteristics of the medicinal product, including indication, dosage, route of administration, and potential for medication errors;
• the target population (patients and HCPs), the context of use, and specific information needs;
• the impact of the RMMs on both the patient and the healthcare system, evaluating the proportionality of the burden imposed;
• the practical feasibility and expected effectiveness of the measure, avoiding unintended negative consequences.

This approach guides marketing authorisation holders (MAHs) toward an evidence-based and justified selection of tools—whether educational, digital, or operational—in alignment with the principle of regulatory appropriateness.

Risk minimisation measures are not static tools. GVP Module XVI Revision 3 emphasises the importance of reassessing and adapting RMMs when clinical, regulatory, or operational conditions change. Key factors that may prompt revision include:

• new pharmacovigilance data or updates to the safety profile of the medicinal product;
• modifications to the marketing authorisation (e.g., new indications, patient populations, formulations);
• results from RMM effectiveness studies, particularly regarding patient representativeness;
• the need for additional materials to maintain a positive benefit-risk balance;
• organisational or technological changes within healthcare systems;
• identification of unintended adverse consequences related to the RMMs themselves;
• international experience with the same tool or measure.

In this context, educational materials should be regarded as dynamic instruments—subject to ongoing revision and optimisation. This is the only way to ensure their continued effectiveness and relevance in real-world clinical practice.

Another key innovation is the integration of advanced tools such as big data analytics and artificial intelligence to support a proactive approach to early risk identification. This has given rise to the concept of risk minimisation beyond the label. It marks a significant paradigm shift: risk minimisation measures should not be limited to the information provided in the product documentation (e.g., Summary of Product Characteristics – SmPC, Package Leaflet – PL, labelling), but may — and in some cases must — extend beyond these boundaries.

This means that regulatory authorities or marketing authorisation holders (MAHs) can propose or implement additional, more targeted tools when standard product information alone is insufficient to ensure the safe use of the medicinal product.

Examples of beyond-the-label measures include:

• targeted training programmes for healthcare professionals (HCPs);
• clinical checklists for structured risk management;
• educational campaigns for patients with complex conditions;
• digital alerts or clinical decision support tools.

The beyond the label approach recognises that, to be effective, RMMs must be tailored to real-world clinical and organisational settings — moving beyond regulatory documentation into tangible practice.

Revision 3 of the GVP Module XVI highlights the growing role of digital technologies in managing educational materials and communicating risk. Mobile apps, QR codes, online platforms, and Real-World Evidence (RWE) are increasingly seen as key tools to enhance adverse event reporting, enable continuous monitoring, and improve the dissemination of regulatory content.

In this context, the CMDh position paper supports the use of mobile technologies in official product information (SmPC, labelling, PL). Marketing authorisation holders (MAHs) may choose, on a country-by-country basis, to integrate mobile scanning features that provide direct access to digital educational materials — a step that may become mandatory in the future.

While digital solutions open up new opportunities to make educational materials more accessible and tailored, they also raise critical challenges that cannot be overlooked. GVP Rev. 3 emphasises the importance of addressing the digital divide — disparities in access to and use of technology, which may stem not only from technical limitations but also from cultural, cognitive, or linguistic barriers.

To ensure truly effective risk communication, companies must adopt a multichannel approach, deploying digital tools only when they are appropriate for the intended population. Where necessary, traditional channels should be maintained or strengthened.

The selection of digital tools for educational materials should be based on a structured assessment, taking into account the medicinal product’s therapeutic profile, the composition of the at-risk population, the nature of the risk to be communicated, technical feasibility, and the acceptability among stakeholders.

Finally, the revision underscores the need for international regulatory cooperation to harmonise RMM strategies and ensure that safety information is understandable and accessible across global markets.

The revised GVP Module XVI promotes a patient-centric approach to pharmacovigilance, where individuals are not merely passive recipients of information but active participants in the risk management process.

Key innovations include:

• direct adverse event reporting by patients;
• evaluation of RMM effectiveness through surveys and focus groups;
• co-creation of educational materials with both healthcare professionals (HCPs) and patients.

This cultural shift strengthens the ethical, qualitative, and operational impact of regulatory action, fostering a more inclusive and effective pharmacovigilance system.

The updated GVP Module XVI introduces mandatory continuous training programs for all personnel involved in pharmacovigilance activities. These programs are expected to adopt hybrid and multichannel formats, including in-person sessions, online platforms, and video tutorials.

This emphasis on ongoing education reinforces the connection between regulatory compliance and the consistent application of good clinical practice in everyday healthcare settings.

Among the updates introduced in Revision 3 is the inclusion of new official definitions aimed at enhancing clarity and consistency in the design and implementation of risk minimisation measures (RMMs).

Specifically:

• RMM Messages refer to key risk-related informational content, i.e. specific instructions for patients and healthcare professionals (HCPs) on actions to take to reduce the risk associated with a given medicinal product.
• RMM Tools are the instruments used to deliver those safety messages. They fall into two main categories:
  • Educational tools, such as risk minimisation guides, checklists, patient cards, or diaries for continuous patient monitoring;
  • Monitoring and control tools, which are more structured and formal, designed to ensure actual control over the medicinal product’s use, especially in complex settings. Examples include: supply chain traceability systems, documented exchange of patient-related information (e.g. test results between HCPs), or qualification requirements for HCPs involved in prescribing, administering, or dispensing the drug.

This new classification framework aims to improve traceability and measurability of RMM effectiveness, while supporting a modular and adaptable approach across varying clinical, technological, and regulatory contexts.

One of the most significant innovations introduced by Revision 3 of GVP Module XVI is the structured, cyclical approach to managing risk minimisation measures (RMMs). The updated process is articulated in five sequential phases:

1. Regulatory implementation of RMMs: During the marketing authorisation (MA) process, appropriate RMMs are defined and approved for each medicinal product.
2. Dissemination to the target population: Educational materials and control tools are distributed to patients, healthcare professionals (HCPs), and other stakeholders involved in the medicinal product’s use.
3. Knowledge acquisition and attitude change: Recipients must comprehend the key messages, internalise their content, and adjust their risk perception accordingly.
4. Adoption of expected behaviours: Understanding must translate into concrete actions, such as following specific instructions, avoiding high-risk practices, or adhering to monitoring protocols.
5. Improvement of health outcomes: The proper application of RMMs should lead to reduced medicinal risk, prevention of adverse events, and safer therapeutic use.

This framework underscores the need for continuous monitoring and feedback to ensure the effectiveness of each phase and the overall success of the RMM strategy.

Looking ahead, Revision 3 also outlines concrete developments in the design and dissemination of risk minimisation measures. Two main directions are emerging:

• Standardisation of RMM material naming conventions: To facilitate the identification and management of educational materials across various regulatory and healthcare contexts, the adoption of a harmonised, clear, and systematic nomenclature is encouraged. This would enhance communication between marketing authorisation holders (MAHs), competent authorities, and healthcare professionals.
• Introduction of an official visual identifier for educational materials, modelled on Germany’s Blaue Hand initiative (by BfArM). This recognisable, authoritative symbol — validated by the relevant authority — would allow both patients and HCPs to immediately identify RMM-approved materials.

These forward-looking proposals highlight the need to make pharmacovigilance not only effective but also visible, understandable, and recognisable to all stakeholders involved.

Another key focus of GVP Module XVI Revision 3 is the evaluation of the effectiveness of risk minimisation measures (RMMs). It is not sufficient to simply implement tools and materials — it is essential to assess whether they effectively reach the intended target population, are understood, and lead to tangible changes in health-related behaviour.

To achieve this, the guidance stresses the importance of a deep understanding of the medicinal product’s use context, including clinical and organisational workflows, the social environment, and patient characteristics. Only by mapping this context is it possible to identify factors that may either support or hinder the RMM’s success, such as information dissemination, health literacy, or patterns of care.

The three key expected outcomes of an effective RMM are:

1. Reach: the measure successfully reaches the intended target population.
2. Behavioural impact: patients and/or healthcare professionals adopt the behaviours necessary to minimise the risk.
3. Clinical benefit: there is a measurable improvement in health outcomes, such as a reduction in the incidence, severity, or public health burden of adverse reactions.

To measure these outcomes, two complementary approaches are proposed:

• Quantitative methods, which assess the distribution and uptake of risk communication materials, helping to identify potential barriers or distribution gaps.
• Qualitative methods, which explore how the target population perceives the risk, understands the safety messages, and what drives adherence or resistance to the proposed measures.

These assessments can be conducted through structured interviews, focus groups, or surveys, and are considered a critical phase to ensure RMMs translate into real-world impact in both clinical practice and patient lives.

The GVP guidelines stress the importance of conducting effectiveness evaluations at every stage of the RMM lifecycle, with attention to both:

• Intended outcomes, such as behaviour change or reduction of adverse drug reactions (ADRs),
• and unintended consequences, such as misinterpretations or cultural barriers.

A structured, multi-step evaluation process is recommended:

1. Coverage and distribution of the materials (e.g., receipt rates, web analytics, channel monitoring).
2. Knowledge and attitudes of the target population (e.g., surveys on risk awareness, interviews on message retention).
3. Behavioural changes (e.g., correct adherence to therapy, proper use of provided tools).
4. Clinical outcomes and unforeseen effects, which must also be tracked and integrated into the final analysis.

This multi-dimensional perspective reinforces a proactive and iterative model of pharmacovigilance, where the success of RMMs is not judged solely by clinical outcomes, but also by the ability to detect indirect signals and continuously enhance risk communication strategies.

Revision 3 of GVP Module XVI represents a paradigm shift in the management of risk minimisation measures (RMMs), elevating them from a mere regulatory requirement to strategic, dynamic tools with measurable impact. For pharmaceutical companies, this means rethinking existing processes: it is no longer sufficient to simply distribute educational materials — companies must now provide documented evidence that RMMs effectively reach target populations, influence behaviour, and improve health outcomes.

This calls for structured, multidisciplinary planning across the entire lifecycle of RMMs — from design to implementation and evaluation. Key elements include the customisation of content, selection of the most effective communication channels, and the long-term sustainability of the chosen strategies. Companies are expected to engage more closely with regulatory authorities and, equally importantly, to listen to both patients and healthcare professionals, co-developing relevant and accessible solutions.

Ultimately, the new GVP XVI encourages companies to turn compliance into value — an opportunity to build trust, enhance the safety profile of their products, and contribute to a more modern, inclusive, and genuinely effective pharmacovigilance system.