Studying the Impact of European Union Regulatory Interventions for Minimising Risks From Medicines: Lessons Learnt and Recommendations.

PURPOSE: The European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) launched a strategy to examine the public health impact of major regulatory interventions aimed at minimising risks of medicinal products. We conducted a lessons learnt analysis of impact studies completed between 2015 and 2023. METHODS: We surveyed PRAC Sponsors and (Co-)Rapporteurs involved in the evaluation of 12 impact studies (10 commissioned by EMA and 2 conducted collaboratively by Member States) to explore how these support regulatory decision-making. Questions covered achievement of study objectives, risk minimisation effectiveness, added value for regulatory decision-making, and recommendations for future impact studies. Themes were generated using thematic content analysis. RESULTS: Survey responses from 15 PRAC Sponsors and (Co-)Rapporteurs from 10 European Union Member States were included in the analysis. Among four cross-sectional surveys and eight drug utilisation studies, 50% achieved all objectives, the other studies partially due to limitations. Two studies concluded that risk minimisation measures were overall effective, two were effective with variation across countries, two were partially effective and four studies showed limited effectiveness. Two studies were deemed inconclusive due to limitations. The reasons for the limited effectiveness of risk minimisation may be explored using mixed-method approaches. Assessment of study feasibility and a priori discussion of effectiveness measurements is important. CONCLUSION: Despite limitations, impact research adds value to regulatory decision-making by addressing knowledge gaps and providing additional information on unintended consequences of regulatory interventions. Our recommendations will help to improve planning, conducting and interpretating future impact studies.

Signals from the Dutch national spontaneous reporting system: Characteristics and regulatory actions.

PURPOSE: The aim of the study is to characterise safety signals based on the Dutch spontaneous reporting system (SRS) and to investigate the association between signal characteristics and Product Information (PI) update stratified by approval type: centrally authorised products (CAPs) versus nationally and decentralised authorised products (NAPs). METHODS: This study evaluates the full cohort of signals disseminated from the Dutch SRS in the period from 2008 to 2017. Each retrieved signal was characterised on a number of aspects. The signal management process from signal generation to a potential PI update was analysed in four steps: (1) signal characterisation; (2) proposed actions by the Dutch national competent authority (NCA) for the signals; (3) presence of PI update (yes/no) and association with signal characteristics; (4) timing from the moment the signal was issued to PI update. For step 1-3 we stratified products in CAPs and NAPs. RESULTS: Of all signals, 88.7% led to a proposed regulatory action by the NCA. Signals from the Dutch SRS for CAPs versus NAPs more often concerned biologicals, important medical events, class effects and shorter periods since marketing authorization. We detected PI updates for 26.2% of CAP signals and 61.3% of NAP signals. CONCLUSIONS: The Dutch SRSs remains an important source of signals. There are some notable differences in the characteristics of signals for CAPs versus NAPs. Signals for NAPs more frequently led to PI updates.

Characteristics of drugs safety signals that predict safety related product information update.

PURPOSE: Investigation of drug safety signals is one of the major tasks in pharmacovigilance. Among many potential signals identified, only a few reflect adverse drug reactions requiring regulatory actions, such as product information (PI) update. Limited information is available regarding the signal characteristics that might predict PI update following signal evaluation. The objective of this study was to identify signal characteristics associated with PI updates following signal evaluation by the European Medicines Agency Pharmacovigilance Risk Assessment Committee during 2012 to 2016. METHODS: A comparative study was performed based on data from 172 safety signals. Characteristics of signals were extracted from the European Pharmacovigilance Issues Tracking Tool database. Multivariable logistic regression analysis was used to assess the relationship between signal characteristics and the decision to update the PI. RESULTS: Multivariable logistic regression analysis showed that the presence of evidence in multiple types of data sources (adjusted odds ratio [OR] 7.8 95% CI [1.5, 40.1]); mechanistic plausibility of the drug-event association (adjusted OR 3.9 95% CI [1.9, 8.0]); seriousness of the event (adjusted OR 4.2 95% CI [1.3, 13.9]); and age of drugs ≤5 years (adjusted OR 3.9 95% CI [1.2, 12.7]) were associated with the decision to change the PI (P < 0.05). CONCLUSIONS: This study identified 4 characteristics of drug safety signals that have shown to be associated with PI changes as outcome of signal evaluation. These characteristics may be used as criteria for selection and prioritization of potential signals that are more likely to necessitate product information updates.

Decision making in drug safety-a literature review of criteria used to prioritize newly detected safety issues.

PURPOSE: In drug safety, there is a lack of guidance on how prioritization of safety issues should be performed. The aim of this literature review is to provide an overview of criteria used for signal prioritization and of the associated decision support frameworks. METHODS: A search strategy was constructed to identify relevant articles in Medline/Embase databases from the period from 1 January 1995 to 31 August 2015. The prioritization criteria were extracted and classified in relevant categories. RESULTS: From an initial set of 63 articles, 11 were retained for full review. The articles mentioned 48 criteria used in the prioritization process, with a median of six criteria per study [range: 1-16]. More than half of the criteria (63%), referred to strength of evidence while 19% related to public health impact, 14% to general public and media attention and 4% to novelty of the drug event association. Fifteen criteria were tested for predictive value with 11 showing positive results, most of them from the strength of evidence category. Six decision-making frameworks are presented, which incorporate criteria from various categories. Five of these frameworks were tested against expert decisions or by other means, but only in one database each and for a limited set of products. CONCLUSIONS: There is a wide range of prioritization criteria described in the literature; however, few of them demonstrated predictive value. Many criteria with predictive value were related to strength of evidence category and to novelty. There were few attempts at integrating different criteria in decision support frameworks. Five of the frameworks were tested for validity and showed usefulness, while at least three are already in use for prioritization. Copyright © 2016 John Wiley & Sons, Ltd.

Muscle rupture associated with statin use.

AIM: Statins are used in the treatment of hyperlipidaemia. They are among the most commonly prescribed drugs worldwide. Statins have been linked to musculoskeletal adverse drug reactions. However muscle rupture has not been discussed as an adverse drug reaction to statins so far. The aim of this article is to give an overview of cases of muscle rupture associated with the use of statins. METHOD: We analyzed the cases of muscle rupture associated with the use of statins that were collected by the Netherlands Pharmacovigilance Centre Lareb complemented with the review of cases from the EudraVigilance database. RESULTS: Fifteen cases of muscle rupture associated with statin use have been identified in the database of the Netherlands Pharmacovigilance Centre. Overall, there was a plausible temporal association of events in most cases. In addition, the EudraVigilance database contained 165 reports of muscle rupture reported in patients using statins. Muscle rupture was disproportionally associated with statin use in both databases. The reporting odds ratio was 23.4 (95% CI 11.9, 46.0) and 14.6 (95% CI 12.3, 17.2), respectively. CONCLUSION: Data from spontaneous reporting systems suggest that use of statins is associated with muscle rupture. Physicians and patients should be aware that this can occur.

Real-World Evidence to Support EU Regulatory Decision Making-Results From a Pilot of Regulatory Use Cases.

Studies using real-world data (RWD) can complement evidence from clinical trials and fill evidence gaps during different stages of a medicine's lifecycle. This review presents the experience resulting from the European Medicines Agency (EMA) pilot to generate RWE to support evaluations by EU regulators and down-stream decision makers from September 2021 to February 2023. A total of 61 research topics were identified for RWE generation during this period, covering a wide range of research questions, primarily generating evidence on medicines safety (22, 36%), followed by questions on the design and feasibility of clinical trials (11, 18%), drug utilization (10, 16%), clinical management (10, 16%), and disease epidemiology. A significant number of questions were related to the pediatric population and/or rare diseases. A total of 27 regulatory-led RWD studies have been conducted. Most studies were descriptive and aimed at estimating incidence and prevalence rates of clinical outcomes including adverse events or to evaluate medicines utilization. The review highlights key learnings to guide further efforts to enable the use and establish the value of real-world evidence (RWE) for regulatory decisions. For instance, there is a need to access additional fit-for-purpose and representative data, and to explore further means to provide timely evidence that meets regulatory timelines. The need for early interactions and close collaboration with study requesters, e.g., from the Agency's scientific Committees, to better understand the research question is equally important. Finally, the review provides our perspective on the way forward to maximize the potential of regulatory-led RWE generation.

What Factors Make EU Regulators Want to Communicate Drug Safety Issues Related to SGLT2 Inhibitors? An Online Survey Study.

INTRODUCTION: Previous studies have found differences in the communication of safety issues among medicines regulatory agencies. OBJECTIVES: To explore (1) to what extent regulators' opinions regarding the need to communicate safety issues related to sodium-glucose cotransporter-2 (SGLT2) inhibitors might be influenced by their concern about the safety issue, and (2) whether regulators' concerns might be influenced by certain characteristics of the safety issue or by the demographic and professional characteristics and attitudes of the regulators. METHODS: An online cross-sectional survey study with a rating-based conjoint analysis among clinical and pharmacovigilance assessors from the EU regulatory network was performed between April and June 2021. Regulators were invited by email, and participants were asked about their level of concern and their opinion regarding the need to communicate about 12 scenarios defined by four characteristics: adverse drug reaction, source of information, causality, and frequency. The outcomes for the first objective were to update the summary of product characteristics (SmPC; yes/no) and to send direct healthcare professional communications (DHPC; yes/no). The determinant was regulators' level of concern (range 0-100%). The outcome of the second objective was regulators' level of concern, and the determinants were the characteristics of the safety issue, demographic and professional characteristics, and attitudes of the regulators (beliefs about medicines and risk perception). RESULTS: A total of 222 regulators completed the survey (64% women; mean age 46 ± 10 years). Depending on the scenario, 54-94% and 25-74% of the participants would update the SmPC or send a DHPC, respectively. The participants' level of concern influenced their opinions regarding the need to update the SmPC and send a DHPC (odds ratio (OR) 13.0; 95% confidence interval (CI) 7.8-21.7 and OR 13.6; 95% CI 9.5-19.2, respectively, for every 10% increase in the level of concern). All characteristics of the safety issue influenced the level of concern. Younger participants, women, and those working for Eastern European agencies had a higher level of concern than older participants, men, and those working in other regions. Beliefs about medicines and general risk perception also influenced their concern. CONCLUSIONS: The opinion regarding the need to communicate safety issues was influenced by the concern of regulators. Regulators' concern was influenced by the characteristics of the safety issue, demographic characteristics, and attitudes. Diverse groups of experts regarding such factors would ensure that various views are incorporated in risk communication decisions.

The community impact of the 2009 influenza pandemic in the WHO European region: a comparison with historical seasonal data from 28 countries.

BACKGROUND: The world has recently experienced the first influenza pandemic of the 21st century that lasted 14 months from June 2009 to August 2010. This study aimed to compare the timing, geographic spread and community impact during the winter wave of influenza pandemic A (H1N1) 2009 to historical influenza seasons in countries of the WHO European region. METHODS: We assessed the timing of pandemic by comparing the median peak of influenza activity in countries of the region during the last seven influenza seasons. The peaks of influenza activity were selected by two independent researchers using predefined rules. The geographic spread was assessed by correlating the peak week of influenza activity in included countries against the longitude and latitude of the central point in each country. To assess the community impact of pandemic influenza, we constructed linear regression models to compare the total and age-specific influenza-like-illness (ILI) or acute respiratory infection (ARI) rates reported by the countries in the pandemic season to those observed in the previous six influenza seasons. RESULTS: We found that the influenza activity reached its peak during the pandemic, on average, 10.5 weeks (95% CI 6.4-14.2) earlier than during the previous 6 seasons in the Region, and there was a west to east spread of pandemic A(H1N1) influenza virus in the western part of the Region. A regression analysis showed that the total ILI or ARI rates were not higher than historical rates in 19 of the 28 countries. However, in countries with age-specific data, there were significantly higher consultation rates in the 0-4 and/or 5-14 age groups in 11 of the 20 countries. CONCLUSIONS: Using routine influenza surveillance data, we found that pandemic influenza had several differential features compared to historical seasons in the region. It arrived earlier, caused significantly higher number of outpatient consultations in children in most countries and followed west to east spread that was previously observed during some influenza seasons with dominant A (H3N2) ifluenza viruses. The results of this study help to understand the epidemiology of 2009 influenza pandemic and can be used for pandemic preparedness planning.

Development of a minimal set of prescribing quality indicators for diabetes management on a general practice level.

OBJECTIVE: To identify the relevant prescribing quality domains of type 2 diabetes mellitus care as a basis for the selection of a minimal set of prescribing quality indicators from a set of previously validated indicators. METHODS: We used the principal factor analysis to identify the underlying dimensions or domains of prescribing quality for 76 general practitioners participating to the Groningen Initiative to Analyse Type 2 Diabetes Treatment project in the Netherlands. From a set of 10 prescribing quality indicators covering various aspects of cardiovascular and metabolic management, we selected a subset of indicators with the highest loading within each identified domain. Next, we evaluated the effect of using this subset on the quintile ranking of practices on their prescribing quality scores. RESULTS: We identified five prescribing quality domains in our data set: two assessing initiation of pharmacotherapy for different risk factors in diabetic patients, two on stepwise intensification of treatment, and one on treatment of patients with cardiovascular disease. A composite score comprising the indicators selected from each of the domains showed good agreement with the composite score comprising all indicators with 82% of general practitioners either not changing their position or shifting their ranking by only one quintile. CONCLUSIONS: We showed that a minimal set of prescribing quality indicators for type 2 diabetes mellitus care should not just focus on the management of different clinical risk factors but also reflect different steps of treatment intensification. The results of our study are relevant for stakeholders when selecting quality indicators to assess the quality of prescribing in diabetic patients.

A pilot qualitative study to explore stakeholder opinions regarding prescribing quality indicators.

BACKGROUND: Information on prescribing quality of diabetes care is required by health care providers, insurance companies, policy makers, and the public. Knowledge regarding the opinions and preferences of all involved parties regarding prescribing quality information is important for effective use of prescribing quality indicators. METHODS: Between June and December 2009 we conducted semi structured interviews with 16 key-informants representing eight different organizations in the Netherlands involved in healthcare quality measurement and improvement. The interview guide included topics on participants' opinions and preferences regarding existing types of prescribing quality indicators in relation to their aim of using quality information. Content analysis methods were used to process the resulting transcripts following the framework of predetermined themes. RESULTS: Findings from this qualitative study of stakeholder preferences showed that indicators focusing on undertreatment are found important by all participants. Furthermore, health care providers and policy makers valued prescribing safety indicators, insurance companies prioritized indicators focusing on prescribing costs, and patients' organization representatives valued indicators focusing on interpersonal side of prescribing. Representatives of all stakeholders preferred positive formulation of the indicators to motivate health care providers to participate in health improvement programs. A composite score was found to be most useful by all participants as a starting point of prescribing quality assessment. Lack of information on reasons for deviating from guidelines recommendations appeared to be the most important barrier for using prescribing quality indicators. According to the health care providers, there are many legitimate reasons for not prescribing the recommended treatment and these reasons are not always taken into account by external evaluators. The latter may cause mistrust of health care providers towards external stakeholders and limit the use of PQI in external quality improvement programs. CONCLUSION: Prescribing quality indicators are considered to be an important tool for assessing quality of provided diabetes care by all participants, although the preferences for specific types of indicators may differ by stakeholder depending on their user aim. Introduction of information systems to register the reasons for deviating from the recommended drug treatment may contribute to a more widespread use of PQI for assessment of provided health care quality to diabetic patents. This study identified the potential preferences regarding quality indicators for diabetes care, and this could be used for development of questionnaires to conduct a survey among a larger group of participants.

Stakeholders' perspectives on quality indicators for diabetes care: a qualitative study.

BACKGROUND: Transparency in diabetes care requires quality indicators that are of interest to stakeholders in order to optimise their usage. Indicator development is often focused on consensus, and little is known about stakeholders' preferences for information on quality. AIM: To explore the preferences of consumers, providers, purchasers and policy makers for different quality domains and indicators in relation to the intended use of quality indicators. METHODS: Between June and December 2009, 14 semi-structured interviews were held with stakeholders who have a decisive vote in the selection of the national indicator set for diabetes care in the Netherlands. The following subjects were explored: (1) the aims of using information on quality; (2) the interpretation of and preferences for the quality domains of safety, timeliness, effectiveness and patient-centredness in relation to the user aims; and (3) the preferences for structure, process or outcome indicators. Content analysis was used to analyse qualitative data. RESULTS: Stakeholders had similar and different aims according to their roles. The interpretations of quality domains varied greatly between the stakeholders. Besides differences in interpretation, their preferences were similar. Most stakeholders prioritised patient-centredness above the other domains of quality, ranked in order of priority as safety, effectiveness and timeliness, whereas purchasers also prioritised efficiency. All stakeholders preferred to use process indicators or a mix of process and outcome indicators. CONCLUSIONS: The preferences of the stakeholders for quality indicators seem to be neither well-refined nor congruent. The implementation of an indicator set can probably be improved if the stakeholders' definitions and preferences for quality domains become more explicit during the selection process for indicators.

A systematic literature review: prescribing indicators related to type 2 diabetes mellitus and cardiovascular risk management.

PURPOSE: Valid prescribing indicators (PI) are needed for reliable assessment of prescribing quality. The purpose of this study is to describe the validity of existing PI for type 2 diabetes mellitus and cardiovascular risk management. METHODS: We conducted a systematic literature search for studies describing the development and assessment of relevant PIs between January 1990 and January 2009. We grouped identified PI as drug- or disease-oriented, and according to the aspects of prescribing addressed and the additional clinical information included. We reviewed the clinimetric characteristics of the different types of PI. RESULTS: We identified 59 documents describing the clinimetrics of 16 types of PI covering relevant prescribing aspects, including first-choice treatment, safety issues, dosing, costs, sufficient and timely treatment. We identified three types of drug-oriented, and five types of disease-oriented PI with proven face and content validity as well as operational feasibility in different settings. PI focusing on treatment modifications were the only indicators that showed concurrent validity. Several solutions were proposed for dealing with case-mix and sample size problems, but their actual effect on PI scores was insufficiently assessed. Predictive validity of individual PI is not yet known. CONCLUSION: We identified a range of existing PI that are valid for internal quality assessment as they are evidence-based, accepted by professionals, and reliable. For external use, problems of patient case-mix and sample size per PI should be better addressed. Further research is needed for selecting indicators that predict clinical outcomes.

Methods to identify the target population: implications for prescribing quality indicators.

BACKGROUND: Information on prescribing quality is increasingly used by policy makers, insurance companies and health care providers. For reliable assessment of prescribing quality it is important to correctly identify the patients eligible for recommended treatment. Often either diagnostic codes or clinical measurements are used to identify such patients. We compared these two approaches regarding the outcome of the prescribing quality assessment and their ability to identify treated and undertreated patients. METHODS: The approaches were compared using electronic health records for 3214 diabetes patients from 70 general practitioners. We selected three existing prescribing quality indicators (PQI) assessing different aspects of treatment in patients with hypertension or who were overweight. We compared population level prescribing quality scores and proportions of identified patients using definitions of hypertension or being overweight based on diagnostic codes, clinical measurements or both. RESULTS: The prescribing quality score for prescribing any antihypertensive treatment was 93% (95% confidence interval 90-95%) using the diagnostic code-based approach, and 81% (78-83%) using the measurement-based approach. Patients receiving antihypertensive treatment had a better registration of their diagnosis compared to hypertensive patients in whom such treatment was not initiated. Scores on the other two PQI were similar for the different approaches, ranging from 64 to 66%. For all PQI, the clinical measurement -based approach identified higher proportions of both well treated and undertreated patients compared to the diagnostic code -based approach. CONCLUSIONS: The use of clinical measurements is recommended when PQI are used to identify undertreated patients. Using diagnostic codes or clinical measurement values has little impact on the outcomes of proportion-based PQI when both numerator and denominator are equally affected. In situations when a diagnosis is better registered for treated than untreated patients, as we observed for hypertension, the diagnostic code-based approach results in overestimation of provided treatment.