XVI.B.1. Principles of risk minimisation

XVI.B.1.1. Risk minimisation within the benefit-risk management cycle of the medicinal product

The pharmacovigilance activities for identifying and assessing risks as well as implementing and evaluating RMM for a medicinal product, as performed by marketing authorisation holders (see XVI.C.2.) and the competent authorities (see XVI.C.3.), start with the medicinal product development in the pre-authorisation phase and continue iteratively throughout the post-authorisation phase.

At the time of granting the marketing authorisation of the medicinal product, a RMP is put in place to describe the pharmacovigilance activities for data collection and the RMM. In the post-authorisation phase, new information on existing risks or RMM may emerge or new risks may be identified, which may require new or adapted RMM or RMM dissemination plans to maintain or improve the positive riskbenefit balance of the medicinal product. This process can be depicted as a learning cycle (see Figure XVI.1.), as part of quality management of pharmacovigilance (see XVI.B.7.).

Within this cyclic process, collecting formative data (see XVI.B.1.3.) and input from patients and healthcare professionals (see XVI.B.1.4.) and evaluating RMM effectiveness (see XVI.B.5.) may support evidence-based decisions for requiring and selecting (see XVI.B.3.) or adapting (see XVI.B.6.) RMM, as well as for developing RMM materials and dissemination plans (see XVI.B.4.).

XVI.B.1.2. Intended outcomes of risk minimisation measures

RMM should have clearly defined intended outcomes in terms of:

• Reaching the target populations;
• Knowledge adoption and attitude formation8 in the target populations and their taking of the intended actions for risk minimisation; and
• Health outcomes in terms of reduced occurrence or severity of adverse reactions or the reduced adverse impact of such reactions on patient or public health.

XVI.B.1.3. Implementation pathway of risk minimisation measures

The intended outcomes of RMM (see XVI.B.1.2.) are achieved along an implementation pathway (see Figure XVI.2.). This pathway distinguishes between:

• Regulatory implementation, which refers to the inclusion of the RMM in the marketing authorisation of the medicinal product (see XVI.C.1.) and the approval of the RMM materials by the competent authorities (see XVI.C.3.2.);
• Dissemination of the RMM, which includes making the product information available and disseminating additional RMM materials to the target populations; and
• Implementation of the RMM in healthcare, which also includes further dissemination of RMM materials from the healthcare professional initially receiving the RMM materials within the healthcare setting and/or to patients, knowledge adoption, attitude formation and actions taken by healthcare professionals and patients as intended for risk minimisation.

While the regulatory implementation of RMM lies within the remit of competent authorities, the development and dissemination of RMM to the target populations fall under the responsibility of the marketing authorisation holders, who are subject to regulatory oversight and inspections (see GVP Module III). Additionally, competent authorities may disseminate information on RMM as part of their legal obligations for safety communication (see GVP Module XV). Generally speaking, dissemination also covers the dissemination of the RMM messages through other channels, e.g. the scientific or general media, which lie outside regulatory oversight, but may be used in the context of wider engagement with healthcare professionals and patients (see XVI B.1.4.) and dissemination planning (see XVI.B.4.2.).

Further dissemination of RMM materials from healthcare professionals to patients may in some instances be an intended action for risk minimisation. Also, wider dissemination of RMM materials or messages within healthcare systems may be necessary to achieve full implementation of RMM. The full implementation of RMM in healthcare takes place through the systems providing healthcare for individual patients. How the intended actions for risk minimisation are integrated in healthcare processes or patient routines will depend on the healthcare settings where the medicinal product is prescribed, dispensed and administered and/or the patient environments, circumstances and care processes.

Within the proactive approach to risk minimisation, implementability refers to the expected opportunities of RMM being implemented effectively in terms of achieving the intended outcomes (see XVI.B.1.2.) and avoiding the potential for unintended outcomes (see B.5.1.), based on evaluative and/or formative evidence on RMM effectiveness and context (see XVI.B.1.1.) and input from patients and healthcare professionals (see XVI.B.1.4.). It is relevant to gain a contextual understanding of the use of the medicine, disease management and overall clinical context, healthcare settings and processes, typical patient environments, circumstances and care processes, health information diffusion, existing knowledge, attitudes and behaviours in target populations, how RMM tools and the intended actions for risk minimisation could be integrated into the given processes, and individual and system factors, which may be enablers or barriers to RMM effectiveness. Both evaluative and formative evidence generation uses the methods described in GVP Module XVI Addendum II.

XVI.B.1.4. Engagement of patients and healthcare professionals in risk minimisation

Engagement across all stakeholders is considered crucial for achieving full implementation (see XVI.B.1.3.) and effectiveness of RMM. Given this shared responsibility, inclusive and appropriate interactions between competent authorities, marketing authorisation holders, healthcare professionals and patients in accordance with their respective roles and responsibilities are important and should be encouraged. For marketing authorisation holders, such interactions should be separate from promotional activities (see XVI.B.1.5.).

Where additional RMM tools are considered, patient and healthcare professional representatives may be approached in particular to:

• Provide input on RMM options regarding e.g. the tools, messages, target populations, ethical acceptability and implementability (see XVI.B.1.3.) to support regulatory decisions on RMM (see XVI.B.3. and XVI.B.6.);
• Contribute to the development of RMM materials, e.g. through user-testing of RMM materials, and provide input on dissemination plans (see XVI.B.4.);
• Support the dissemination via multiple channels, including those outside the regulatory oversight, to address the media preferences of the target populations and to support the implementation of RMM in healthcare (see XVI.B.1.3.);
• Provide input on and participate in the evaluation of RMM effectiveness (see XVI.B.5.).

XVI.B.1.5. Non-promotional nature of risk minimisation and personal data protection

Any visualisations in the package leaflet or labelling of the packaging shall exclude any element of a promotional nature [DIR Art 62]. Likewise, any RMM material should not contain or be combined with any promotional elements, either direct or veiled, and follow locally applicable policies. Also studies evaluating RMM effectiveness should not contain any promotional element and be separate from any promotional activity, and non-interventional post-authorisation safety studies (PASS) shall not be performed where the act of conducting the study promotes the use of a medicinal product [DIR Art 107m(3)] (see GVP Module VIII).

Any contact information of healthcare professionals or patients which may possibly be gathered through RMM-related activities, including stakeholder engagement (see XVI.B.1.4.), must not be used for any other, including promotional, activities and must be handled in accordance with the provisions of the legislation on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, as laid down in Regulation (EU) 2016/679 (General Data Protection Regulation) and Regulation (EU) 2018/1725 of the European Parliament and of the Council.

In the context of RMM, the invented name of the medicinal product is not considered a promotional element, but should be used as rarely as possible (see XVI.B.4.1.1.).

The marketing authorisation holder`s and/or the product`s logo should generally be avoided; however, if suggested to appear for a given reason, it/they should appear only once in each RMM material and not be larger than the heading font size.