Following the thalidomide tragedy of the 1960s, a risk-oriented paradigm became a priority for regulatory authorities in reforming the testing and registration procedures for medicinal products, leading to the emergence of the international pharmacovigilance system [1]. An important tool was recognised as the assessment of the expected benefit-to-risk ratio of medicinal products, conducted using various methods throughout the product life cycle at any stage of circulation and characterised by a number of limitations [2]. Regulatory requirements and guidance on drug safety increased, yet remained focused on product characterisation prior to, rather than after, market entry, with no procedures or regulations in place for considering risk management post-authorisation.

While early medicinal product regulatory initiatives could be characterised as attempts at "risk management," by the end of the 1990s, the pharmacovigilance system had undergone a transformation towards a more proactive approach [3]. As stated in the strategic plans of the world's two leading regulatory agencies—the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA)—part of this approach within a highly regulated environment is proactive pharmacovigilance aimed at early detection and minimisation of therapeutic risks [4, 5]. Within the proactive framework, modern pharmacovigilance systems are directed at identifying changes in the benefit-risk ratio of pharmacotherapy that become apparent only during routine product use [6].

The objective of this review is to describe current international trends in the implementation of pharmacotherapy risk management strategies within the context of regulatory science, which, by examining the conceptual activities necessary to support regulatory decisions, facilitates the transition of regulatory practice towards ensuring the safe and appropriate use of medicinal products.

This review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We analysed studies related to formal risk minimisation programmes and their evaluation, published between 2008 and 2024 and indexed in MEDLINE/PubMed and Google Scholar databases. Studies were identified using appropriate Medical Subject Headings terms and related keywords: risk management; pharmacovigilance; drug safety; risk assessment; risk minimization measures; safety communications. Initial search results yielded 1736 references. Publication selection criteria included: availability of a full-text version in English, publication type—original article, review, or systematic review. Additionally, the bibliographies of peer-reviewed articles were manually screened. Articles not meeting the study objectives, duplicate articles, posters, and conference materials (reports and abstracts) were excluded. The complete literature search and article selection process is presented in Figure 1. The final review included 59 articles.

Figure 1. Flow diagram of selection of articles

Note: reasons for excluding articles from the review (n=159): erroneous topic, not associated with risks, full text not available, articles analysing the impact of other interventions.

In recent years, the risk management system specifically concerning the use and impact of medicinal products in humans has evolved rapidly, with increasing integration of risk assessment into drug development and regulatory decision-making [7, 8]. Despite differences in the wording of the term "risk management" in the regulatory documents of the United States and the European Union (EU), both descriptions are conceptually similar. According to the EMA definition, a risk management system is "...a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, including the assessment of the effectiveness of these activities and interventions"¹.

A distinguishing feature of modern pharmacovigilance is proactive risk management throughout the medicinal product life cycle, based on specific approaches. In 2001, the International Conference on Harmonisation (ICH) agreed on a conceptual document to define guidance on risk management (ICH E2E), finalised in 2004. The ICH E2E guideline² provides a structured, repeatable process for identifying and assessing risks to more accurately define all information on the safety profile of a medicinal product at the time of registration and in the early post-registration phase through two fundamental concepts: a safety specification describing the product's risk profile, and a pharmacovigilance plan outlining how these risks will be monitored and characterised. However, the issue of risk minimisation measures was not addressed [9]. In turn, in 2005, the report of Working Group VI of the Council for International Organizations of Medical Sciences (CIOMS)³ recommended developing a pharmacovigilance concept that should begin at the early stages of medicinal product development and continue into the post-registration period.

Based on the ICH E2E guideline, US and EU regulators adopted similar approaches to implementing risk control programmes, issuing in 2005 guidance documents on the development and use of Risk Minimization Action Plans (RiskMAP) and Risk Management Plans (EU-RMP), respectively. Subsequently, regulators in the US and the EU put forward a number of common risk management concepts, one of which presupposed a "common and continuous process of risk minimisation throughout the product life cycle with the aim of optimising the benefit-risk ratio" [9]. This was achieved through the use of specific risk minimisation measures and tools, as well as the evaluation of the effectiveness of these measures.

In 2014, this concept was reflected in the document of CIOMS Working Group IX⁴, which outlined the principles for identifying and applying risk minimisation tools in addition to evaluating the effectiveness of such measures. These guiding principles defined risk management planning and became an international regulatory requirement, thereby implementing proactive approaches to safety surveillance and risk assessment of medicinal products. Despite some elements of coordination, the current global situation consists of diverse risk management requirements across different jurisdictions, with national or regional regulators having implemented various risk minimisation requirements.

In both the US and EU member states, the regulator is legally entitled to require marketing authorisation holders to develop, implement, and evaluate a risk minimisation programme as a pharmacovigilance tool and a means of medicinal product market access [4, 10, 11]. In the US, the regulator's release of conceptual documents led in 2005 to the publication of guidance documents with recommendations on the following three topics:

a. pre-registration risk assessment⁵;b. good pharmacovigilance practice and pharmacoepidemiological assessment⁶;c. development and use of Risk Minimization Action Plans (RiskMAP)⁷.

The latter guidance served as the basis for the subsequent development of a more stringent and mandatory programme related to the adverse effects of certain medicinal products [12]. In the EU, the legal basis for fundamental changes in the risk management system was Article 8 of Directive 2001/83/EC⁸, requiring the inclusion in the marketing authorisation application for a medicinal product of "a detailed description of the pharmacovigilance and, where appropriate, the risk management system which the applicant will introduce," and Article 6 of Regulation (EC) No 726/2004⁹. In 2005, based on the ICH E2E recommendation that entered into force in the EU, the EMA guideline on risk management systems for medicinal products for human use was issued¹⁰. Subsequently, in 2006, the regulator published a detailed standard for the structure and content of the EU-RMP. In 2008, the final version of another key document, "Guidelines on Pharmacovigilance for Medicinal Products for Human Use (Volume 9A)"¹¹, was published, incorporating the EMA recommendations of 2005.

Under the Federal Food, Drug, and Cosmetic Act (FD&C Act) of 1938, the regulatory agency is responsible for ensuring the safety and effectiveness of all prescription medicinal products for patient use [13–15]. The Food and Drug Administration Amendments Act (FDAAA) of 2007 added a new section 505–1 (21 U.S.C. 355–1)¹² to the FD&C Act, expanding the FDA's authority over the national drug safety regulatory system. With the enactment of FDAAA, the regulator gained the ability to approve medicinal products and biological products whose registration might otherwise have been delayed indefinitely due to potential safety concerns.

Under Title IX (Subtitle A) of FDAAA, the regulator was granted the authority to request marketing authorisation holders to develop a Risk Evaluation and Mitigation Strategy (REMS) programme at any point in the medicinal product life cycle to ensure that the benefits of pharmacotherapy outweigh its risks. This was reaffirmed by the FDA Safety and Innovation Act (FDASIA) of 2012¹³. The REMS programme, as a mandatory risk management plan utilising tools beyond the prescribing information, essentially represents a paradigm shift from the limited enforcement authority of RiskMAPs, initially considered voluntary [12].

The legislative provisions of FDAAA enabled patients to have safe access to certain medicinal products with known or potential serious risks that would otherwise be unavailable [10, 13, 16–20]. FDAAA granted the FDA the authority to require manufacturers to make changes to the product label when new safety information emerges. Should a decision be made that a REMS programme is necessary, the regulator must consider "the following six factors:

In the early stages of implementation, most REMS programmes included concepts focused on disseminating information about medicinal product risks. In 2009, the regulator published a detailed draft guidance for industry, revised in 2017 and finalised in 2023, entitled "Format and Content of a REMS Document"¹⁵. Under the FDA's authority, the document established the goals and requirements of the REMS programme. Two additional documents specifically concerning the REMS programme were issued by the regulator earlier in 2011. The first document clarified the role of "Medication Guides," while the second, a revised draft guidance for industry (updated in 2019), covered the impact of FDAAA on post-marketing safety studies and clinical trial requirements. The issued documents set out general requirements and expected outcomes but lack specific tools that manufacturers could employ.

Provided that the regulator, within the REMS implementation plan, makes the necessary determination for each of its components, the manufacturer may be required to provide certain information to patients, such as a Medication Guide (MG)¹⁶ and a Patient Package Insert (PPI), as well as to healthcare professionals, such as a Communication Plan (CP). Restrictions on drug distribution or use may also be prescribed through one or more "Elements to Assure Safe Use" (ETASU) [10, 21]. An MG may be required if the regulatory agency determines that the drug "poses a serious and significant public health concern requiring the distribution of FDA-approved patient information," which can help inform about how to use the drug and avoid serious adverse reactions [20]. However, after the FDA issued the 2011 document on the role of MGs, the regulator ceased requiring them as a primary educational tool and mandatory component of the REMS programme, but retained them as part of the approved prescribing information. In most cases, the FDA includes an MG as part of the REMS programme only if there are any clinical interventions, such as patient counselling. Regarding the Communication Plan (CP), the REMS programme may require manufacturers to directly contact healthcare providers to address issues in healthcare delivery, develop specific packaging technology, or ensure the safe disposal of drugs that pose a serious risk of overdose or abuse [22].

Under the new section 505–1 of the FD&C Act (21 U.S.C. 355–1), the regulator may also require that, "because of the inherent toxicity or potential harmfulness [of the drug]," the REMS programme include additional elements known as ETASU (REMS-ETASU). Before requiring the inclusion of ETASU in a programme, the FDA must make two fundamental determinations. First, it must conclude that the drug is effective but associated with serious adverse reactions and could only be approved if ETASU are capable of mitigating the specific serious risk identified in the prescribing information. Second, for a drug initially approved without ETASU, it must be determined that other, less burdensome components, such as MG or CP, cannot mitigate the serious risk. Examples of serious and life-threatening risks include organ damage, disease progression and death, foetal exposure (e.g., embryo-foetal toxicity, developmental effects, and teratogenic effects), as well as severe allergic reactions [10, 15]. The most common risks noted in REMS programmes were embryo-foetal toxicity and drug abuse or misuse [21].

In most REMS-ETASU programmes, the stated goals involve a combination of increasing awareness of a specific risk and reducing its frequency or importance. REMS programme objectives may differ depending on the nature of the target risk. In cases where the risk is predictable and preventable through a specific intervention, the goals should clearly state this. Examples include verifying a negative pregnancy test result during treatment with drugs that have embryo-foetal toxicity or monitoring white blood cell counts in patients taking a product that may cause agranulocytosis. Conversely, some REMS-ETASU programmes target risks that are not necessarily predictable, preventable, or manageable. In such cases, more ambiguously worded goals are noted [10].

Thus, ETASU are used for medicinal products that would otherwise be unavailable due to serious safety risks, and these elements are unique to each REMS programme. According to the implementation plan, which represents a monitoring system and evaluation of those responsible for performing specific REMS tasks, ETASU may impose certain requirements that must be met by healthcare professionals, pharmacies, patients, and other stakeholders. Elements may include training and certification of specialists, certification of pharmacies or other dispensing organisations, restrictions on dispensing conditions, required documentation of safe conditions prior to dispensing, requirements for ongoing patient monitoring, and/or patient enrolment in a registry [23].

Section 505–1 of the FD&C Act requires that patient access to the drug and the burden on the healthcare delivery system be considered as primary factors when developing a REMS-ETASU programme. The law states that ETASU must not "unduly burden patient access to the drug," considering the specific important risk to be mitigated, and must be "commensurate with the specific serious risk listed in the prescribing information." The law specifically identifies three patient categories:

Furthermore, Section 505–1 defines "the extent to which [measures] are practicable," which must be undertaken to minimise the burden on the healthcare system. These measures include aligning ETASU for a given drug with those for other drugs with similar important risks and developing ETASU "to be compatible with established distribution, procurement, and dispensing systems for drugs" [20].

Prior to the recent amendment to Section 505–1, the REMS statute presumptively required that generic equivalents subject to Abbreviated New Drug Applications (ANDA) use a Shared System REMS (SS REMS) with the listed reference drug (usually the innovator product) if that drug is subject to a REMS-ETASU programme [13, 20]. Under the amended statutory provision, ANDAs may now use an SS REMS with the listed reference drug or use "a different, comparable aspect" of ETASU¹⁷. ETASU are considered "different, [but] comparable" if they use different methods or tools but achieve the same degree of safety as the original ETASU [20].

Over the past two decades, increasing attention has been focused on modernising post-marketing safety and the medicinal product risk management system, including the method of implementation and the timeline for submitting REMS programme effectiveness assessments. The core components of a REMS programme include mechanisms for informing healthcare professionals about appropriate medicinal product use, describing product-related risks to patients, and controlling product access through risk screening, i.e., by conducting questionnaires, diagnostic testing, and using specialised pharmacies. There are two ways to add, modify, or remove any goal or component of an approved REMS programme¹⁸. The first method is initiated by the holder of the approved application for a drug subject to a REMS programme, for which "adequate justification" must be submitted along with the proposed change. The second pathway occurs when the FDA requires changes, for example, based on a determination that one or more goals or elements must be added, modified, or removed from an approved REMS programme. This is necessary to, first, ensure that the drug's benefits outweigh its risks; second, minimise the burden on the healthcare delivery system; and third, consider different, comparable aspects of ETASU with respect to an abbreviated new drug application [20]. The regulator may also decide to completely revoke a REMS programme, as has been done for a number of medicinal products. In accordance with the statutory language regarding when a REMS programme may be required, the FDA has clarified that it will terminate a REMS programme if it determines that there is no longer a need for measures "to ensure that the benefits of the drug outweigh its risks"¹⁹.

The content of each REMS programme depends on its goals. At a minimum, companies marketing products with a REMS programme must, after product launch, undertake an obligation to evaluate the effectiveness of risk control measures at regular intervals, submitting a schedule for its assessments. Providing the regulator with REMS assessment reports at established intervals (18 months, 3 years, and 7 years) allows for understanding the programme's impact on proximal measures (e.g., knowledge, attitudes, and behaviour of involved parties) and distal measures (safety-related outcomes), as well as analysing the effectiveness of individual programme components, such as patient labelling and packaging, the communication plan for healthcare professionals, and other healthcare system elements implemented to ensure safe medicinal product use [15]. The REMS assessment plan is set out in the regulator's initial approval letters for all NDAs (New Drug Applications) and BLAs (Biologics License Applications) and is publicly available on the REMS@FDA²⁰ website (or at DRUGS@FDA). As of July 10, 2024, 72 active programmes are reflected, most of which include complex multi-level interventions. Title IX of FDAAA also required the FDA to develop a post-marketing system for identifying and analysing medicinal product risks, checking the adverse event database every two weeks and posting new safety signals quarterly on the regulator's established website [19].

In 2019, the regulator issued a draft guidance for industry entitled "REMS Assessment: Reporting and Planning"²¹, which encouraged "applicants and the research community to develop new methods for REMS programme assessment." Five categories for assessment were defined, including:

Depending on the complexity of the REMS programme, the number of assessment measures may vary, and each specific plan includes a range of process and outcome measures. An example of a process measure might be the number of individuals in healthcare facilities and pharmacies who have received training regarding the REMS programme. An example of an outcome measure might be the number and frequency of occurrence of specific adverse reactions of interest, such as the rate of serious bleeding or severe neutropenia [22].

Ensuring compliance with all FDA-approved REMS programmes within a healthcare system—which are numerous, unique, and constantly evolving—is a challenging task [24]. Primarily, such programmes must be developed by manufacturers for products that carry risks, relying on the experience and knowledge of healthcare professionals. Although REMS programmes play an important role in promoting medicinal products to market, numerous concerns have been raised by specialists regarding their effectiveness, notably logistical constraints and the need for costly resources for implementation [10].

At the same time, recognition of the burden of REMS programmes, particularly REMS-ETASU, on the healthcare system prompted the regulator in 2011 to pursue their integration²², the goal of which, by improving standardisation and programme effectiveness assessment across different platforms using various tools and methods, is to incorporate them into healthcare information technology [18]. As a next step, the regulator identified an initiative to build a common platform for REMS programmes, the advantages of which include reducing the workload of integration, simplifying the development process, and creating centralised tools and resources [18]. Finally, the implementation and evaluation of the effectiveness of a REMS programme represents an integral part of the cycle encompassing Benefit-Risk Assessment, Communication, and Evaluation (BRACE) throughout the therapeutic product life cycle [18, 25]. Meanwhile, the effectiveness and impact of programmes are often questioned and not always evident [10, 21, 22, 26, 27], making their support and, consequently, compliance difficult [18, 28].

A number of scientific evaluations of the REMS programme have been conducted [27, 29–35], which, in the case of specific products, yielded varying results or revealed systematic deficiencies in programme structure and function. In some cases, the REMS programme was associated with a significant reduction in potentially unsafe use of prescription drugs [30], while in other circumstances, REMS programmes were so limited in their design and implementation that their success could not be evaluated [35], or such evaluations revealed no impact [34]. A general consensus is emerging that the limited nature of evaluations stems from problems with collecting actual data on the effectiveness of risk minimisation programmes, along with the absence of a standardised format for assessment plans [22].

A report by the US Office of the Inspector General (2012) noted that gaps in reporting on programme effectiveness limit the regulator's ability to determine whether risk minimisation programmes actually enhance drug safety, and recommended the development and implementation of a plan to identify, prepare, review, and evaluate REMS programme components [36]. In response, experts proposed improving programmes by incorporating elements of a "continuous learning system" [26, 37, 38]. Such an approach emphasises ongoing staff training and improvement, transparency, patient orientation, responsiveness to the healthcare context, and consideration of external environmental factors. The risk management process in this evolving learning healthcare system plays a central role, assessing the product's benefit-risk ratio over time, implementing risk minimisation measures, evaluating the impact of such measures, and, as necessary, modifying them to ensure maximum effectiveness and adaptation of the product's registration status as new information becomes available [25, 39]. Furthermore, to improve the quality and consistency of reporting on therapeutic risk minimisation and support evidence synthesis, a checklist entitled "Reporting recommendations Intended for pharmaceutical risk Minimization Evaluation Studies" (RIMES) was recently published [40]. In this regard, rapid growth of scientific recommendations has been noted in this area [41, 42].

In the EU, the foundation of the pharmacovigilance system is represented by the regulatory network consisting of the competent authorities, known as National Competent Authorities (NCAs) of the Member States, the European Commission (EC), and the EMA. Ongoing cooperation between them ensures coordination and alignment of individual efforts to achieve the common goal of public health protection through an approach based on the existence of clear roles and responsibilities [43]. The EU regulatory model provides that while NCAs retain responsibility for medicinal products authorised in their territory, the EMA provides coordination to support the scientific evaluation, supervision, and safety monitoring of all medicinal products on the EU market. A key instrument responsible for all activities of the risk management system is the Pharmacovigilance Risk Assessment Committee (PRAC), established within the EMA. The review of the European pharmacovigilance system, initiated in 2005, led to its strengthening and significant changes to the existing regulatory framework²³. Directive 2010/84/EU and Regulation (EU) No 1235/2010, adopted by the European Parliament in December 2010 and amending the existing documents, initiated substantial changes in the safety monitoring of medicinal products in the EU, consolidating the pharmacovigilance system. The legislation, representing the most significant change in the regulation of human medicinal products since 1995, was accompanied by an implementing regulation (EU No 520/2012), a legally binding act published by the EC in June 2012, detailing various aspects of the application of the new legislation. In parallel, EMA and NCA experts developed guidelines on Good Pharmacovigilance Practices (GVP)²⁴. A significant feature of the updated EU legislation, which entered into force in July 2012, was the 16 modules of the GVP guidelines, covering the core pharmacovigilance processes [11, 44–48]. The GVP guidelines, as a set of measures to improve the conduct of pharmacovigilance, apply to applicants/marketing authorisation holders, the EMA, and regulatory authorities in EU Member States. These measures cover products authorised for sale both under the centralised authorisation procedure through the EMA and through national and mutual recognition actions. Current GVP practice integrates the core European pharmacovigilance processes and approaches specific to a product or target population.

The EU-RMP, introduced into practice by the EMA in 2005 and later presented in the 2008 guidance ("Volume 9A"), became a legally binding element of the registration dossier for obtaining marketing authorisation in the EU for any medicinal product with the implementation of the GVP guidelines in 2012. As a proactive planning instrument, the EU-RMP is focused on managing important risks throughout the product life cycle to ensure that the benefit of a specific medicinal product exceeds its risks by the maximum achievable margin [47, 49]. The role of the EU-RMP as a key document evolved in parallel with the updating of regulatory guidance, reflecting the increased experience of both NCAs and the EMA, as well as marketing authorisation holders [47]. The regulatory document adopted by the regulator in June 2012, entitled "Guideline on Good Pharmacovigilance Practices (GVP), Module V – Risk Management Systems," intended for risk management planning, represented a shift in focus from simple risk management to understanding risks in the context of benefit. Moreover, in April 2014, the first revision of Module V (Version 1) of the GVP guidelines entered into force, addressing primarily the clarification of terminology²⁵. Following numerous assessments and proposals received from stakeholders, the regulator published a more comprehensive revision of Module V (Version 2) of the GVP guidelines in March 2017²⁶, marking a paradigm shift in the approach to risk management planning. Alongside this, the "Guidance on the format of the risk management plan (RMP) in the EU – in integrated format, version 2.0.1" entered into force in October 2018²⁷, accompanying Module V (Version 2) of the GVP guidelines. Essentially, Module V (Version 2) of the GVP guidelines underwent three main changes: 1) additional clarification of the focus of the EU-RMP regarding the safety issues to be included; 2) increased attention to the dynamic nature of the EU-RMP, including considerations for the reclassification and removal of safety-related issues throughout the product life cycle; and 3) updated requirements to support the development of risk-proportionate EU-RMPs depending on the type of initial marketing authorisation application (e.g., generics, fixed combinations, and biosimilars) [48].

According to the regulatory documentation, the EU-RMP consists of three interrelated and iterative key components: the safety specification, the pharmacovigilance plan, and the risk minimisation plan [44, 47, 48, 50, 51]. The safety specification summarises data on the product's safety profile at a specific point in time, focusing on "important identified risks," "important potential risks," and "missing information"—concepts collectively termed "safety concerns." In the context of risk management, the term "important" refers to anything that will depend on a number of factors, including the impact on the individual patient, the seriousness of the risk, and the public health impact. The classification of important risks to be included in the EU-RMP was reassessed over time: from adverse events, including topics from Section 4.8 "Undesirable Effects" of the Summary of Product Characteristics (SmPC) from 2005 to 2012, to unexpected adverse reactions, which, according to Directive 2010/84/EU, are clinically important and are likely to be included in or may be added to Section 4.3 "Contraindications" or 4.4 "Special warnings and precautions for use" of the product information from 2012 onwards. A consequence of the changing requirements and format of the EU-RMP was the numerous legacy of products authorised before 2012, when serious work began on the corresponding conversion of documentation for existing products to meet the new requirements, which is still ongoing.

Safety concerns require identification, further characterisation, and quantification of new important risks, as well as the synthesis of knowledge to address issues concerning missing information or specific risk minimisation measures. The EU-RMP is unequivocally focused on considered important identified and potential risks, as they may primarily affect the product's benefit-risk balance or have public health implications. An identified risk is defined as an undesirable clinical outcome for which there is adequate scientific evidence of a causal relationship with the medicinal product. A potential risk is also defined as an undesirable clinical outcome for which there is scientific evidence to suspect a possible causal relationship with the drug, although the available data are insufficient to confirm it. At the same time, the concept of "missing information" means limited knowledge of the product's safety for a specific intended use, e.g., long-term or in special patient populations. Missing information should be limited to gaps in safety knowledge when using the product for approved indications, where there are scientific grounds to suspect that its safety profile differs from that previously characterised [47, 48]. Thus, as a result of significant changes in the content of the regulatory document, the focus is on a more thoughtful, concise, effective, and evidence-based EU-RMP. This contrasts with the initial revision of the guidance on the EU-RMP, which often led to the compilation of extensive lists of safety concerns, many of which did not require active risk management [48].

The pharmacovigilance plan, describing the methods for monitoring and/or further characterising the important risks included in the safety specification, establishes how risks and missing information about them will be identified, characterised, and tracked in the post-registration period. This plan consists of two types of activities: (1) routine pharmacovigilance activities, going beyond adverse reaction reporting and signal detection; and (2) additional pharmacovigilance activities. The types of activities described may include interventional (clinical), non-interventional (epidemiological), or non-clinical studies. Although the EU-RMP was intended as a planning document, its specific role in the pharmacovigilance system and how it should be shaped over time remained unclear until the introduction of the updated Module V (Version 2) of the GVP guidelines. The regulator provided necessary clarifications regarding the dynamic nature of risk management planning; namely, it is "a continuous process that occurs throughout the product's life cycle, beginning at the pre-registration stage, being assessed during the marketing authorisation application, and continuing throughout the post-authorisation period." It is expected that as the product matures, as new knowledge about its benefit-risk profile is gained, the EU-RMP specification will change, which over time will lead to changes in the safety concerns. Thus, in contrast to earlier versions, Module V (Version 2) of the GVP guidelines contains explanations on the reclassification and removal of safety concerns within the EU-RMP, based on the need and feasibility of their further assessment and/or the need for specific risk minimisation measures (RMM).

The risk minimisation plan, as the third key component of the EU-RMP, defines the strategy for minimising important and potential risks through a plan of risk minimisation measures to optimise the benefit-risk balance. Alongside routine risk minimisation measures, additional measures are considered for specific safety concerns that cannot be addressed by routine measures. In April 2014, the regulator published Module XVI (Version 1) of the GVP guidelines for the first time, as guidance on the selection of tools and effectiveness indicators for risk minimisation measures. In March 2017, its revised version—Module XVI (Version 2) of the GVP guidelines—was approved, and in 2021, a draft of the next update (Version 3) was prepared. According to Module XVI (Version 2) of the GVP guidelines, "risk minimisation measures are interventions aimed at preventing or reducing the occurrence of adverse reactions associated with exposure to a medicinal product, or reducing their severity or impact on the patient should an adverse reaction occur. The planning and implementation of risk minimisation measures and the evaluation of their effectiveness are key elements of risk management." It should be noted that evaluating the effectiveness of risk minimisation measures is becoming an actively developing area of regulatory science [52–54].

Similar to the structure of the pharmacovigilance plan, the risk minimisation plan consists of two types of measures. The first type includes "routine" measures (rRMM) applicable to all medicinal products, with an emphasis on recommendations for specific clinical measures to address important risks. The second type includes "additional" measures (aRMM), which are considered necessary for the safe and effective use of the product [45, 52, 54–59]. Most safety concerns can be adequately addressed through rRMM, including restrictions on pack size and distribution channels, the legal status of the drug, appropriate wording of information in the SmPC for healthcare professionals, and Patient Information Leaflets (PIL). However, this may prove insufficient, allowing for the introduction of aRMM supplementing rRMM. aRMM may include additional educational materials for healthcare professionals and patients, more stringent controlled access programmes/distribution systems, Pregnancy Prevention Programmes (PPP), and Direct Healthcare Professional Communications (DHPC). The need for aRMM for a medicinal product is assessed both at the time of obtaining centralised marketing authorisation and during the post-registration period [55, 60]. Furthermore, new risk information may necessitate post-registration introduction, modification, or discontinuation of aRMM [51]. The additional burden of aRMM on healthcare professionals, patients, and marketing authorisation holders must be proportional to the level of risk(s) [59].

Monitoring the effectiveness of aRMM, as an important element of medicinal product risk management, is an unconditional requirement of Directive 2010/84/EU, which states that the marketing authorisation holder must "monitor the outcome of the risk minimisation measures contained in the RMP or established as conditions of the marketing authorisation" [54]. To this end, Module XVI (Version 2) of the GVP guidelines provides a regulatory framework for evaluating the effectiveness of aRMM. The guidance emphasises that the timing of aRMM effectiveness measurement should be determined on a case-by-case basis for any medicinal product. Nevertheless, recommendations are proposed for time points that are of particular importance for such assessment, namely, after the initial implementation of aRMM (e.g., within 12–18 months) and at the time of marketing authorisation renewal (i.e., five years after initial registration).

Evaluating the effectiveness of aRMM is recommended using process indicators and/or final outcome indicators, preferably using the "dual evidence" approach, as recommended in guidelines and literature [61, 62]. Process indicators measure the level of programme implementation, its execution according to plan, as well as the impact on the acquisition of clinical knowledge and changes in clinical actions and behaviour of the target user group. Outcome indicators provide the overall level of risk control achieved through aRMM, for example, a reduction in the frequency and/or severity of adverse reactions or other safety-related outcomes [45, 53, 61–63]. To establish whether these aRMM were indeed effective and to decide whether corrective actions should be undertaken, studies evaluating the effectiveness of these measures at various time points after aRMM implementation are necessary. Systematic evaluation to confirm aRMM effectiveness represents the final and arguably most complex step to be undertaken to preserve public health [52, 61, 64].

As a rule, aRMM can be evaluated through routine activities, for example, submitting Periodic Safety Update Reports (PSURs) for the medicinal product to the regulatory agency and/or additional pharmacovigilance activities. However, the need for speed in implementing additional activities must be properly balanced with study quality [5, 59]. Under European pharmacovigilance legislation, studies conducted to evaluate the effectiveness of RMM fall under the competence of Post-Authorisation Safety Studies (PASS). As a regulatory framework for PASS, Module VIII (Version 3) of the GVP guidelines establishes guiding principles from study protocol development to the final report under PRAC oversight [65]. PASS is defined as any study relating to an authorised medicinal product conducted with the aim of identifying, characterising, or quantifying a safety hazard, confirming the safety profile of the medicinal product, or measuring the effectiveness of risk management measures. Most such studies are cross-sectional surveys designed primarily to assess the knowledge and self-reported behaviour of the target audience in relation to the content of RMM, as well as Drug Utilisation Studies (DUS) using secondary data sources [54, 66–68]. However, the sampling methodologies used in RMM effectiveness evaluation studies are poorly understood. Primary attention should be paid to the representativeness of the study sample in terms of generalising the impact of aRMM on the target population. Recommendations indicate the need for a thorough consideration of the source population, description of the sampling frame, provision of detailed information, sampling methods, and documentation of the proportion of non-respondents and their characteristics [69]. Although collecting evidence and conducting detailed outcome assessments are time-consuming, if aRMM adjustments are necessary, they should be implemented as quickly as possible to protect patient health and/or reduce unnecessary burden on stakeholders [52]. The electronic register of EU post-authorisation studies (EU PAS Register) [70], available through the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), serves as a repository for PASS protocols and reports. It has been used in a number of studies to assess the characteristics and methodological aspects of aRMM evaluation [45, 54, 62, 66, 68]. Thus, formal evaluation of aRMM effectiveness in the post-registration phase is crucial for the continuous reassessment of the medicinal product's benefit-risk balance, as it verifies whether aRMM goals have been achieved and whether these measures are sufficiently integrated into routine clinical practice [5, 59].

The implementation of the American REMS programme and its European equivalent—the risk management plan (EU-RMP), of which risk minimisation measures are a part—has advanced the evolution of risk management standards within the pharmacovigilance system. As a rule, both concepts, REMS and EU-RMP, are concerned with managing and preventing important risks associated with medicinal products, with the aim of ensuring that benefits outweigh risks. Nevertheless, neither regulator provides specific guidance on how risk should be weighed against benefit, either qualitatively or quantitatively.

Following the US and the EU, which established risk management systems in the early years of the new century, new regulations were adopted worldwide, fundamentally changing the regulatory configuration and providing a much more structured and targeted approach to drug safety. In some countries, there is no specific legislative basis enabling the government to require a pharmaceutical company to submit an RMP. Regulatory authorities take action based on broader and less specific powers under existing rules. In other countries, a legislative approach has been adopted whereby laws require the implementation of RMPs with appropriate risk minimisation measures for certain medicinal products. In 2016, the Russian Federation, as a member state of the Eurasian Economic Union (EAEU), adopted the EAEU GVP guidelines for the first time, prepared by a working group based on the EU GVP guidelines (2012), which necessitated the unification of the existing national pharmacovigilance system. A detailed analysis of the requirements of the European and Eurasian GVP guidelines allows for the identification of potential differences, which is important when planning and harmonising the work of pharmacovigilance systems in the EAEU and the EU. At the same time, the current version of the EAEU GVP guidelines (from 2022) is not a simple translation of the EU GVP guidelines, remaining synchronised with the European version in force at the beginning of 2021, taking into account the provisions and requirements of other EAEU regulatory acts.

The existing risk management paradigm, exerting strategic influence throughout the product life cycle, is a critically important topic for the pharmaceutical industry and regulatory authorities in obtaining marketing approval for a drug. The key drug safety programmes, known as Risk Evaluation and Mitigation Strategies (REMS) in the US and Additional Risk Minimisation Measures in the EU, should be periodically evaluated to determine how effective they are in minimising the target risk associated with pharmacotherapy. Without improved reporting and transparency, opportunities to gather evidence in this area and to benefit from past risk reduction efforts remain limited. Risk minimisation is currently a dynamically developing area of research at the intersection of pharmacovigilance, pharmacoepidemiology, and regulatory science, which offers innovative approaches and plays an important role in advancing patient-centred healthcare. At the same time, to improve evaluation methods, enhance the effectiveness of risk minimisation programme development, and develop new, more effective risk minimisation tools and associated implementation strategies, there is a need for broader interdisciplinary collaboration. Factors such as changing public expectations, new technologies and types of therapeutic products, as well as the growing personalisation of medicine, while impacting the pharmacovigilance system, are becoming grounds for changes in the approach to pharmacotherapy risk management.