Evaluation of Effectiveness of Risk Minimisation Measures in Europe
- Autores: Esther Artime Freire
- Directores de la Tesis: Macarena Garrido Estepa (dir. tes.), Rafael Herruzo Cabrera (codir. tes.)
- Lectura: En la Universidad Autónoma de Madrid ( España ) en 2021
- Idioma: español
- Tribunal Calificador de la Tesis: Fernando Rodríguez Artalejo (presid.), Alberto Borobia Pérez (secret.), Francisco José de Abajo Iglesias (voc.)
- Programa de doctorado: Programa de Doctorado en Epidemiología y Salud Pública por la Universidad Autónoma de Madrid; la Universidad de Alcalá y la Universidad Rey Juan Carlos
- Materias:
- Enlaces
- Tesis en acceso abierto en: Biblos-e Archivo
- Resumen
Background: Therapeutic Risk Minimisation (RM) has become as an area of extensive research in recent years with the release of Good Pharmacovigilance Practice Module XVI in 2014 which provides a regulatory framework for selection, development and evaluation of the effectiveness of additional risk minimisation measures (aRMMs) in Europe. Over a quarter of new products currently approved centrally by the European Medicines Agency (EMA) have accompanying aRMMs to manage and mitigate risks that could have serious consequences for patients and are considered to be insufficiently managed by routine measures alone. Most of these aRMMs are educational and communication materials for healthcare professionals (HCPs) or patients such as brochures, leaflets, guides, checklists, Direct HCP Communications (DHPCs), patient cards, pregnancy prevention programmes (PPPs). Safety concerns addressed by aRMMs range from adverse reactions associated with the drug to medication and administration errors, or the increased risk in special populations such as pregnant women.
Efforts are being made in Europe to evaluate the effectiveness and implementation of aRMMs, to establish whether an intervention has been effective, and, if not, why and which corrective actions are necessary. The effectiveness of aRMMs may be assessed through process indicators (e.g. receipt, use, knowledge, self-reported behaviour, mainly via survey studies), behavioural changes (e.g. drug utilization studies) and/or health/safety outcomes (e.g. rates of adverse events). The term risk minimisation evaluation (hereinafter ‘RMEv’) is used in this document to describe a study or group of studies that assess the effectiveness of aRMMs for one specific product. Studies linked to one product are considered part of the product RMEv. RMEv should ideally include measures of effectiveness at the three levels of evaluation: process indicators, behavioural outcomes, and health/safety outcomes. However, this may vary by product.
This thesis evaluates subject participation, country selection, study results and regulatory consequences of survey studies evaluating the effectiveness of aRMMs via process indicators in Europe (hereinafter EU RM Surveys). Additionally, this thesis describes RMEv which include process indicators and outcomes and provides a potential methodological framework for RMEv at the three evaluation levels (process indicators, behavioural outcomes, and health/safety outcomes) via a non-interventional post-authorisation safety study (PASS) with results endorsed by EMA regulators. The study was conducted to evaluate the effectiveness of the abatacept (ORENCIA®) patient alert cards (PACs) in rheumatoid arthritis (RA) patients and HCPs. Two PACs are available, one for each formulation (intravenous [IV] and subcutaneous [SC]), to help inform patients and HCPs of the potential risks and actions required during treatment with the product, specifically for infections and allergic reactions, with the ultimate goal of reducing the occurrence of undesirable outcomes (e.g., hospitalisations), or severity (e.g., reducing delays in seeking medical care).
Methods: We conducted a systematic literature review in the EU PAS Register, PubMed and grey literature to search for study reports and manuscripts of completed EU RM Surveys between Jan 2011 and Jan 2018. Regulatory consequences/actions were extracted from Assessment Reports of study results issued by competent authorities. Random effects models to combine proportions were used for: participation rates (i.e. proportion of subjects invited who completed the survey; proportion of subjects eligible who completed the survey), receipt (i.e. proportion of participants who reported having received the materials), reading (i.e. proportion of participants who reported having read the materials among those who received them), use (i.e. proportion of participants who reported having used the materials among those who received them), and knowledge (i.e. proportion of participants who correctly responded the knowledge questions).
The search was updated in October 2019 using the EU PAS Register, PubMed, and grey literature to capture a greater number of EU RM Surveys. Studies identified were used to extract more detailed data on country selection and subject participation overall and by country. This allowed to calculate: number and percentage of studies in which each country participated, number and percentage of completers that each country provided, by study and overall: 1) as the percentage of completers each country provided to the overall number of completers in all studies; or 2) as the percentage of completers each country provided to the overall number of completers in studies with that country participation identified. Response rate was calculated as the percentage of participants who completed the survey among those invited to participate. The range of response rates was described.
As part of the search conducted in October 2019 studies to assess the effectiveness of aRMMs (hereinafter EU RM studies) using behavioural and/or health/safety outcomes were also retrieved. Identified studies linked to one product were assigned to the product RMEv. Only RMEv that included both process indicators and outcomes (behavioural and/or health/safety outcomes) were reviewed. Data were extracted which included: at RMEv level (ATC group, type of aRMM, targeted safety concerns, number of studies conforming the RMEv i.e., 1 study, 2 studies or ≥3 studies) and at study level (study design, countries, outcome measures, data sources). Where available study results were obtained and summarised.
A PASS study evaluating the effectiveness of abatacept PACs and consisting of three sub-studies was carried out in five European countries: 1) survey of HCPs (nurses and physicians), 2) survey of patients, and 3) retrospective chart review in the same patients who completed the survey. This permitted linking clinical and safety outcomes obtained via the chart review with survey responses in the same patients. Survey responses were analysed descriptively, and summary scores for endpoints (scores of utility, utilisation, knowledge, behaviour, and global score) were calculated. All analyses were performed overall and by receipt versus non-receipt of the PACs.
The study assessed whether better responses provided by abatacept-treated patients in the patient survey were associated with improved outcomes (e.g. availability of results of screening tests for tuberculosis (TB) and viral hepatitis (VH) prior to abatacept use, occurrence of infections leading to hospitalisation and/or infections leading to emergency room visits and time from occurrence of infection to receiving medical attention). Univariate analyses correlated within-patient clinical and safety outcomes responses to process indicators in the patient survey.
For all the analyses, differences between groups were assessed using parametric and non-parametric statistical methods as applicable. P-values < 0.05 were considered statistically significant.
Results: In the initial search conducted in January 2018, 109 EU RM studies were identified, of which 24 had a survey component and results available at the time of the analysis. Of these, 23 studies targeted HCPs. The pre-specified sample size was reached in 52% of studies. The pooled HCP participation was 5% defined as completers/invited and 89% for completers/eligible. Receipt of materials was recalled by 60% of HCPs and 77% of items scored knowledge >60%. Eight studies targeted patients/caregivers. The pre-specified sample size was reached in only two. The pooled participation was 93%, defined as completers/eligible. Materials were received by 50–80% of patients and read by over 90%. Patients only scored knowledge >60% in 38% of items. Further action was requested by regulators in 59% of studies.
In the updated search conducted in October 2019, of 129 EU RM studies, the number of completed surveys raised up to 48. Twenty-eight different European countries participated in the 44 surveys that targeted HCPs (mean: 6 countries per study). UK, Spain, France and Germany were the most frequently selected countries, contributing 64% of all participants with country-specific data. Seventeen different European countries participated in the 14 surveys that targeted patients/caregivers (mean: 5 countries per study). UK, Germany, France and Spain were the most frequently selected countries, contributing 66% of all participants with country-specific data.
In the search of October 2019, 102 product-specific RMEv were identified, of which 18 (18%) had both process indicators and outcomes. Of the 18 RMEv, ten consisted of one study only, five of two studies, and three of three or more studies. A total of 30 studies were included within the 18 RMEv. The designs of the studies were: 19 (63%) cross-sectional surveys (47% targeted patients and 89% healthcare professionals), 17 (57%) retrospective studies (47% using pre/post approach) and 3 (10%) prospective studies. Nineteen studies included process indicators that were receipt (n=14), use (n=12), knowledge (n=17) and self-reported behaviour (n=15). Regarding outcomes, 67% of the 18 RMEv evaluated behavioural outcomes and 50% health/safety outcomes. Three of the 18 RMEv evaluated both behavioural and health/safety outcomes. For five RMEv, correlations between process indicators and outcomes were performed, two at the patient level. Results were available for 14 of the 18 RMEv. In HCP surveys, the median percentage was 57% for receipt, 92% for reading, 80% for use, 77% for knowledge and 74% for behaviour. In patient surveys, the median percentage was 56% for receipt, 87% for reading, 65% for use, 47% for knowledge and 69% for behaviour. Knowledge was better in healthcare professionals than patients (p < 0.05). Three of the 5 RMEv which included a correlation analysis had results available. Of these, only one (the abatacept study later described) found a positive trend for a lower occurrence of outcomes as process indicators improved, though this was not statistically significant.
In the abatacept case study, data on 190 patients and 79 HCPs (50 physicians and 29 nurses) were analysed. Sixty percent of patients were aware of the PAC, of whom 95% had received it. Knowledge of risk of infection was higher among patients who had received the PAC vs those who had not (64% vs 46%; p = 0.013). Infections leading to hospitalisation increased with decreasing patient survey global scores: scores of >67%, 34%-67% and ≤ 33% were associated with hospitalisation rates of 2.5%, 5.2% and 8.4%, respectively (p = 0.4). Among HCPs, 90% were aware and 68% had accessed the PAC. More nurses than physicians were aware (93% vs 88%), had accessed (78% vs 74%), read (90% vs 59%), distributed (81% vs 66%) and explained the content (94% vs 43%) of the PAC. Knowledge of risk of infection was higher among HCPs who had (91%) vs those who had not (73%) accessed/received the PAC (p = 0.053).
Conclusions: The field of therapeutic RM has become an area of intensive research since the implementation of GVP XVI. As of October 2019, at least 129 EU RM studies had been designed and conducted to assess the effectiveness of RMMs for 102 different products in Europe. About forty percent of EU RM Surveys provided evidence that supports the effectiveness of RMMs based on regulatory Assessment Reports. The remaining sixty percent of studies required further action for distribution strategies, re-distribution, and follow-up assessment, changes to existing materials, further data awaited and, in a minority, removal of the materials. However, this review identified some challenges that remain in the design, conduct, and reporting of survey studies, which may benefit from more detailed guidance, use of common definitions, standardization of reporting. Some of the limitations of cross-sectional study designs (i.e., surveys) may be overcome by drug utilisation and outcomes evaluations which have been used conjunctively with EU RM Surveys in eighteen percent of RMEv to supplement the results of process indicators. There are currently few studies correlating within-patient survey results with heath/safety outcomes. This thesis provided a potential framework for the evaluation of effectiveness of aRMMs via a case study involving surveys and a retrospective chart review to correlate process indicators and safety outcomes in the same patients. This novel study design bridges the gap of linking process indicators with outcomes at the individual-patient level and strengthens the clinical relevance of results from surveys. The results support the effectiveness of the abatacept PACs. The practical impact of this study resulted in no modifications to the content of the PACs or further evaluations being requested by EMA regulators. The learnings of this thesis may be used by MAHs, academic groups and regulatory authorities to inform the design of future RMEv approaches combining process indicators and outcomes.
