Duration of Effectiveness Evaluation of Additional Risk Minimisation Measures for Centrally Authorised Medicinal Products in the EU Between 2012 and 2021.

INTRODUCTION: In studies evaluating the effectiveness of additional risk minimisation measures (aRMMs), the need for speed must be properly balanced with the quality of the study. We assessed the duration of aRMM effectiveness evaluations, using additional pharmacovigilance activities, for centrally authorised medicinal products in the European Union. METHODS: We established a cohort of medicinal products with aRMMs at marketing authorisation (MA) that were centrally authorised from July 2012-December 2021 using the European Public Assessment Reports. Evaluation studies were identified from the Risk Management Plans at the time of MA. Subsequently, we retrieved protocols, final study reports, Pharmacovigilance Risk Assessment Committee (PRAC) assessment reports, and PRAC minutes. We calculated the probability of completing an effectiveness evaluation within 60 months after MA using time-to-event analyses. Besides, we compared the planned final report with the actual final report date. RESULTS: We identified 134 medicinal products authorised with aRMMs, of which almost half (n = 63, 47.0%) had an effectiveness evaluation study. The probability of an evaluation for a medicinal product being completed within 60 months after MA was 20.7% (95% CI 6.8-32.6). Regarding study design, the probability of completing a study was higher for cross-sectional studies when compared to cohort studies (p = 0.002). Moreover, 81.0% of studies were delayed when compared to their planned final report date. CONCLUSION: The probability of completing an aRMM effectiveness evaluation at time for renewal of the MA was only one in five. Furthermore, estimates of the duration of studies around MA are too optimistic, with the majority being delayed.

Introduction or Discontinuation of Additional Risk Minimisation Measures During the Life Cycle of Medicines in Europe.

INTRODUCTION: Additional risk minimisation measures (aRMMs) may be required to minimise important risks of medicines. aRMMs may be required at the time of authorisation, but may also be introduced or discontinued during the product life cycle as new safety information arises. The aim of this study is to describe post-authorisation introductions of new aRMMs and discontinuations of existing aRMMs for medicines authorised in the European Union (EU). METHODS: We performed a retrospective cohort study that included all new active substances authorised through the EU centralised procedure between January 1st 2006 and December 31st 2017. Data was extracted from European Public Assessment Reports available on the website of the European Medicines Agency (ema.europa.eu). Medicines were followed up from the date of marketing authorisation (MA) until first introduction or discontinuation of aRMMs, excluding Direct Healthcare Professional Communications (DHPCs), withdrawal/suspension/revocation of the MA, or July 1st 2018, when data extraction took place. Descriptive statistics were used to analyse frequency data, and survival analysis was used to calculate 5- and 10-year probability of introduction or discontinuation of aRMMs. RESULTS: A total of 476 medicines were authorised during the study period. The probability of getting aRMMs after authorisation for products authorised without aRMMs was 3.5% [95% confidence interval (CI) 1.2-5.7] within 5 years after authorisation and 6.9% (95% CI 2.6-11) within 10 years after authorisation. For products authorised with aRMMs, the probability of discontinuation of aRMMs was 0.9% (95% CI 0-2.6) within 5 years and 8.3% (95% CI 0-16.1) within 10 years after authorisation. CONCLUSIONS: We found low probabilities of introduction and discontinuation of aRMMs (excluding DHPCs) during the product life cycle for medicines authorised between 2006 and 2017. The low rate of discontinuation may potentially be due to a lack of robust data on effectiveness of aRMMs. Further research is needed to get more insight into the dynamics of aRMMs during the medicine life cycle.

Measuring the impact of the 2012 European pharmacovigilance legislation on additional risk minimization measures.

AIMS: Additional risk minimization measures (aRMMs) may be needed to ensure that the benefits continue to outweigh the risks for medicines associated with serious risks. Prior research showed an increasing trend in medicines with aRMMs. We assessed whether the European pharmacovigilance legislation may have impacted the number and type of aRMMs. METHODS: We included new active substances approved between 1 January 2010 and 31 December 2015. Information extracted from the summary of the Risk Management Plan at the time of licensing included date and type of marketing authorization, presence and type of aRMMs. We tested for differences using Pearson's Χ2 test and segmented Poisson regression. RESULTS: We identified 231 medicines approved during the study period, of which 30% had aRMMs at the time of licensing. ARMMs were in place for 38% of medicines before July 2012 and for 28% after (p = 0.16). Segmented Poisson regression did not show changes in trend or level of medicines with aRMMs. DISCUSSION AND CONCLUSION: During the study period, no significant differences in the proportion or trend of products with aRMMs at the time of licensing before and after the pharmacovigilance legislation were identified.

Post-approval evaluation of effectiveness of risk minimisation: methods, challenges and interpretation.

Evaluation of the effectiveness of drug risk-minimisation measures is mandatory for both risk evaluation and mitigation strategies (REMS) in the United States and risk management plans in the European Union (EU-RMPs). Such evaluations aim to assess the impact of risk-minimisation measures on the knowledge, attitudes or behaviours of healthcare professionals or patients, the incidence of safety concerns, and their impact on the overall benefit-risk balance. Although many effectiveness evaluation models and methods are available, regulatory guidance and policy are still evolving. This paper considers evaluation strategies, challenges in evaluating risk minimisation post-authorisation, possible outcome measures and their interpretation, and potential emerging regulatory policy issues. Particular challenges include appropriate data collection, perceived and real burdens of performing evaluation on clinical practice, lack of comparators and benchmarking, and uncertainty about the best outcome measures.

Additional risk minimisation measures in the EU - are they eligible for assessment?

PURPOSE: "Additional" risk minimisation measures (aRMMs) can be necessary to optimise the benefit-risk balance of a drug. Evaluation of effectiveness of these measures has become mandatory with the new European Union (EU) pharmacovigilance legislation in force since July 2012. The aim of this study was to classify the aRMMs in the EU with a special emphasis on the possibilities to analyse the effectiveness of these aRMMs in existing electronic healthcare databases (EHDs). METHODS: European Public Assessment Reports were reviewed to identify key elements of the aRMMs. Researchers categorised the key elements based on the objectives, i.e. knowledge change or behavioural change and sub-categorised the behavioural changes. They assessed for each key element if it would be eligible for analysis in existing EHDs. RESULTS: 68 drugs with aRMMs contained 801 key elements of which 57% aimed at behavioural changes. 22% of all key elements, all aimed behavioural changes, were assessed eligible for analysis in existing EHDs. These mainly concerned recommendations targeted at healthcare professionals regarding drug prescription, e.g. dose recommendations, contraindications or the need to perform laboratory tests for patient monitoring. CONCLUSIONS: Only a limited proportion of key elements of the aRMMs could potentially be monitored in existing EHDs as these data sources cannot capture all the required data. Due to difference between existing EHDs, not necessarily all available EHDs are appropriate for every drug or aRMM. To facilitate rapid evaluation of aRMM implementation and timely adjustments, industry and regulatory authorities should agree well-defined key elements of aRMMs leading to unambiguous actions of the target group.

Risk minimization activities of centrally authorized products in the EU: a descriptive study.

BACKGROUND: : Since the new legislation on risk management, which came into force in November 2005, an EU Risk Management Plan (EU-RMP) is a required part of the authorization dossier of innovative drugs licensed in the EU. The EU-RMP can include additional risk minimization activities (RMAs) to strengthen the benefit-risk balance of a drug. This study describes the additional RMAs of centrally authorized medicinal products authorized between 1 January 1995 and 1 January 2010. METHODS: : The European Public Assessment Reports of all centrally authorized products were analysed to identify characteristics of the product (active substance, authorization date, Anatomical Therapeutic Chemical classification), the additional RMAs and the corresponding safety concerns (classified at Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class level). RESULTS: : Additional RMAs were identified for 58 of the 391 active substances that were authorized as of 1 January 2010. The proportion of active substances with additional RMAs was 5% among those authorized before, and 29% among those approved after the new risk management legislation. Since the new legislation, blood products and antineoplastic and immunomodulating agents most often had additional RMAs. All active substances with additional RMAs required the provision of educational material, most frequently involving healthcare professionals (n = 57) and the patient (n = 31). Thirty-three active substances required additional RMAs on top of the provision of educational material, most frequently including patient monitoring and screening (n = 19). CONCLUSIONS: : The proactive pharmacovigilance approach is evolving and the number of products with additional RMAs is growing since the introduction of the EU-RMP. The provision of educational material is the primary additional risk minimization strategy in the EU. The effect of additional RMA implementation has to be explored.