What are the patients' and health care professionals' understanding and behaviors towards adverse drug reaction reporting and additional monitoring?

BACKGROUND: The additional monitoring (AM)/black triangle concept is aimed to enhance ADR reporting for certain types of medicinal products for which the safety profile is less well established. PURPOSE: The objective of this survey was to assess (a) attitudes towards ADR reporting and reasons for not reporting an ADR and (b) awareness of AM among HCPs, patients or their careers in EU countries. METHODS: An online questionnaire which was available in all EU languages was completed by 2918 responders coming from all EEA countries. RESULTS: The main factors motivating to report an ADR were severity or novelty of the reaction or novelty of the medicine. The main factors for not reporting an ADR was the fact that the ADR is already known (35%), the ADR was not serious (18%) or reporter was not sure if the ADR was related to the medicine (15%). Half of the respondents indicated that they have seen AM statement before. Thirty percent of the responders had correct understanding of the AM concept while 20 % misunderstood the concept. CONCLUSION: Underreporting occurs but it seems this is because of reporter's prioritisation towards certain type of ADRs. AM aims to increase reporting for certain medicines, however, approximately half of responders have seen the AM symbol before and 20% of all responders (independent of their previous awareness) misunderstood the concept.

Regulatory and health technology assessment advice on postlicensing and postlaunch evidence generation is a foundation for lifecycle data collection for medicines.

The understanding of the benefit risk profile, and relative effectiveness of a new medicinal product, are initially established in a circumscribed patient population through clinical trials. There may be uncertainties associated with the new medicinal product that cannot be, or do not need to be resolved before launch. Postlicensing or postlaunch evidence generation (PLEG) is a term for evidence generated after the licensure or launch of a medicinal product to address these remaining uncertainties. PLEG is thus part of the continuum of evidence development for a medicinal product, complementing earlier evidence, facilitating further elucidation of a product's benefit/risk profile, value proposition, and/or exploring broader aspects of disease management and provision of healthcare. PLEG plays a role in regulatory decision making, not only in the European Union but also in other jurisdictions including the USA and Japan. PLEG is also relevant for downstream decision-making by health technology assessment bodies and payers. PLEG comprises studies of different designs, based on data collected in observational or experimental settings. Experience to date in the European Union has indicated a need for improvements in PLEG. Improvements in design and research efficiency of PLEG could be addressed through more systematic pursuance of Scientific Advice on PLEG with single or multiple decision makers. To date, limited information has been available on the rationale, process or timing for seeking PLEG advice from regulators or health technology assessment bodies. This article sets out to address these issues and to encourage further uptake of PLEG advice.

Ability of Primary Care Health Databases to Assess Medicinal Products Discussed by the European Union Pharmacovigilance Risk Assessment Committee.

This study measured the exposure to different categories of medicinal products discussed by the European Union (EU) Pharmacovigilance Risk Assessment Committee from September to November 2018 in four electronic primary care health databases: IQVIA Medical Research Data-UK, IQVIA Medical Research Data-France, IQVIA Medical Research Data-Germany, and Clinical Practice Research Datalink Aurum, in the entire lifespan of each database until August 31, 2018. The assessment of 83 centrally authorized products and 45 nationally authorized products showed that coverage was better for products marketed for longer duration and worse for orphan drugs. The ability to detect associations against hypothetical comparators was better for more common events and for larger effect sizes. Coverage of advanced therapies was worse for those typically administered in a specialized rather than primary care setting. This study shows that to enable better informed regulatory decisions there is a need to access complementary data sources, particularly capturing secondary care prescribing.

Patient Registries: An Underused Resource for Medicines Evaluation : Operational proposals for increasing the use of patient registries in regulatory assessments.

INTRODUCTION: Patient registries, 'organised systems that use observational methods to collect uniform data on a population defined by a particular disease, condition, or exposure, and that is followed over time', are potentially valuable sources of data for supporting regulatory decision-making, especially for products to treat rare diseases. Nevertheless, patient registries are greatly underused in regulatory assessments. Reasons include heterogeneity in registry design and in the data collected, even across registries for the same disease, as well as unreliable data quality and data sharing impediments. The Patient Registries Initiative was established by the European Medicines Agency in 2015 to support registries in collecting data suitable to contribute to regulatory assessments, especially post-authorisation safety and effectiveness studies. METHODS: We conducted a qualitative synthesis of the published observations and recommendations from an initiative-led multi-stakeholder consultation and four disease-specific patient registry workshops. We identified the primary factors facilitating the use of registry data in regulatory assessments. We generated proposals on operational measures needed from stakeholders including registry holders, patients, healthcare professionals, regulators, marketing authorisation applicants and holders, and health technology assessment bodies for implementing these. RESULTS: Ten factors were identified as facilitating registry use for supporting regulatory assessments of medicinal products. Proposals on operational measures needed for implementation were categorised according to three themes: (1) nature of the data collected and registry quality assurance processes; (2) registry governance, informed consent, data protection and sharing; and (3) stakeholder communication and planning of benefit-risk assessments. CONCLUSIONS: These are the first explicit proposals, from a regulatory perspective, on operational methods for increasing the use of patient registries in medicines regulation. They apply to registry holders, patients, regulators, marketing authorisation holders/applicants and healthcare stakeholders broadly, and their implementation would greatly facilitate the use of these valuable data sources in regulatory decision-making.

The ENCePP Code of Conduct: A best practise for scientific independence and transparency in noninterventional postauthorisation studies.

PURPOSE: The ENCePP Code of Conduct provides a framework for scientifically independent and transparent pharmacoepidemiological research. Despite becoming a landmark reference, practical implementation of key provisions was still limited. The fourth revision defines scientific independence and clarifies uncertainties on the applicability to postauthorisation safety studies requested by regulators. To separate the influence of the funder from the investigator's scientific responsibility, the Code now requires that the lead investigator is not employed by the funding institution. METHOD: To assess how the revised Code fits the ecosystem of noninterventional pharmacoepidemiology research in Europe, we first mapped key recommendations of the revised Code against ISPE Good Pharmacoepidemiology Practices and the ADVANCE Code of Conduct. We surveyed stakeholders to understand perceptions on its value and practical applicability. Representatives from the different stakeholders' groups described their experience and expectations. RESULTS: Unmet needs in pharmacoepidemiological research are fulfilled by providing unique guidance on roles and responsibilities to support scientific independence. The principles of scientific independence and transparency are well understood and reinforce trust in study results; however, around 70% of survey respondents still found some provisions difficult to apply. Representatives from stakeholders' groups found the new version promising, although limitations still exist. CONCLUSION: By clarifying definitions and roles, the latest revision of the Code sets a new standard in the relationship between investigators and funders to support scientific independence of pharmacoepidemiological research. Disseminating and training on the provisions of the Code would help stakeholders to better understand its advantages and promote its adoption in noninterventional research.

EU-funded initiatives for real world evidence: descriptive analysis of their characteristics and relevance for regulatory decision-making.

INTRODUCTION: A review of European Union (EU)-funded initiatives linked to 'Real World Evidence' (RWE) was performed to determine whether their outputs could be used for the generation of real-world data able to support the European Medicines Agency (EMA)'s regulatory decision-making on medicines. METHOD: The initiatives were identified from publicly available websites. Their topics were categorised into five areas: 'Data source', 'Methodology', 'Governance model', 'Analytical model' and 'Infrastructure'. To assess their immediate relevance for medicines evaluation, their therapeutic areas were compared with the products recommended for EU approval in 2016 and those included in the EMA pharmaceutical business pipeline. RESULTS: Of 171 originally identified EU-funded initiatives, 65 were selected based on their primary and secondary objectives (35 'Data source' initiatives, 15 'Methodology', 10 'Governance model', 17 'Analytical model' and 25 'Infrastructure'). These 65 initiatives received over 734 million Euros of public funding. At the time of evaluation, the published outputs of the 40 completed initiatives did not always match their original objectives. Overall, public information was limited, data access was not explicit and their sustainability was unclear. The topics matched 8 of 14 therapeutic areas of the products recommended for approval in 2016 and 8 of 15 therapeutic areas in the 2017-2019 pharmaceutical business pipeline. Haematology, gastroenterology or cardiovascular systems were poorly represented. CONCLUSIONS: This landscape of EU-funded initiatives linked to RWE which started before 31 December 2016 highlighted that the immediate utilisation of their outputs to support regulatory decision-making is limited, often due to insufficient available information and to discrepancies between outputs and objectives. Furthermore, the restricted sustainability of the initiatives impacts on their downstream utility. Multiple projects focussing on the same therapeutic areas increase the likelihood of duplication of both efforts and resources. These issues contribute to gaps in generating RWE for medicines and diminish returns on the public funds invested.

Imposed registries within the European postmarketing surveillance system: Extended analysis and lessons learned for regulators.

PURPOSE: Building on previous research, we examined whether delayed study start and low patient accrual rates found in 31 postauthorization registry-based studies requested by European Medicines Agency (EMA) are maintained after 2 additional years of follow-up. METHOD: The registries identified in the previous EMA study and the same methodology were used. The follow-up was extended from June 2015 to November 2017. The information available for the following variables was updated: marketing authorization status, study and registry status, study end date, planned duration, number of patients planned to be enrolled, and actual patients enrolled. Data were collected from several nonpublic in-house sources such as the study protocols, interim and final study reports, risk management plans, and periodic safety update reports. RESULTS: As of November 2017, 10 (32.2%) studies were finalized (vs. 9.7% as of June 2015), 14 (45.2%) were still ongoing (vs. 64.5%). Four of the ongoing studies had patients' accrual lower than 50%. Six of the finalized studies had a delayed completion, with a median delay of 3 years. As of November 2017, the median patients' accrual percentages were 24% for ongoing studies (vs. 8.5%) and 101% for finalized studies (vs. 24%). CONCLUSION: Overall, the rate of recruitment and timely finalization were improved after 2 years of additional follow-up but show that further work is needed to facilitate use of registry data for regulatory purposes, a work that has started via the EMA registry initiative.

Registries in European post-marketing surveillance: a retrospective analysis of centrally approved products, 2005-2013.

PURPOSE: Regulatory agencies and other stakeholders increasingly rely on data collected through registries to support their decision-making. Data from registries are a cornerstone of post-marketing surveillance for monitoring the use of medicines in clinical practice. This study was aimed at gaining further insight into the European Medicines Agency's (EMA) requests for new registries and registry studies using existing registries and to review the experience gained in their conduct. METHODS: European Public Assessment Reports were consulted to identify products for which a request for a registry was made as a condition of the marketing authorisation. All centrally authorised products that received a positive opinion of the EMA Committee for Medicinal Products for Human Use between 1 January 2005 and 31 December 2013 were included. Data regarding registry design and experiences were collected from EMA electronic record keeping systems. RESULTS: Of 392 products that received a positive Committee for Medicinal Products for Human Use opinion during 2005-2013, 31 registries were requested for 30 products in total. Sixty-five percent were product registries whereas 35% were disease registries and 71% of the registries had a primary safety objective. Most commonly reported issues with registries were delayed time to start and low patient accrual rates. CONCLUSIONS: The delays found in getting new registries up and running support the need to improve the timeliness of data collection in the post-marketing setting. Methodological challenges met in conducting this study highlighted the need for a clarification of definitions and epidemiological concepts around patient registries. The results will inform the EMA Patient Registry initiative to support use of existing patient registries for the post-authorisation benefit-risk monitoring of medicinal products. © 2017 Commonwealth of Australia. Pharmacoepidemiology & Drug Safety © 2017 John Wiley & Sons, Ltd.

The IMI PROTECT project: purpose, organizational structure, and procedures.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally.

New assessment of dependency in demented patients: impact on the quality of life in informal caregivers.

UNLABELLED: A qualitative tool was recently developed for evaluation of dependency in a demented population. This tool assesses the impact of cognitive impairment on functional status, taking into account disability in both the basic and the instrumental activities of daily living. The purpose of the present paper was to study the impact of dependency on informal caregivers who assist demented patients at home, with this new useful tool. METHODS: A cross-sectional analysis was undertaken of the subgroup of 145 demented patients of the National Dementia Economic Study, aged > or = 65 years, living in the community, with an available caregiver. A neuropsychological assessment of patients (Mini-Mental State Examination) and a comprehensive evaluation of caregivers (quality of life, Short Form Health Survey-36, depression, Sense of Competence) were recorded. A total of 32.4% were dependent, disabled in both basic and instrumental functions, 42.1% were non-dependent but with instrumental functional disabilities and 25.5% were non-dependent. Impact of dependency on the caregiver's experience was significant for different aspects (satisfaction with caregiving, subjective burden, quality of life, depression). Medical and non-medical costs increased with the severity of functional disability. Findings indicate that this tool is also useful to assess the impact of progression of functional disability in patients with dementia, on the caregiver issues. The consequences appeared both on personal feelings and on quality of life and financial involvement in management of the patient. Cognitive impairment appears to have more moderate repercussions in these areas.

Evaluation of outcomes in chronic venous disorders of the leg: development of a scientifically rigorous, patient-reported measure of symptoms and quality of life.

OBJECTIVE: The purpose of this study was to develop a practical and scientifically rigorous, patient-reported outcome measure to evaluate quality of life and symptoms across the range of conditions (eg, telangiectasias, varicose veins, edema, skin changes, leg ulcers) in chronic venous disorders of the leg (CVDL). METHODS: This study was a psychometric study within the VEnous INsufficiency Epidemiological and Economic Study (VEINES), an international, prospective cohort study to evaluate clinical outcomes, quality of life, costs, and use of health services in CVDL. The study was set in the 166 general practices and 116 specialist clinics in Belgium, France, Italy, and Canada (Quebec) that participated in the VEINES study plus in additional specialist clinics in Ottawa and Montreal. Field testing was carried out in three samples of patients in four countries (Belgium, France, Italy, Canada), including participants in the VEINES study (n dagger 1531) and patients recruited in additional samples of 88 English-speaking patients (Canada) and 53 French-speaking patients (Belgium, France). The reliability and validity sample (n = 615) included 527 VEINES patients and 88 patients from the supplementary English-speaking sample. The test-retest sample (n = 135) included 53 French-speaking and 82 English-speaking patients from the supplementary samples. The responsiveness sample included 1516 VEINES patients. The 26-item VEINES-QOL/Sym is a new, patient-reported questionnaire to evaluate symptoms and quality of life and is available in four language versions (English, French, Italian, French Canadian). RESULTS: Standard psychometric tests confirmed the acceptability (missing data, item endorsement frequencies, floor and ceiling effects), reliability (internal consistency, item-total, inter-item correlations) and validity (content, construct, convergent, discriminant, known groups) of the four language versions of the VEINES-QOL/Sym and the test-retest reliability of the English and French versions and provided preliminary evidence of responsiveness in a pooled language sample. CONCLUSION: The VEINES-QOL/Sym is a practical and scientifically sound, patient-reported measure of outcomes in CVDL that has been developed with rigorous methods. As the only fully validated measure of quality of life and symptoms that is appropriate for use across the full spectrum of CVDL-related conditions, that is quick and easy to administer, and that is available in four languages, the VEINES-QOL/Sym provides a rigorous tool for improving the evaluation of outcomes in clinical trials, epidemiologic studies, and audit.