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. 2025 Feb;48(2):161-177.
doi: 10.1007/s40264-024-01487-5. Epub 2024 Nov 21.

Challenges in the Implementation of EU Risk Minimisation Measures for Medicinal Products in Clinical Practice Guidelines: Mixed Methods Multi-Case Study

Mathias Møllebæk  1 , Helga Gardarsdottir  2   3 , Alexia-Georgia Bikou  4 , Ana Kodrič  5 , Ana Marta Silva  6 , Armin Andersen  7 , Christos Kontogiorgis  4 , Elita Poplavska  8 , Fariba Ahmadizar  9 , Foteini Dermiki-Gkana  4 , Ieva Rutkovska  8 , Inês Ribeiro Vaz  6 , Mitja Kos  5 , Paula Barão  10 , Renske Grupstra  2 , Teresa Leonardo Alves  11 , Anna Birna Almarsdóttir  12
Affiliations

Challenges in the Implementation of EU Risk Minimisation Measures for Medicinal Products in Clinical Practice Guidelines: Mixed Methods Multi-Case Study

Mathias Møllebæk et al. Drug Saf. 2025 Feb.

Abstract

Introduction: Risk minimisation measures (RMMs) aim to ensure safe use of medicines, but their implementation in clinical practice is complicated by the diversity of stakeholders whose clinical decision making they seek to inform. Clinical practice guidelines (CPGs) are considered integral in clinical decision making.

Objectives: To determine the extent to which RMMs are included in the relevant CPGs and to describe factors that determine RMM inclusion.

Methods: A multi-case study design using quantitative document analysis of CPGs combined with qualitative interviews with informants from organisations that issue CPGs. Cases from five therapeutic areas (TAs) with a regulatory requirement for further RMMs were studied individually in six EU member states (Denmark, Greece, Latvia, Netherlands, Portugal and Slovenia). Clinical practice guidelines were analysed using pre-defined coding frameworks. Interviewees were sampled purposively for experience and knowledge about CPG development and RMM inclusion. Verbatim interview transcripts were analysed inductively.

Results: In total, 136 CPGs were analysed, and RMM information about TAs was included in 25% of CPGs. Based on 71 interviews we found that factors that determine RMM inclusion in CPGs include clinicians' low awareness of RMMs despite awareness of RMMs' safety concern, low expectation of RMMs' clinical utility, and unfamiliarity with pharmacovigilance data supporting RMMs and perceived incompatibility of CPGs' scope and purpose and RMM information.

Conclusions: The inclusion of RMM information in relevant CPGs is remarkably limited. It may be explained by characteristics of CPGs and of RMMs as well as lack of connection between national regulators and organisations and authors developing CPGs. More collaboration between stakeholders, national regulators and the EMA may advance implementation.

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Conflict of interest statement

Declarations. Funding: Open access funding provided by Copenhagen University. The research leading to these results was conducted as part of the activities of the EU PE&PV (Pharmacoepidemiology and Pharmacovigilance) Research Network, which is a public academic partnership coordinated by the Utrecht University, The Netherlands. The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2020/46/TDA/L4.02. This document expresses the opinion of the authors of the paper, and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. Conflict of Interest: FD; AB; CK; HG; ABA; AA; AMS; IRV; PB; AP; IR; RG; FA; TLA declare no competing interests. MM is employed by Copenhagen Centre for Regulatory Sciences (CORS). CORS is a cross-faculty university anchored institution involving various public (Danish Medicines Agency, Copenhagen University) and private (Novo Nordisk, Lundbeck, Ferring Pharmaceuticals, LEO Pharma) stakeholders as well as patient organisations (Rare Diseases Denmark). The Centre is purely devoted to the scientific aspects of the regulatory field and with a patient-oriented focus and the research is not company-specific product or directly company related. In the past 7 years, CORS has received funding from Novo Nordisk, Lundbeck, Ferring Pharmaceuticals and LEO Pharma for projects not related to this study. MK has research contracts with Krka, Vizera, Clinres and Pharmalinea with the aim of statistical analysis and a grant from AstraZeneca as support to developments of sustainability and resilience of the Slovenian healthcare system after the COVID-19 pandemic. AK has research contracts with Krka with the aim of statistical analysis. Ethics Approval: The study has been approved for ethics by relevant review boards in the EU, namely the Ethics Committee of the Faculty of Medicine of the University of Porto, Portugal (rapport no. 92/CEFMUP/2023); the Research Ethics Committee, Greece (no. 11328/51,21/10/2022.); Institutional Review Board, Faculty of Pharmacy, University of Ljubljana, Slovenia (UL FFA EMA IMPACT 20.10.2022). Ethics approval was not required for this study in Denmark (as per The Danish National Center For Ethics, see https://nationaltcenterforetik.dk/ansoegerguide/overblik/hvad-skal-jeg-anmelde ), the Netherlands (as per the Central Committee on Research Involving Human Subjects, see https://english.ccmo.nl/investigators/legal-framework-for-medical-scientific-research/your-research-is-it-subject-to-the-wmo-or-not ), and Latvia (as per the Latvian Association of Sociology, see http://sociologija.lv/etika-2/lsa-kodekss/ ). Consent to Participate: All interviewees received due information about the research project and submitted written informed consent forms about participation and citation prior to interviews. Processing of personal data complied with the EU General Data Protection Regulation. Consent for Publication: All interviewees received due information about the research project and submitted written informed consent forms about publication and citation prior to interviews. Processing of personal data complied with the EU General Data Protection Regulation. Availability of Data and Material: Data on organisations and clinical practice guidelines are available upon reasonable request. Please contact Helga Gardarsdottir (H.Gardarsdottir@uu.nl). Interview transcripts are not available. Code Availability: Not applicable. Author Contributions: The conceptualisation of the work was carried out by MM, HG, and ABA. The methodology was developed by MM, IRV, AMS, PB, HG, RG, EP, IR, AB, CK, FD, TLA, FA, and MK. Formal analysis and investigation were conducted by MM, AA, AK, IRV, AMS, PB, HG, RG, EP, IR, AB, CK, FD, and MK. The original draft preparation was done solely by MM. Writing review and editing were performed by MM, AA, AK, IRV, AMS, PB, HG, RG, EP, IR, AB, CK, FD, TLA, FA, and MK. Funding acquisition was managed by MM, HG, and TLA while supervision of the project was overseen by MM and HG. Project administration was handled by HG with visualisations created by RG. All authors have read and approved the final manuscript.

Figures

Fig. 1
Fig. 1
General steps in the process of updating clinical practice guidelines (CPGs) as identified in interviews with CPG authors in the European Union (EU) member states of particular interest
Fig. 2
Fig. 2
Procedure for identification and eligibility screening of entities that issue/update clinical guidelines
Fig. 3
Fig. 3
Flowchart of inclusion process for mapping of relevant organisations; identifying clinical guidelines; performing content analysis of eligible clinical guidelines; recruiting key informants for interviews. RMM risk minimisation measure
See this image and copyright information in PMC

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References

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