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ENCePP Guide on Methodological Standards in Pharmacoepidemiology


4.3. Patient registries


4.3.1. Definitions


A patient registry is an organised system that collects data and information on a group of patients defined by a particular disease, condition or exposure, and that serves a pre-determined scientific, clinical and/or public health (policy) purpose. A registry-based study is the investigation of a research question using the data collection infrastructure or patient population of one or more existing or new patient registries. A registry-based study may be a non-interventional trial/study or a clinical trial/study.


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 and does not include specific aspects related to the use of patient registries as source population and/or existing data collection and analysis system.


4.3.2. Conceptual differences between a registry and a study


As illustrated in Imposed registries within the European postmarketing surveillance system (Pharmacoepidemiol Drug Saf. 2018;27(7):823-26) and the EMA’s Draft Guideline on registry-based studies (2020) 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. A registry-based study may only use the data relevant for the specific study objectives and may need to be enriched with additional information on outcomes, lifestyle data, immunisation or mortality information obtained from linkage to existing databases such as national cancer registries, prescription databases or mortality records


4.3.3. Methodological aspects


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 EMA 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. These opinions provide an 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 (2018), 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 developed Methodological guidelines and recommendations for efficient and rational governance of patient registries (2015) to facilitate interoperability and 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 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, potentially resulting 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, but the issues of data integrity, completeness, timeliness, validation and adjudication of endpoints need to be carefully addressed.


4.3.4. Population registries


In European Nordic countries, a comprehensive registration of data for nearly 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. Review of 103 Swedish Healthcare Quality Registries (J Intern Med. 2015; 277(1): 94–136) describes 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


4.3.5. Registries which capture special populations


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.


Pregnancy registries include pregnant women followed until the end of pregnancy and provide information on pregnancy outcomes. Besides the difficulties of recruitment and retention of pregnant women, specific challenges of using pregnancy registries for observational studies on adverse effects of vaccines administered during pregnancy include the identification of relevant control groups for comparisons and completeness of information on pregnancy outcomes as 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. These studies may require linkage with data captured in birth defects registries, teratology information services or electronic health care records where mother-child linkage is possible. In addition, the likelihood of vaccination increases with gestational age whereas the likelihood of foetal death decreases. The EMA’s Draft Guideline on good pharmacovigilance practices. Product- or Population-Specific Considerations III: Pregnant and breastfeeding women (2019) 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 datasources, 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.


4.3.6 Disease registries in regulatory practice and health technology assessment


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 Draft Guideline on registry-based studies (2020) discusses the use of registries for conducting registry-based 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 (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 usage in HTA.




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