Introducing a core dataset for real-world data in multiple sclerosis registries and cohorts: Recommendations from a global task force.

BACKGROUND: As of September 2022, there was no globally recommended set of core data elements for use in multiple sclerosis (MS) healthcare and research. As a result, data harmonisation across observational data sources and scientific collaboration is limited. OBJECTIVES: To define and agree upon a core dataset for real-world data (RWD) in MS from observational registries and cohorts. METHODS: A three-phase process approach was conducted combining a landscaping exercise with dedicated discussions within a global multi-stakeholder task force consisting of 20 experts in the field of MS and its RWD to define the Core Dataset. RESULTS: A core dataset for MS consisting of 44 variables in eight categories was translated into a data dictionary that has been published and disseminated for emerging and existing registries and cohorts to use. Categories include variables on demographics and comorbidities (patient-specific data), disease history, disease status, relapses, magnetic resonance imaging (MRI) and treatment data (disease-specific data). CONCLUSION: The MS Data Alliance Core Dataset guides emerging registries in their dataset definitions and speeds up and supports harmonisation across registries and initiatives. The straight-forward, time-efficient process using a dedicated global multi-stakeholder task force has proven to be effective to define a concise core dataset.

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.

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.

Collaborative Real-World Evidence Among Regulators: Lessons and Perspectives.

The International Coalition of Medicines Regulatory Authorities (ICMRA), comprising 38 global medicines regulatory authorities, collaborates on shared challenges, notably during the COVID-19 pandemic. This article focuses on the ICMRA COVID-19 Real-World Evidence (RWE) and Observational Studies Working Group. The Working Group aimed to address challenges related to RWE and observational studies during the pandemic, resulting in impactful studies and ICMRA statements on international collaboration for RWE and COVID-19 vaccine safety. Reflecting on 3 years of collaboration, the Working Group surveyed members for insights, and recommendations were formulated to enhance research preparedness, collaboration, and response to future public health emergencies. The lessons learned highlight the importance of global collaborations, governance structures for rapid decision-making, and effective utilization of existing networks. Recommendations include the establishment of an international governance structure, a "coalition of the willing" for swift research collaboration, dedicated sub-groups, periodic workshops, common protocols, joint timelines, and data model templates, leveraging existing infrastructure, and strengthening outreach for transparency and engagement. The Working Group envisions repurposing into an RWE strategic and operational entity, contributing to global public health emergency response mechanisms. In conclusion, the Working Group's success lies in effective communication, collaborative research, and leveraging existing infrastructure, with ongoing contributions to global emergency response mechanisms.

Framework for Multistakeholder Patient Registries in the Field of Rare Diseases: Focus on Neurogenetic Diseases.

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.

Contribution of Real-World Evidence in European Medicines Agency's Regulatory Decision Making.

Real-world data/evidence (RWD/RWE) may provide insightful information on medicines' clinical effects to guide regulatory decisions. While its contribution has been recognized for safety monitoring and disease epidemiology across medicines' life cycles, using RWD/RWE to demonstrate efficacy requires further evaluation. This study aimed to (i) characterize RWD/RWE presented by applicants to support claims on medicines' efficacy within initial marketing authorization applications (MAAs) and extension of indication applications (EoIs), and (ii) analyze the contribution of RWD/RWE to regulatory decisions on medicines' benefit-risk profile. RWD/RWE was included to support efficacy in 32 MAAs and 14 EoIs submitted 2018-2019. Of these, RWD/RWE was part of the preauthorization package of 16 MAAs and 10 EoIs, and was (i) considered supporting the regulatory decision in 10 applications (five MAAs, five EoIs), (ii) considered not supporting the regulatory decision in 11 (seven MAAs, four EoIs), and (iii) not addressed at all in the evaluation of 5 applications (four MAAs, one EoI). Common limitations of submitted RWD/RWE included missing data, lack of representativeness of populations, small sample size, absence of an adequate or prespecified analysis plan, and risk of several types of bias. The suitability of RWD/RWE in a given application still requires a case-by-case analysis considering its purpose of use, implying reflection on the data source, together with its assets and limitations, study objectives and designs, and the overall data package issued. Early interactions and continuous dialogues with regulators and relevant stakeholders is key to optimize fit-for-purpose RWE generation, enabling its broader use in medicines development.

Real world evidence: Perspectives from a European Society of Cardiology Cardiovascular Round Table with contribution from the European Medicines Agency.

Real world data (RWD) refers to healthcare information that is routinely collected in electronic healthcare records (EHR), hospital and pharmacy records, patient and disease registries, and health insurance databases. The collection and analysis of this vast amount of data is an important complement to that obtained from conventional randomised controlled trials (RCT). Real world data has been used for healthcare quality improvements, to conduct clinical trials, to support drug and device development, and to inform medical guidelines. The utility of RWD may be facilitated by common data models, which standardise format and content, and allow data from different health systems to be analysed together. The European Society of Cardiology (ESC) supports the use of RWD in collaboration with national cardiac societies, regulatory authorities, and industry to encourage continuous quality of care improvements at the hospital and country level, to conduct registry-based randomised clinical trials (R-RCT) and to facilitate safety surveillance of novel drugs and devices. The European Medicines Agency (EMA) is developing systems and processes to enable the use of RWD that can help in trial planning, defining clinical contexts, and enhancing outcome assessments. RWD can also contribute to the measurement of the impact of regulatory actions, such as contraindications or restriction of indications by looking at medicines use patterns over time across European Member States. A number of other initiatives from the European Commission and the EMA are underway to strengthen the EU's health security framework, and foster the collection and utilisation of RWD.

Contribution of patient registries to regulatory decision making on rare diseases medicinal products in Europe.

Between 2000 and 2021, the European Medicines Agency (EMA) assigned the orphan designation to over 1,900 medicines. Due to their small target populations, leading to challenges regarding clinical trial recruitment, study design and little knowledge on the natural history of the disease, the overall clinical evidence submitted at the time of marketing authorisation application for these medicines is often limited. Patient registries have been recognised as important sources of data on healthcare practices, drug utilisation and clinical outcomes. They may help address these challenges by providing information on epidemiology, standards of care and treatment patterns of rare diseases. In this review, we illustrate the utility of patient registries across the different stages of development of medicinal products, including orphans, to provide evidence in the context of clinical studies and to generate post-authorisation long term data on their effectiveness and safety profiles. We present important initiatives leveraging the role of registries for orphan medicinal products' development and monitoring to ultimately improve patients' lives.

Collection of Data on Adverse Events Related to Medicinal Products: A Survey Among Registries in the ENCePP Resources Database.

INTRODUCTION: As patient registries are not subject to regulatory requirements on the collection of adverse events (AEs) related to medicinal products, they may not have foreseen the collection of such information on a routine basis or as part of specific data collection schemes. OBJECTIVE: The European Medicines Agency conducted a survey among registries to better understand their approach towards the collection, management and reporting of AEs related to medicines. METHOD: An online survey composed of 15 questions was distributed in May 2020 to registries listed in the European Network of Centres in Pharmacoepidemiology and Pharmacovigilance (ENCePP) resources database for completion by August 2020. Aggregated results are presented in this paper. RESULTS: One third of the registries completed the survey (31/85; 36.5%). Most of the respondents routinely collect information on medicines (29/31; 93.5%), out of which 65.5% (19/29) also collect data on AEs and adverse drug reactions (ADRs). Frequencies and timelines for collecting and reporting AEs/ADRs vary widely across registries, as does their level of experience in providing data to third parties for regulatory purposes. CONCLUSIONS: The low response rate may indicate little interest in this topic or that registries were not originally developed for routine data collection on AEs/ADRs and, ultimately, monitoring of the safety of medicines. Results indicate that clear guidance on the collection and use of real-world data in regulatory frameworks and strengthened collaboration between registry holders, academia, regulators and medicines developers are needed to achieve comprehensive and high levels of quality of safety data captured by registries to support regulatory decision making. These will hopefully be enabled by the European Medicines Regulatory Network strategy to 2025.

Prescribing Patterns of Codeine and Alternative Medicines in Children in Europe.

INTRODUCTION: Concerns over serious respiratory depression in children led to two European Union (EU) referral procedures (in 2013 and 2015) to review the benefit-risk balance of codeine in this population when used for pain relief, cough or cold. Consequently, codeine should no longer be used in children aged < 12 years and restrictions were introduced for treatment in children ≥ 12 years. OBJECTIVE: This multinational collaborative study aimed to assess the effectiveness of these risk minimisation measures by evaluating changes in prescribing of codeine and alternative treatments. METHOD: Children under 12 and 12-18 years old were followed between 2010 and 2017 to analyse quarterly trends in prescribing of codeine and alternative treatments in electronic health records from France, Germany, Norway, Spain and the United Kingdom using interrupted time series analysis. RESULTS: Overall prescribing of codeine in children decreased in all five countries, reaching near zero prevalence in children under 12 years of age. This was accompanied by an increase in use of other opioid analgesics in France (from 0.15 to 0.56 prevalence per 100 person-years immediately after the first referral), Norway (from 0.0006 to 0.0013 at the end of the study), the United Kingdom (from 0.018 to 0.05 at the end of the study), and an increase in non-opioid analgesics in Norway (from 0.045 to 0.075 at the end of the study) after the referral on pain relief indication. The referral on cough/cold indication led to a decrease in use of opioid and non-opioid antitussives in children aged < 12 years in France (from 10 to 7 and 20 to 16, respectively) and had no impact in other countries. Overall prescribing trends for codeine and alternatives were similar across both age groups within each country. CONCLUSION: The decrease in use of codeine shows that healthcare professionals followed the adopted measures and switched prescribing practices for pain management in children aged < 18 years towards opioid or non-opioid analgesics depending on national clinical and reimbursement settings. Whist the magnitude of the first referral on pain differed between countries, the second referral on cough/cold had only a minimal impact on the use of codeine and antitussives.

Marketing Authorization Applications Made to the European Medicines Agency in 2018-2019: What was the Contribution of Real-World Evidence?

Information derived from routinely collected real-world data has for a long time been used to support regulatory decision making on the safety of drugs and has more recently been used to support marketing authorization submissions to regulators. There is a lack of detailed information on the use and types of this real-world evidence (RWE) as submitted to regulators. We used resources held by the European Medicines Agency (EMA) to describe the characteristics of RWE included in new marketing authorization applications (MAAs) and extensions of indication (EOIs) for already authorized products submitted to the EMA in 2018 and 2019. For MAAs, 63 of 158 products (39.9%) contained RWE with a total of 117 studies. For 31.7% of these products, the RWE submitted was derived from data collected before the planned authorization. The most common data sources were registries (60.3%) followed by hospital data (31.7%). RWE was mainly included to support safety (87.3%) and efficacy (49.2%) with cohort studies being the most frequently used study design (88.9%). For EOIs, 28 of 153 products (18.3%) contained RWE with a total of 36 studies. For 57.1% of these products, studies were conducted prior to the EOIs. RWE sources were mainly registries (35.6%) and hospital data (27.0%). RWE was typically used to support safety (82.1%) and efficacy (53.6%). Cohort studies were the most commonly used study design (87.6%). We conclude that there is widespread use of RWE to support evaluation of MAAs and EOIs submitted to the EMA and identify areas where further research is required.

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

The fourth sentence under the heading "1.1 Use of Patient Registries for Supporting Regulatory Assessments" in "1 Introduction" section should read as below.

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.

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.

Electronic healthcare databases in Europe: descriptive analysis of characteristics and potential for use in medicines regulation.

OBJECTIVE: Electronic healthcare databases (EHDs) are useful tools for drug development and safety evaluation but their heterogeneity of structure, validity and access across Europe complicates the conduct of multidatabase studies. In this paper, we provide insight into available EHDs to support regulatory decisions on medicines. METHODS: EHDs were identified from publicly available information from the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance resources database, textbooks and web-based searches. Databases were selected using criteria related to accessibility, longitudinal dimension, recording of exposure and outcomes, and generalisability. Extracted information was verified with the database owners. RESULTS: A total of 34 EHDs were selected after applying key criteria relevant for regulatory purposes. The most represented regions were Northern, Central and Western Europe. The most frequent types of data source were electronic medical records (44.1%) and record linkage systems (29.4%). The median number of patients registered in the 34 data sources was 5 million (range 0.07-15 million) while the median time covered by a database was 18.5 years. Paediatric patients were included in 32 databases (94%). Completeness of information on drug exposure was variable. Published validation studies were found for only 17 databases (50%). Some level of access exists for 25 databases (73.5%), and 23 databases (67.6%) can be linked through a personal identification number to other databases with parent-child linkage possible in 7 (21%) databases. Eight databases (23.5%) were already transformed or were in the process of being transformed into a common data model that could facilitate multidatabase studies. CONCLUSION: A Few European databases meet minimal regulatory requirements and are readily available to be used in a regulatory context. Accessibility and validity information of the included information needs to be improved. This study confirmed the fragmentation, heterogeneity and lack of transparency existing in many European EHDs.