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 individual patients 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.
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 two Qualification Opinions for two registry platforms, the ECFSPR for cystic fibrosis and the EBMT for blood & marrow transplantation, with an evaluation of their potential use as data sources for registry-based studies. 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The FDA issued the draft guidance Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products Guidance for Industry (2021).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 and other stakeholders with considerations when either proposing to design a registry or using an existing registry to support regulatory decision-making about a drug's effectiveness or safety.
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 is sometimes 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 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 term population registry or register is sometimes 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 illustrated 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 enrollment 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), the randomised registry-based trial may support enhanced generalisability of findings, rapid consecutive enrollment, 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.
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 OMOP common data model of the OHDSI group. The OMOP CDM was originally designed for electronic health care records and claims data which represent 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 booklet (p. 36), result in 810 million unique patient records. Registry data is only slowly getting introduced to the OMOP CDM.
Special populations can be identified based on age (e.g., paediatric or elderly), pregnancy status, renal or hepatic function, race, or genetic differences. Some registries are focused on these particular populations. Examples of these are the birth registries in Nordic countries and registries for rare diseases.
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. Observational 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’s 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’s 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. Example of population-based registers allowing to assess outcome of drug exposure during pregnancy are the European network of registries for the epidemiologic surveillance of congenital anomalies EUROCAT, 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).
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 the classical data sources, therefore paediatric specific registries are important. The CHMP Guideline on Conduct of Pharmacovigilance for Medicines Used by the Paediatric Population (2005) 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.
Other registries that focus on special populations (e.g., the UK Renal Registry) can be found in the ENCePP Inventory of data sources and the European Platform on Rare Diseases Registration (EU RD Platform).
Use of real-world data (RWD), including registries, to support regulatory decisions is a topic of increasing interest. Several studies have evaluated the frequency and usefulness of information based on RWD in marketing authorisation applications, but not all stratified results 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 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 analysis 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).
Incorporating data from clinical practice into the drug development process is a growing interest from 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 of where registries can provide clinical practice data is the building of predictive models that incorporate data from both 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.
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.
Currently, there is no comprehensive catalogue of disease registries existing in Europe with information on their data elements and availability for research.