Introduction to R-RCT

On this page you will find an introduction to what registry-based randomised clinical trials (R-RCTs) are and how they can be used.

What are registry-based randomised clinical trials (R-RCT)?

Registry-based randomised clinical trials (R-RCTs) are defined as prospective randomised trials (RCT) that to some extent use registries for their implementation. The most common type of registries used for R-RCT are quality registries. A quality registry is a structured collection of personal data established specifically for the purpose of systematically and continuously developing and ensuring the quality of healthcare, and not primarily for research purposes.

An R-RCT can use a registry in different ways. What is appropriate in each case depends, for example, on the design of the registry and whether there is any possibility of adapting the registry with a technical solution/study application for the needs of the study as well as how the registry is used by the staff in everyday clinical practice. For example, in an R-RCT, the registry can be used to find suitable study participants for inclusion, background and outcome measures, or for collection of existing patient reported measures (PROMs). If study-specific PROMs are to be collected, this is best done via a complementary Electronic Data Capture (EDC) system such as an eCRF.

Tasks/elements that can be performed with quality registries

This overview is mainly intended to support the planning and implementation of R-RCTs where the study is conducted by collecting data from an existing quality registry.

  • Through a developed technical solution/study application, selected inclusion criteria for the study can be monitored and the clinic staff can be alerted in the quality registry if a patient would be suitable for the study.
  • Screening/inclusion and possible randomisation of study patients in connection with registration in the quality registry through technical solution/study application.
  • Study-specific variables for screening/inclusion and possible randomisation are collected in specific study database.
  • Using existing registry variables as study variables. The variables of the registries can be found on the registry's websites and on the Swedish Research Council's metadata service RUT External link..
  • Manage participating clinics, display the inclusion in the R-RCT on the registry website, display detailed information on screened patients in logged-in mode for each clinic.
  • Export screening and inclusion information for each clinic through technical solution/study application.
  • Data extraction for reports/monitoring/interim analysis. Extraction takes place according to the particular registry centre’s data extraction processes for quality registries.

When is R-RCT suitable?

R-RCT is best suited for questions about treatment strategies or method comparisons. Questions involving the comparison of already approved medicinal products or CE-marked medical devices are also possible but require permission from the Swedish Medical Products Agency (please read more under the section Consequences of trials that belong under GCP).

A well-defined primary objective with few secondary objectives based on existing registry variables is recommended. The more secondary objectives(outcome measures) and/or the desire to collect variables that are not in the registry, the more work and the higher the cost.

The simplest form of R-RCT compares established treatments for an outcome measure (endpoint) that can be taken from information already collected in the registry (or by cross-checking with another registry). Mortality, hospitalisation and/or readmission are common outcome measures (endpoints) that can be monitored without affecting the regular healthcare process.

Issues to consider for a successful R-RCT:

  • The study is planned together with representatives of the registry.
  • Do study-relevant variables have good coverage in the registry?
  • Is it mandatory to fill in the critical variables of the study in the registry?
  • The continuous development of the quality registry, which may involve changes in variables during the study period.
  • What is the coverage of the study's target population in the registry?
  • Is it a direct registration in the register or is the routine to register later? This must be considered during planning.
  • How fast do clinics record data in the registry? What is the time delay between an event (e.g. a bleeding/myocardial infarction/other complication) and its actual registration in the registry?
  • Are the data in the registry of sufficient quality, in terms of external and internal validity, to form the basis of research on?
  • How is the ongoing monitoring of the registry conducted?

System support

Much of what makes an R-RCT cost-effective is that it can be integrated into the healthcare system and is a registry that is already used in the healthcare system. However, it is not evident that all qualityregistries are designed, implemented and used in a way that makes them suitable as a basis for an R-RCT. Regardless of the registry's design,, specific technical solutions/study applications must be adapted and quality assured for each individual study. The fact that the registry contains data on patients is only of value if it is the same data that the study needs and if it is maintained with sufficient quality.

Make careful analysis with the technical management

Once there is an idea for an R-RCT, a careful analysis of how the registry will be used in the study is needed. It should be analysed with the technical management of the registry whether it is possible to adapt the registry with the technical solution/study application required and at what cost. Other options for data collection that do not involve adaptation of the registry should be explored. A combination of registry data and eCRF is common in an R-RCT.

If the study is to be conducted under Good Clinical Practice (GCP)

If the study is to be conducted under Good Clinical Practice (GCP), it is a requirement that electronic systems used in the study must have been formally validated. In such a case, integrating randomisation into the quality registry is not recommended, as validation involves a high workload for the registry management team and a higher cost for the study. For these studies, an alternative technical solution should be used to use a study application independent of the registry where additional patient information is entered and the randomisation is done. Subsequently, manual or automatic data extractions are made from the registry. It could be beneficial to add a link to the study application in the quality registry to simplify the process for clinical staff.

Time and resources

Building a technical solution/study application for an R-RCT requires careful planning. All the requirements needed to develop the technical solution/study application must be carefully planned in collaboration between researchers, registry controllers and the “supplier” of the technical solution/study application. The planning should also include management of the study within the registry and a plan for data export and removal of the study within the registry. During the study, no variables used in the study should be updated (either registry variables or study-specific variables in the technical solution/study application) without discussing the implications of these changes. The study should be aware of the registry's long-term development plan and how it may affect the study. A plan for communication between the study and the registry should be established.

Time savings with R-RCT

The start-up period for an R-RCT is significantly longer and more time-consuming than for a traditional RCT. There is often a waiting period to start an R-RCT in a registry depending on the registry's regular priorities and other ongoing R-RCTs. The cost of preparing an R-RCT should be compared to the potential time gain estimated in the overall conduct of the study.
The time savings are made in the clinics where research support staff get more time to include patients. The entry time in the eCRF is reduced as the information is partly entered directly into the registry. Patients can be randomised and included faster because the registry can automatically give an alert when a patient is suitable for the study, if the technical support for it is available. However, this requires clinic staff to be logged into the register and enter data directly when the patient is present. Usually this means that the registry detects whether the inclusion criteria for the R-RCT are met and then provides a notification that the patient meets the requirements for the relevant R-RCT. Considering the practices of the clinics can therefore be crucial for a successful R-RCT.

Cost of an R-RCT

The cost of an R-RCT depends on many factors and needs to be calculated for each individual study. An R-RCT involves some new costs compared to a traditional RCT. Depending on the extent and complexity of the technical solutions and validation required for the study, there will be an increased management cost in terms of technical support such as:

  • Operation
  • Bug fixes
  • Adjustment of solution
  • Support
  • Data extraction

This should be compared to the time and cost for clinicians to enter study data into a traditional eCRF. It is therefore important to take this into account at the planning stage of an R-RCT.


The possibilities to ensure data quality differ between quality registries and eCRFs. This is because in an eCRF there is the possibility to add logic controls to the specific study. Data in registries are collected for a different purpose and under different legislation and it is therefore possible that there is a different practice on how and what to document. Another factor that may make a difference is that there may be a larger group of staff entering data into a register. If specific instructions or directions are required for data entry in the study, an eCRF should be used.

Ongoing quality control

Ongoing quality control is most easily done by extracting data from the registry or by continuously saving the study data in an EDC or study database if a technical solution/study application for this is available. The agreement for data extraction for quality control should be established between the study and CPUA authorities before the start of the study and mentioned in the application to the ethical review board. If the study falls under GCP then please read more in the section Consequences of studies falling under GCP.

Advantages and disadvantages of R-RCTs and RCTs

As a rule of thumb, an R-RCT can be regarded as most effective when:

  • The study is integrated in only one registry.
  • All safety and primary outcomes are available in registries.
  • Minimal changes must be made to the clinic's normal workflow.
  • No completion/follow-up needs to be done in an EDC system.
  • The study has a short recruitment and follow-up period.
  • The patient population is large.
  • Patients are randomised to compare established and approved treatments.
  • Training requirements to comply with the protocol are low.
  • The registry where the inclusion will be made is used at the time of meeting the patient.

When choosing between designing the study as an R-RCT or as a traditional RCT, the advantages and disadvantages of the concepts should be considered.

Advantages and disadvantages of an R-RCT





Screening and randomisation integrated in the registry

More patients are contacted

The registry must be used for randomisation

Reminder of the study for all patients that are suitable

Pre-screening may be more difficult to perform depending on the design of the register

Less selected population

Only simple randomisation protocols

Data collection via registries (screening and randomisation in separate study application)

Follow-up of the whole population

Data from patients not included in the registry are missing

Routine data collection

Cost of transferring data from registry to study database

Less extra work/patient/clinic

Cost of adding variables that are not present in the registry

Impact on existing registry/study variables may change over time

Management of patients who want to leave the registry/trial

Changes to variables without audit study (some traceability in registries)

Cost of validating the mapping

Increased cost of managing the transfer/integration

Advantages and disadvantages of RCTs





Data collection via eCRF only

Clinics without registries can participate in the study

Manual input of data outside of regular clinical work

Easy to export to analysis format

Training and entry into the eCRF

Possibility to tailor the questions to the needs of the study

  • Cost of creating the eCRF
  • Cost of user management

Easier to clean and process collected data

Easier to manage queries in clinics

Well-defined study database

Data cleaning/monitoring - EDC

  • Ordinary handling of queries when the clinic checks against the medical records
  • The EDC often supports monitoring,


Advantages and disadvantages of R-RCT

An advantage of the R-RCT is that it is easy to include all registry-linked clinics in Sweden. Even smaller clinics without research experience and research infrastructure can participate. In most countries outside of Sweden and the Nordic countries, there are a limited number of registries with appropriate quality required to conduct an R-RCT, which means that if many countries are to participate in a study, an RCT or a combination of RCT and R-RCT may be a more suitable option.

Like clinical studies in general, R-RCTs are subject to laws and other regulatory frameworks. This means that an R-RCT must comply with both the laws and regulations for quality registries and for a clinical study.

Legal issues

It is important that both the researcher initiating the study and the registry organisation are aware of the regulations of an R-RCT and a quality registry and how they differ.

Ensure that everyone understands that:

  • Registry data and study data are subject to different laws even though the data may be identical. Thus, the registry database cannot also store study data; that must be stored in a separate study database. However, a study may request an extraction of registry data to be used as study data.
  • The management of a registry patient and the management of a study participant are not subject to the same laws. This means that a patient's withdrawal from the registry and a study participant's termination of participation in the study have different consequences for the data collected. Please see table below.

Examples of where the regulatory framework for both quality registries and clinical studies must be considered:

  • Data in the registry must be deleted at the person's request.
  • Data in the registry must be cleared after a number of years unless permission is obtained.
  • Data in the registry may be used for business development and quality assurance in aggregated form. Following approval from the ethical review board, identified data may be requested for research.
  • The data in the registry may change.
  • Changes to registry data are not required to be logged.
  • Direct access to registry data assumes that a patient relationship exists and needs to be logged.

  • Data in the study collected until the person decides to leave the study can be retained in the study database.
  • Study data should be archived in accordance with current legislation.
  • A study may use the data described in the study protocol and is subject to approval of the study from the ethical review board.
  • Data in the study should remain unchanged after the study database is locked.
  • Changes to study data must be logged until the database is locked (audit trail) and saved for the duration of the archive time.
  • Access to study data needs to be logged for the audit trail.

Consequences of studies falling under GCP

An R-RCT studying medicinal products or medical devices also requires an authorisation from the Medical Products Agency. If there is uncertainty about the need for authorisation, it is recommended to contact the Medical Products Agency. The study then needs to follow aspecific application processes depending on the product (medicinal product or medical device) and the overall framework for Good Clinical Practice (GCP). For studies with medicinal products, this is described in ICH-GCP and for studies with medical devices it is ISO 14155:2020.

An R-RCT that falls under GCP must follow the requirements for clinical studies. This entails that:

  • Authorisation from the Medical Products Agency is also required. Our step-by-step guide to the research process provides information on medicines and medical technology products.
  • If an EDC is used in the R-RCT, changes must be traceable (audit trail).
  • The technical solution/study application must undergo formal validation.
  • There are regulatory requirements for safety reporting.
  • Monitoring is a requirement. Take advantage of our research support within monitoring/quality control.
  • Storage requirements and storage time for all study-related documentation (sponsor and investigator)

These points all represent an increase in complexity and cost. For more information, see our step-by-step guide to the research process.

Registry requirements for R-RCTs

The technical R-RCT framework can be developed to keep the registry as far as possible outside the study, but some of the regulatory framework will still have spillover effects on the design and features of the registry. It is important that the interaction design of the registry is such that the user is never in doubt as to whether they are using features from the registry or the study. The access control must also work in such a way that only authorised personnel are allowed to access the study functions in the registry.


If the study falls under GCP, there is a requirement that electronic systems used in the trial have undergone formal validation. The technical solution/study application must then be validated before the start of the study to ensure that everything works as intended: that data out matches data in, that the randomisation module works, that login to the system works, etc.

Validation can be at different levels depending on the design and structure of the study and is described in a validation plan. A validation report describes the outcome of the validation.

Validation of data quality and completion and coverage rates should also be done for the variables in the quality registry that the study intends to use.