Additional Risk Minimisation Measures for Medicinal Products in the European Union: A Review of the Implementation and Effectiveness of Measures in the United Kingdom by One Marketing Authorisation Holder

Abstract

IntroductionAdditional risk minimisation measures (aRMMs) for medicinal products are necessary to address specific important safety issues which may not be practically achieved through routine risk management measures alone. The implementation and determination of effectiveness for aRMMs can be a challenge as it involves multiple stakeholders. It is therefore important to have concise objectives to avoid undue burden on patients, healthcare professionals and the healthcare system.AimThe aim of this study was to examine how aRMMs are implemented and how effectiveness is assessed in the European Union (EU) using practical examples from Roche Products Limited in the United Kingdom (UK) (referred to as the ‘Company’).MethodsThree centrally authorised products were selected from the Company’s portfolio, each of which had aRMMs to address important safety concerns; specifically, teratogenicity, medication error and infections. The implementation of EU aRMMs, effectiveness checks and specific UK activities were analysed. Hard copy folders and electronic sites for Company aRMMs were used to assess process indicators. Periodic benefit-risk evaluation reports for specified time intervals and the Company safety database was used in checking safety outcomes for the selected products. For each product, the effectiveness of aRMMs was analysed based on specific process indicators and the subsequent safety outcomes. Literature searches were performed on scientific databases for the purposes of the broader study.ResultsThe main process indicators in measuring effectiveness of Company aRMMs were distribution metrics for educational materials, assessment of awareness and clinical actions among healthcare professionals (HCPs). Case reports of pregnancy, medication errors and progressive multifocal leukoencephalopathy (PML) were the outcome indicators for Erivedge®▼, Kadcyla®▼ and MabThera® (the latter specifically in autoimmune indications: rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis) respectively. No pregnancy, one medication error and 10 confirmed PML cases were reported for Erivedge®▼, Kadcyla®▼ and MabThera® respectively.ConclusionsFor the chosen products, a reasonable awareness of aRMMs amongst HCPs is a positive indicator of success in the use of educational materials. However, low response rates from surveys indicate that voluntary feedback may not always achieve the desired level of response in measuring effectiveness. There is a challenge in determining overall effectiveness of aRMMs due to a lack of defined success thresholds. Further regulatory guidance to outline the elements and desired outcomes of aRMMs will be useful for consistency in achieving successful outcomes.

Evaluation of the Effectiveness of Additional Risk Minimization Measures for Voriconazole in the EU: Findings and Lessons Learned from a Healthcare Professional Survey

“…However, despite many strengths, surveys also have limitations [24]. The low response rates from surveys suggest that providing feedback on a voluntary basis does not always achieve the desired level of response [33]. Many limitations are illustrated by this survey.…”

“…A review of all completed aRMM evaluation surveys (classified as PASS) from the EU PAS Register found that only 2 of 11 cross-sectional surveys selected 80% as a predefined threshold of success [23]. Better understanding of the suitable thresholds for aRMM success [33] and whether these thresholds differ by stakeholder, specialty, risk, or other factors, would be valuable when making conclusions about the program's effectiveness.…”

Description of the Risk Management of Medication Errors for Centrally Authorised Products in the European Union

“…administration errors) can be difficult to identify in such data. Surveys to investigate whether HCPs understand the material may be biased, as HCPs who are more aware of the educational material may be more inclined to participate in such a survey [28]. In addition, it is possible that those who read the material, but also experienced the ME, are less likely to participate because of social desirability bias.…”

“…We observed that for most CAPs in our dataset, studies to assess the effectiveness of aRMMs for MEs were agreed upon. However, only a few effectiveness studies concerning MEs have been published in publicly available domains [28,29]. Public availability of these studies could help develop new techniques to measure the effectiveness of aRMMs and improve outcomes.…”

Prescribers’ compliance is part of benefit-risk assessment of medicines and it can lead to failure of risk minimization measures and withdrawals of medicines

“…Most of the safety concerns related to medicinal products may be assuaged with routine RMMs, including pack size restrictions, adequate wording in patient information leaflets (PILs) which are included in the pack with medicine, and a summary of product characteristics (SmPC)-a legal document approved as part of the marketing authorization of a medicinal product, which includes information for healthcare professionals on how to use the medicine 9 .…”