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8.3.1. Definitions
8.3.2. General guidance on patient registries
8.3.3. Types of patient registries
8.3.4. Registry-based studies
8.3.5. Interoperability between registries
8.3.6. Registries which capture special populations
8.3.7. Disease registries in regulatory practice and health technology assessment
8.3.8. Registry catalogues
A patient registry is defined in the EMA’s Guideline on registry-based studies (2021) as an organised system that collects uniform data (clinical and other) to identify specified outcomes for a population defined by a particular disease, condition or exposure. It should be considered as an infrastructure for the standardised recording of data from routine clinical practice on individuals identified by a characteristic or an event.
A registry-based study is the investigation of a research question using the data collection infrastructure or patient population of one or several patient registries. A registry-based study may be a non-interventional study or a clinical trial.
8.3.2. General guidance on patient registries
The EMA’s Guideline on registry-based studies (2021) includes an Annex discussing several aspects of good practice considered relevant for the use of registries for registry-based studies and other possible regulatory purposes. It addresses the registry population, data elements, quality management, governance and data sharing.
The EMA’s Scientific Advice Working Party issued a Qualification Opinion for several registry platforms, including the ECFSPR for cystic fibrosis, the EBMT for blood & marrow transplantation and the Enroll HD for Huntington disease, with an evaluation of their potential use as data sources for registry-based studies in specific regulatory contexts. These opinions provide an indication of the methodological components expected by regulators for using a disease registry for such studies.
The US Agency for Health Care Research and Quality (AHRQ) published ‘good registry practices’ under the title Registries for Evaluating Patient Outcomes: A User's Guide, 4th Edition (2020), which provide comprehensive methodological guidance on planning, design, implementation, analysis, interpretation and evaluation of the quality of a registry.
The FDA issued the draft guidance Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products Guidance for Industry (2021). This guidance provides sponsors (marketing authorisation applicants and holders) and other relevant stakeholders with considerations when proposing to design a registry, or when using an existing registry to support regulatory decision-making about a drug's effectiveness or safety.
8.3.3. Types of patient registries
The characteristic or event defining entry into a patient registry may be the diagnosis of a disease (disease registry), the occurrence of a condition or event (e.g., pregnancy registry), a birth defect (e.g., birth defect registry), a molecular or a genomic feature, or any other patient characteristics.
The term product registry has been used for a data collection system where data are collected on patients exposed to a particular medicinal product, single substance or therapeutic class in order to evaluate their use or their effects. Such system should rather be considered a clinical trial or non-interventional study, as data is collected for the purpose of a specific pre-planned analysis in line with performing a trial/study. Moreover, it does not include specific aspects related to the use of patient registries as source population or existing data collection system.
The terms population registry or register have been used to describe the type of registries that exist in European Nordic countries. In these countries, a comprehensive registration of data covering the entire population allows linkage between different patient registries that may include hospital encounters, diagnoses and procedures, such as the Norwegian Patient Registry, the Danish National Patient Registry or the Swedish National Patient Register. Review of 103 Swedish Healthcare Quality Registries (J Intern Med. 2015; 277(1): 94–136) describes healthcare ‘quality’ registries initiated mostly by Swedish physicians that focus on specific disorders. Data recorded may include aspects of disease management, self-reported quality of life, lifestyle and general health status and provide an important data source for research.
As outlined in Imposed registries within the European postmarketing surveillance system (Pharmacoepidemiol Drug Saf. 2018;27(7):823-26) and the EMA’s Guideline on registry-based studies (2021), there are important methodological differences between the registries and the conduct of registry-based studies. Patient registries are often integrated into routine clinical practice with systematic and sometimes automated data capture in electronic healthcare records. A registry-based study may only use the data relevant for the specific study objectives, is often limited in time and may need to be enriched with additional information on outcomes, lifestyle data, immunisation or mortality information. Such information may be obtained from linkage to existing databases such as national cancer registries, prescription databases or mortality records.
Results obtained from analyses of registry data may be affected by the same biases as those of studies described in Chapter 5 of this Guide. Factors that may influence the enrolment of patients in a registry may be numerous (including clinical, demographic and socio-economic factors) and difficult to predict and identify. This will potentially result in a biased sample of the patient population in case the recruitment has not been exhaustive. Bias may also be introduced by differential completeness of follow-up and data collection.
As illustrated in The randomized registry trial--the next disruptive technology in clinical research? (N Engl J Med. 2013; 369(17): 1579-81) and Registry-based randomized controlled trials: what are the advantages, challenges and areas for future research? (J Clin Epidemiol. 2016;80:16-24), and more recently in Registry randomised trials: a methodological perspective (BMJ Open 2023; 13(3)), randomised registry-based trials may support enhanced generalisability of findings, rapid consecutive enrolment, and the potential completeness of follow-up for the reference population, when compared with conventional randomized effectiveness trials. Defining key design elements of registry-based randomised controlled trials: a scoping review (Trials 2020;21(1):552) concludes that the low cost, reduced administrative burden and enhanced external validity make registries an attractive research methodology to be used to address questions of public health importance. However, the issues of data integrity, completeness, timeliness, validation and adjudication of endpoints need to be carefully addressed.
8.3.5. Interoperability between registries
A complexity of using registry data for regulatory purposes and analyses is the need for interoperability between different registries covering a same disease or condition. In most cases, there is no global alignment on how to collect data (data format, expression of a variable) in registries and often no mandatory standards to be applied for the data collected (content/variables). Interoperability of disease registries has been addressed in several workshops on disease-specific registries organised by EMA. The reports of these workshops are available on the EMA Patient registries initiative website. They describe the expectations from different stakeholders on common data elements to be collected and the best practices on topics such as governance, data quality control, data sharing or reporting of safety data.
One way to approach the challenge of heterogeneity between registries is the adaptation of globally common data structures in preparing registry data for joint analyses. One example is the Observational Medical Outcomes Partnership common data model (OMOP CDM) of the Observational Health Data Sciences and Informatics - OHDSI group. The OMOP CDM was originally designed for electronic healthcare records and claims data representing the majority of the 331 data sources from 34 countries. Data mapped to the OMOP CDM in January 2022, as stated by OHDSI in Our Journey (p. 36), resulted in 810 million unique patient records. Registry data is only slowly getting introduced to the OMOP CDM.
8.3.6. Registries which capture special populations
Special populations can be identified based on age (e.g., birth, paediatric or elderly), pregnancy status, renal or hepatic function, race, or genetic differences. Some registries are focused on these particular populations.
For paediatric populations, specific and detailed information as neonatal age (e.g., in days), pharmacokinetic parameters and organ maturation need to be considered and is usually missing from traditional data sources, therefore paediatric-specific registries are important. The Guideline on good pharmacovigilance practices (GVP) Product- or Population-Specific Considerations IV: Paediatric population (2018) provides further relevant information. An example of registry which focuses on paediatric patients is Pharmachild, which captures children with juvenile idiopathic arthritis undergoing treatment with methotrexate or biologic agents.
Pregnancy registries include pregnant women followed until the end of pregnancy and provide information on pregnancy outcomes. Use of pregnancy registries for observational studies on adverse effects of medicinal products administered during pregnancy are often faced with multiple challenges, which may vary from registry to registry. They include not only the recruitment and retention of pregnant women, but also the identification of relevant control groups for comparisons and the complete recording of information on pregnancy outcomes. Embryonic and early foetal loss are often not recognised or recorded and data on the gestational age at which these events occur are often missing. Non-interventional studies may therefore require linkage with data captured in birth defects registries, teratology information services or electronic health care records where mother-child linkage is possible. The EMA Draft Guideline on good pharmacovigilance practices. Product- or Population-Specific Considerations III – Pregnancy prevention programme and other pregnancy-specific risk minimisation measures (2022) provides methodological recommendations for use of a pregnancy registry for data collection in additional pharmacovigilance activities. The FDA Draft Postapproval Pregnancy Safety Studies Guidance for Industry (2019) include recommendations for designing a pregnancy registry with a description of research methods and elements to be addressed. The Systematic overview of data sources for drug safety in pregnancy research (2016) provides an inventory of pregnancy exposure registries and alternative data sources on safety of prenatal drug exposure and discusses their strengths and limitations. Examples of population-based registries allowing to assess outcome of drug exposure during pregnancy are the European network of registries for the epidemiologic surveillance of congenital anomalies EUROCAT, the EUROmediSAFE inventory of data sources, and the pan-Nordic registries which record drug use during pregnancy as illustrated in Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design (BMJ 2015;350:h1798).
In the context of rare diseases, the European Reference Networks (ERNs), consisting of 24 virtual networks composed of healthcare providers across Europe, aim to facilitate discussion on such complex diseases and conditions that require highly specialised treatment, and concentrated knowledge and resources. One of the purposes of the European Rare Disease Research Coordination and Support Action consortium (ERICA), in which all 24 networks take part, is to build on the strengths of the individual ERNs and create a platform that integrates all ERNs research and innovation capacity. Various activities intend to advance the development and integration of ERN-wide rare disease registries and their utilisation for joint research initiatives. The Network supports the creation of biorepositories within and across ERNs, and promotes the use of the European Platform on Rare Diseases Registration (EU RD Platform) for research.
Other registries that focus on special populations can be found in the ENCePP Inventory of data sources, in the European Platform on Rare Diseases Registration (EU RD Platform), and in Orphanet.
8.3.7. Disease registries in regulatory practice and health technology assessment
Use of real-world data (RWD), including registry data, to support regulatory decision-making is a topic of high interest. Several studies have evaluated the frequency and usefulness of information based on RWD in marketing authorisation applications, but did not present results stratified by data source. The article Marketing Authorization Applications Made to the European Medicines Agency in 2018-2019: What was the Contribution of Real-World Evidence? (Clin Pharmacol Ther. 2022;111(1):90-7) shows that registries were the most common type of RWD sources referred to in marketing authorisation applications and extensions of indications submitted to the EMA in 2018 and 2019 (60.3% and 46.4% respectively of the medicinal products presented with RWE). The follow-up study described in Contribution of Real- World Evidence in European Medicines Agency’s Regulatory Decision Making (Clin Pharmacol Ther. 2023;113(1):135-151) provides an in-depth review of real-world evidence (RWE) submitted in recent centralised applications in the EU, illustrated by examples of RWE contribution to regulatory decision-making.
The article Patient Registries: An Underused Resource for Medicines Evaluation: Operational proposals for increasing the use of patient registries in regulatory assessments (Drug Saf. 2019;42(11):1343-51) proposes sets of measures to improve use of registries in relation to: (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. The EMA’s Guideline on registry-based studies (2021) discusses methodological aspects for the use of registries for conducting registry-based studies and recommends performing a feasibility assessment of the suitability of a registry for a specific research question to facilitate early discussions with regulators. The use of registries to support the post-authorisation collection of data on safety and effectiveness of medicinal products in the routine treatment of diseases is also discussed in the EMA Guideline on good pharmacovigilance practices (GVP) – Module VIII -Post-authorisation safety studies (2017) and the EMA Scientific guidance on post-authorisation efficacy studies (2016).
As outlined in Real World Data in Health Technology Assessment of Complex Health Technologies - PMC (Front Pharmacol. 2022; 13: 837302), incorporating data from clinical practice into the drug development process is of growing interest for Health Technology Assessment (HTA) bodies and payers since reimbursement decisions can benefit from better estimation and prediction of effectiveness of treatments at the time of product launch. An example where registries can provide clinical practice data is the building of predictive models that incorporate data from both randomised clinical trials (RCTs) and registries to generalise results observed in RCTs to a real-world setting. In this context, the EUnetHTA Joint Action 3 project has issued the Registry Evaluation and Quality Standards Tool (REQueST) aiming to guide the evaluation of registries for effective use in HTA.
Patient experience data collected through patient registries can inform medicine development, enhance regulatory decision-making, and result in more patient-relevant outcomes to study, however, the generation of these data remains challenging as highlighted for example in A review of patient-reported outcomes used for regulatory approval of oncology medicinal products in the European Union between 2017 and 2020 (Front Med (Lausanne). 2022 Aug 12;9:968272).
Several data source catalogues provide different levels of access to different amounts of information on disease registries, such as the ENCePP Resource database of data sources, the EHDEN data partners listing or the EMIF Catalogue. The European Platform on Rare Diseases Registration (EU RD Platform) serves as a platform for information on registries for rare diseases and has developed a harmonised set of common data elements for rare disease registration.
In the context of the EMA/HMA Big Data Initiative, the ENCePP Resource database of data sources and the EU PAS Register will be enhanced and replaced in 2024 by two new catalogues of RWD sources and non-interventional studies in view of facilitating the identification by regulators, researchers and pharmaceutical companies of data sources and studies suitable to address research questions, based on the FAIR (findable, accessible, interoperable and reusable) data principles.
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