A patient registry is an organised system that uses observational methods to collect uniform data on specified outcomes in a population defined by a particular disease, condition or exposure. A registry-based study is an investigation of a research question using a patient registry infrastructure for patient recruitment and data collection. The term ‘registry’ is sometimes used incorrectly to designate a cohort study with primary data collection or a list of all patients meeting the eligibility criteria for a study (the term ‘patient log’ or ‘patient log-list’ could be used for the latter purpose).
A patient registry 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, for example the diagnosis of a disease (disease registry), the occurrence of a condition (e.g., pregnancy registry), a birth defect (e.g. birth defect registry), a molecular or a genomic feature or any other patient characteristics, or an encounter with a particular healthcare service. The term product registry is sometimes used for a 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, but such system should rather be considered a clinical trial or a non-interventional study as data is collected for a specific pre-planned analysis purpose in line with performing a trial/study.
As illustrated in Imposed registries within the European postmarketing surveillance system (Pharmacoepidemiol Drug Saf 2018; 27(7):823-826), there are methodological differences between registries and registry-based studies.
Patient registries are often integrated into routine clinical practice with systematic and sometimes automated data capture in electronic healthcare records. Whilst the duration of a registry is normally open-ended, that of a registry-based study is dictated by the time needed to define and collect data relevant for the specific study objectives. Studies may also require introduction of specific procedures, questionnaires or data collection tools. Studies are set up and managed based on a limited number of endpoints and a specific protocol, whereas patient registries should focus on system specifications in order to ensure continuous, efficient and collaborative data collection, safe data hosting and availability of retrievable, interoperable and re-usable data.
A registry can be used as a source of patients for studies based on either primary data collection (where the events of interest for the study are collected directly from the patients, caregivers, healthcare professionals or other persons involved in the patient care) or secondary use of data already collected (where the study uses data collected for another purpose, analogously to the use of electronic healthcare records). For this purpose, registry data can be enriched with additional information on outcomes, lifestyle data, immunisation or mortality information obtained from linkage to the existing databases such as national cancer registries, prescription databases or mortality records.
To support better use of existing registries for the benefit-risk evaluation of medicines, the EU regulatory network developed the Patient registries initiative. As part of this initiative, the European Medicines Agency organised several workshops on disease-specific registries. The reports of these workshops describe regulators’ expectation on common data elements to be collected and best practices on topics such as governance, data quality control, data sharing or reporting of safety data. The ENCePP Resource database of data sources is also used to support an inventory of existing disease registries.
The EMA’s Scientific Advice Working Party issued two Qualification Opinions for two registry platforms, the ECFSPR and the EBMT, with an evaluation of their potential use as data sources for registry-based studies. Although they apply only to two registry platforms, these opinions provide a good indication of the key methodological components expected by regulators for using a disease registry for such studies.
The US Agency for Health Care Research and Quality (AHRQ) published a comprehensive document on ‘good registry practices’ entitled Registries for Evaluating Patient Outcomes: A User's Guide, 3rd Edition, which provides methodological guidance on planning, design, implementation, analysis, interpretation and evaluation of the quality of a registry. There is a dedicated section for linkage of registries to other data sources. The EU PARENT Joint Action developed Methodological guidelines and recommendations for efficient and rational governance of patient registries to facilitate cross-border use of registries.
Results obtained from analyses of registry data may be affected by the same biases as those of studies described in Chapter 5.2 Bias and confounding. Registry-based studies are sensitive to selection bias. This is due to the fact that factors that may influence the enlistment of patients in a registry may be numerous (including clinical, demographic and socio-economic factors) and difficult to predict and identify, potentially resulting in a biased sample of the patient population in case the recruitment has not been exhaustive. In addition, registry-based studies may also introduce selection bias in the recruitment or selection of registered patient for the specific study, as well as in the differential completeness of follow-up and data collection. It is therefore important to systematically compare the characteristics of the study population with those of the source population.
As illustrated in The randomized registry trial--the next disruptive technology in clinical research? (N Engl J Med 2013; 369: 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, but several challenges need to be considered (see also Chapter 5.6.3).
In European Nordic countries, a comprehensive registration of data for a high proportion or all of the population allows linkage between government-administered 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. They may however lack information on lifestyle factors, patient-related outcomes and laboratory data. A Review of 103 Swedish Healthcare Quality Registries (J Intern Med 2015; 277(1): 94–136) describes additional healthcare quality registries focusing on specific disorders initiated in Sweden mostly by physicians with data on aspects of disease management, self-reported quality of life, lifestyle, and general health status, providing an important source for research.
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. The European Platform on Rare Diseases Registration (EU RD Platform) serves as platform for information on registries for rare diseases and has developed a set of common data elements for the European Reference Network and other rare disease registries.
The FDA’s Draft Postapproval Pregnancy Safety Studies Guidance for Industry (May 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 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 datasources, therefore paediatric specific registries are important. The CHMP Guideline on Conduct of Pharmacovigilance for Medicines Used by the Paediatric Population 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.
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):1343-1351) 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. Appendix 1 of Module VIII of the Good pharmacovigilance practice discusses the use of registries for conducting post authorisation studies. The use of registries to support the post-authorisation collection of data on effectiveness and safety of medicinal products in the routine treatment of diseases is also discussed in the EMA Scientific guidance on post-authorisation efficacy studies. Use of existing disease registries is recommended as they allow continued assessment of disease outcomes and a comparison of different treatment options using a similar methodology. Data of existing registries could be supplemented with additional data collection or linkage to external data sources.
When efficacy has been demonstrated in RCTs, registry-based studies may also be useful to study aspects related to long term effectiveness and safety in heterogeneous populations, study effect modifiers such as doses that have been prescribed by physicians and that may differ from those used in RCTs, and study patient sub-groups defined by variables such as age, co-morbidities, use of concomitant medication or genetic factors, or other factors that might influence effectiveness or safety.
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 usage in HTA.